Integrative Molecular Phenotyping
INTEGRATIVE MOLECULAR
PHENOTYPING
WHEELOCK LABORATORY
DEPARTMENT OF MEDICAL
BIOCHEMISTRY AND BIOPHYSICS
WHEELOCK LABORATORY
DEPARTMENT OF MEDICAL
BIOCHEMISTRY AND BIOPHYSICS
WHEELOCK LABORATORY
DEPARTMENT OF MEDICAL
BIOCHEMISTRY AND BIOPHYSICS
WHEELOCK LABORATORY
DEPARTMENT OF MEDICAL
BIOCHEMISTRY AND BIOPHYSICS
WHEELOCK LABORATORY
DEPARTMENT OF MEDICAL
BIOCHEMISTRY AND BIOPHYSICS
WHEELOCK LABORATORY

PubMed

The Acetic Acid Produced by Lactobacillus Species Regulates Immune Function to Alleviate PEDV Infection in Piglets

Wed, 27/03/2024 - 11:00
Probiotics Antimicrob Proteins. 2024 Mar 27. doi: 10.1007/s12602-024-10243-1. Online ahead of print.ABSTRACTPorcine epidemic diarrhea virus (PEDV) infection results in significant mortality among newborn piglets, leading to substantial economic setbacks in the pig industry. Short-chain fatty acids (SCFA), the metabolites of intestinal probiotics, play pivotal roles in modulating intestinal function, enhancing the intestinal barrier, and bolstering immune responses through diverse mechanisms. The protective potential of Lactobacillus delbrueckii, Lactobacillus johnsonii, and Lactococcus lactis was first noted when administered to PEDV-infected piglets. Histological evaluations, combined with immunofluorescence studies, indicated that piglets receiving L. lactis displayed less intestinal damage, with diminished epithelial cell necrosis and milder injury levels. Differences in immunofluorescence intensity revealed a significant disparity in antigen content between the L. lactis and PEDV groups, suggesting that L. lactis might suppress PEDV replication, the intestine. We then assessed short-chain fatty acid content through targeted metabolomics, finding that acetate levels markedly varied from other groups. This protective impact was confirmed by administering acetate to PEDV-infected piglets. Data suggested that piglets receiving acetate exhibited resistance to PEDV. Flow cytometry analyses were conducted to evaluate the expression of innate and adaptive immune cells in piglets. Sodium acetate appeared to bolster innate immune defenses against PEDV, marked by elevated NK cell and macrophage counts in mesenteric lymph nodes, along with increased NK cells in the spleen and macrophages in the bloodstream. Acetic acid was also found to enhance the populations of CD8+ IFN-γ T cells in the blood, spleen, and mesenteric lymph, CD4+ IFN-γ T cells in mesenteric lymph nodes and spleen, and CD4+ IL-4+T cells in the bloodstream. Transcriptome analyses were carried out on the jejunal mucosa from piglets with PEDV-induced intestinal damage and from healthy counterparts with intact barriers. Through bioinformatics analysis, we pinpointed 189 significantly upregulated genes and 333 downregulated ones, with the PI3K-AKT, ECM-receptor interaction, and pancreatic secretion pathways being notably enriched. This transcriptomic evidence was further corroborated by western blot and qPCR. Short-chain fatty acids (SCFA) were found to modulate G protein-coupled receptor 41 (GPR41) and 43 (GPR43) in porcine intestinal epithelial cells (IPEC-J2). Post-acetic acid exposure, there was a notable upsurge in the ZO-1 barrier protein expression in IPEC-J2 compared to the unexposed control group (WT), while GPR43 knockdown inversely affected ZO-1 expression. Acetic acid amplified the concentrations of phosphorylated PI3K and AKT pivotal components of the PI3K/AKT pathway. Concurrently, the co-administration of AKT agonist SC79 and PI3K inhibitor LY294002 revealed acetic acid's role in augmenting ZO-1 expression via the P13K/AKT signaling pathway. This study demonstrates that acetic acid produced by Lactobacillus strains regulates intestinal barrier and immune functions to alleviate PEDV infection. These findings provide valuable insights for mitigating the impact of PEDV in the pig industry.PMID:38536635 | DOI:10.1007/s12602-024-10243-1

Metabolic changes contribute to maladaptive right ventricular hypertrophy in pulmonary hypertension beyond pressure overload: an integrative imaging and omics investigation

Wed, 27/03/2024 - 11:00
Basic Res Cardiol. 2024 Mar 27. doi: 10.1007/s00395-024-01041-5. Online ahead of print.ABSTRACTRight ventricular (RV) failure remains the strongest determinant of survival in pulmonary hypertension (PH). We aimed to identify relevant mechanisms, beyond pressure overload, associated with maladaptive RV hypertrophy in PH. To separate the effect of pressure overload from other potential mechanisms, we developed in pigs two experimental models of PH (M1, by pulmonary vein banding and M2, by aorto-pulmonary shunting) and compared them with a model of pure pressure overload (M3, pulmonary artery banding) and a sham-operated group. Animals were assessed at 1 and 8 months by right heart catheterization, cardiac magnetic resonance and blood sampling, and myocardial tissue was analyzed. Plasma unbiased proteomic and metabolomic data were compared among groups and integrated by an interaction network analysis. A total of 33 pigs completed follow-up (M1, n = 8; M2, n = 6; M3, n = 10; and M0, n = 9). M1 and M2 animals developed PH and reduced RV systolic function, whereas animals in M3 showed increased RV systolic pressure but maintained normal function. Significant plasma arginine and histidine deficiency and complement system activation were observed in both PH models (M1&M2), with additional alterations to taurine and purine pathways in M2. Changes in lipid metabolism were very remarkable, particularly the elevation of free fatty acids in M2. In the integrative analysis, arginine-histidine-purines deficiency, complement activation, and fatty acid accumulation were significantly associated with maladaptive RV hypertrophy. Our study integrating imaging and omics in large-animal experimental models demonstrates that, beyond pressure overload, metabolic alterations play a relevant role in RV dysfunction in PH.PMID:38536505 | DOI:10.1007/s00395-024-01041-5

New Insights into the Umami and Sweet Taste of Oolong Tea: Formation of Enhancer <em>N</em>-(1-carboxyethyl)-6-(hydroxymethyl) pyridinium-3-ol (Alapyridaine) in Roasting Via Maillard Reaction

Wed, 27/03/2024 - 11:00
J Agric Food Chem. 2024 Mar 27. doi: 10.1021/acs.jafc.3c09011. Online ahead of print.ABSTRACTRoasting is pivotal for enhancing the flavor of Wuyi rock tea (WRT). A study investigated a novel compound that enhances the umami taste of WRT. Metabolomics of Shuixian tea (SXT) and Rougui tea (RGT) under light roasting (LR), medium roasting (MR), and heavy roasting (HR) revealed significant differences in nonvolatiles compounds. Compared LR reducing sugars and amino acids notably decreased in MR and HR, with l-alanine declining by 69%. Taste-guided fractionation identified fraction II-B as having high umami and sweet intensities. A surprising taste enhancer, N-(1-carboxyethyl)-6-(hydroxymethyl) pyridinium-3-ol (alapyridaine), was discovered and identified. It formed via the Maillard reaction, positively correlated with roasting in SXT and RGT. Alapyridaine levels were highest in SXT among the five oolong teas. Roasting tea with glucose increased alapyridaine levels, while EGCG inhibited its formation. HR-WRT exhibited enhanced umami and sweet taste, highlighting alapyridaine's impact on WRT's flavor profile. The formation of alapyridaine during the roasting process provides new insights into the umami and sweet perception of oolong tea.PMID:38536213 | DOI:10.1021/acs.jafc.3c09011

NMR Untargeted and HPLC-MS/MS Targeted Metabolomic Approaches for Evaluating Styrene Exposure in the Urine of Shipyard Workers

Wed, 27/03/2024 - 11:00
Toxics. 2024 Feb 28;12(3):182. doi: 10.3390/toxics12030182.ABSTRACTDue to its chemical properties, styrene is largely employed in the manufacturing of several products including rubber, polymers and resins, and it is particularly suitable for shipbuilding industry purposes. In this context, the main exposure to styrene occurs in occupational settings. Despite its widespread use, its long-term effects on human health at the occupational level are still unclear. The aim of this pilot study was to evaluate changes in styrene exposure biomarkers related to the metabolic and oxidative stress profiles in the urine of seventeen shipyard workers and seventeen non-exposed subjects. Urinary metabolites were assessed by means of NMR spectroscopy, including mandelic and phenylglyoxylic acids; four oxidative stress biomarkers, namely 8-oxo-7,8-dihydroguanine, 8-oxo-7,8-dihydroguanosine, and 8-oxo-7,8-dihydro-2'-deoxyguanosine and 3-nitrotyrosine, were evaluated via HPLC-MS/MS. The metabolic profiles of exposed workers showed both long- and short-term metabolic responses to styrene exposure compared to non-exposed subjects. From the comparison between non-exposed and before-shift workers, only 8-oxo-7,8-dihydroguanine and 8-oxo-7,8-dihydro-2'-deoxyguanosine levels were significantly different (long term exposure response). At the same time, comparing the non-exposed group with after-shift workers, we observed lower levels of pseudouridine and 1-methylnicotinamide and higher glutamine levels in after-shift workers. The comparison between before-shift and after-shift workers showed that 8-oxo-7,8-dihydroguanine significantly increased after the shift, suggesting its involvement in the exposure to styrene (short-term exposure response). The obtained results, although preliminary, allow us to lay the basis for further human studies aimed at establishing a global understanding of styrene metabolism.PMID:38535915 | DOI:10.3390/toxics12030182

Integration of Multi-Omics, Histological, and Biochemical Analysis Reveals the Toxic Responses of Nile Tilapia Liver to Chronic Microcystin-LR Exposure

Wed, 27/03/2024 - 11:00
Toxins (Basel). 2024 Mar 14;16(3):149. doi: 10.3390/toxins16030149.ABSTRACTMicrocystin-LR (MC-LR) is a cyanobacterial metabolite produced during cyanobacterial blooms and is toxic to aquatic animals, and the liver is the main targeted organ of MC-LR. To comprehensively understand the toxicity mechanism of chronic exposure to environmental levels of MC-LR on the liver of fish, juvenile Nile tilapia were exposed to 0 μg/L (control), 1 μg/L (M1), 3 μg/L (M3), 10 μg/L (M10), and 30 μg/L (M30) MC-LR for 60 days. Then, the liver hepatotoxicity induced by MC-LR exposure was systematically evaluated via histological and biochemical determinations, and the underlying mechanisms were explored through combining analysis of biochemical parameters, multi-omics (transcriptome and metabolome), and gene expression. The results exhibited that chronic MC-LR exposure caused slight liver minor structural damage and lipid accumulation in the M10 group, while resulting in serious histological damage and lipid accumulation in the M30 group, indicating obvious hepatotoxicity, which was confirmed by increased toxicity indexes (i.e., AST, ALT, and AKP). Transcriptomic and metabolomic analysis revealed that chronic MC-LR exposure induced extensive changes in gene expression and metabolites in six typical pathways, including oxidative stress, apoptosis, autophagy, amino acid metabolism, primary bile acid biosynthesis, and lipid metabolism. Taken together, chronic MC-LR exposure induced oxidative stress, apoptosis, and autophagy, inhibited primary bile acid biosynthesis, and caused fatty deposition in the liver of Nile tilapia.PMID:38535815 | DOI:10.3390/toxins16030149

Metabolomic and Proteomic Profiling of Athletes Performing Physical Activity under Hypoxic Conditions

Wed, 27/03/2024 - 11:00
Sports (Basel). 2024 Mar 5;12(3):72. doi: 10.3390/sports12030072.ABSTRACTProteomic and metabolomic research enables quantitation of the molecular profile of athletes. Multiomic profiling was conducted using plasma samples collected from 18 male athletes performing aerobic activity (running) at high altitude. Metabolomic profiling detected changes in the levels of 4-hydroxyproline, methionine, oxaloacetate, and tyrosine during the recovery period. Furthermore, proteomic profiling revealed changes in expression of proteins contributing to the function of the immune system, muscle damage, metabolic fitness and performance, as well as hemostasis. Further research should focus on developing metabolic models to monitor training intensity and athlete adaptation.PMID:38535735 | DOI:10.3390/sports12030072

A Multiomics Assessment of Preoperative Exercise in Pancreatic Cancer Survivors Receiving Neoadjuvant Therapy: A Case Series

Wed, 27/03/2024 - 11:00
Pathophysiology. 2024 Mar 20;31(1):166-182. doi: 10.3390/pathophysiology31010013.ABSTRACTTo molecularly characterize the impact of exercise on mitigating neoadjuvant treatment (NAT)-induced physical decline in pancreatic ductal adenocarcinoma (PDAC) patients, a multi-omics approach was employed for the analysis of plasma samples before and after a personalized exercise intervention. Consisting of personalized aerobic and resistance exercises, this intervention was associated with significant molecular changes that correlated with improvements in lean mass, appendicular skeletal muscle index (ASMI), and performance in the 400-m walk test (MWT) and sit-to-stand test. These alterations indicated exercise-induced modulation of inflammation and mitochondrial function markers. This case study provides proof-of-principal application for multiomics-based assessments of supervised exercise, thereby supporting this intervention as a feasible and beneficial intervention for PDAC patients to potentially enhance treatment response and patient quality of life. The molecular changes observed here underscore the importance of physical activity in cancer treatment protocols, advocating for the development of accessible multiomics-guided exercise programs for cancer patients.PMID:38535623 | DOI:10.3390/pathophysiology31010013

Metabolomics-Guided Discovery of New Dimeric Xanthones from Co-Cultures of Mangrove Endophytic Fungi Phomopsis asparagi DHS-48 and Phomopsis sp. DHS-11

Wed, 27/03/2024 - 11:00
Mar Drugs. 2024 Feb 23;22(3):102. doi: 10.3390/md22030102.ABSTRACTThe co-culture strategy, which mimics natural ecology by constructing an artificial microbial community, is a useful tool for the activation of biosynthetic gene clusters (BGCs) to generate new metabolites, as well as to increase the yield of respective target metabolites. As part of our project aiming at the discovery of structurally novel and biologically active natural products from mangrove endophytic fungi, we selected the co-culture of a strain of Phomopsis asparagi DHS-48 with another Phomopsis genus fungus DHS-11, both endophyted in mangrove Rhizophora mangle considering the impart of the taxonomic criteria and ecological data. The competition interaction of the two strains was investigated through morphology observation and scanning electron microscopy (SEM), and it was found that the mycelia of the DHS-48 and DHS-11 compacted and tangled with each other with an interwoven pattern in the co-culture system. A new approach that integrates HPLC chromatogram, 1HNMR spectroscopy, UPLC-MS-PCA, and molecular networking enabled the targeted isolation of the induced metabolites, including three new dimeric xanthones phomoxanthones L-N (1-3), along with six known analogs (4-9). Their planar structures were elucidated by an analysis of their HRMS, MS/MS, and NMR spectroscopic data and the absolute configurations based on ECD calculations. These metabolites showed broad cytotoxic activity against the cancer cells assessed, of which compounds 7-9 displayed significant cytotoxicity towards human liver cells HepG-2 with IC50 values ranging from 4.83 μM to 12.06 μM. Compounds 1-6 exhibited weak immunosuppressive activity against the proliferation of ConA-induced (T-cell) and LPS-induced (B-cell) murine splenic lymphocytes. Therefore, combining co-cultivation with a metabolomics-guided strategy as a discovery tool will be implemented as a systematic strategy for the quick discovery of target bioactive compounds.PMID:38535443 | DOI:10.3390/md22030102

Development and Metabolomic Profiles of Bactrocera dorsalis (Diptera: Tephritidae) Larvae Exposed to Phytosanitary Irradiation Dose in Hypoxic Environment Using DI-SPME-GC/MS

Wed, 27/03/2024 - 11:00
Insects. 2024 Mar 6;15(3):177. doi: 10.3390/insects15030177.ABSTRACTX-ray irradiation and modified atmospheres (MAs) provide eco-friendly, chemical-free methods for pest management. Although a low-oxygen atmospheric treatment improves the performance of some irradiated insects, its influence on the irradiation of quarantine insects and its impacts on pest control efficacy have yet to be investigated. Based on bioassay results, this study employed direct immersion solid-phase microextraction (DI-SPME) combined with gas chromatography-mass spectrometry (GC-MS) to determine metabolic profiles of late third-instar B. dorsalis larvae under normoxia (CON, Air), hypoxia (95% N2 + 5% O2, HY), super-hypoxia (99.5% N2 + 0.5% O2, Sup-HY), irradiation-alone (116 Gy, IR-alone), hypoxia + irradiation (HY + IR) and super-hypoxia + irradiation (Sup-HY + IR). Our findings reveal that, compared to the IR-alone group, the IR treatment under HY and Sup-HY (HY + IR and Sup-HY + IR) increases the larval pupation of B. dorsalis, and weakens the delaying effect of IR on the larval developmental stage. However, these 3 groups further hinder adult emergence under the phytosanitary IR dose of 116 Gy. Moreover, all IR-treated groups, including IR-alone, HY + IR, and Sup-HY + IR, lead to insect death as a coarctate larvae or pupae. Pathway analysis identified changed metabolic pathways across treatment groups. Specifically, changes in lipid metabolism-related pathways were observed: 3 in HY vs. CON, 2 in Sup-HY vs. CON, and 5 each in IR-alone vs. CON, HY + IR vs. CON, and Sup-HY + IR vs. CON. The treatments of IR-alone, HY + IR, and Sup-HY + IR induce comparable modifications in metabolic pathways. However, in the HY + IR, and Sup-HY + IR groups, the third-instar larvae of B. dorsalis demonstrate significantly fewer changes. Our research suggests that a low-oxygen environment (HY and Sup-HY) might enhance the radiation tolerance in B. dorsalis larvae by stabilizing lipid metabolism pathways at biologically feasible levels. Additionally, our findings indicate that the current phytosanitary IR dose contributes to the effective management of B. dorsalis, without being influenced by radioprotective effects. These results hold significant importance for understanding the biological effects of radiation on B. dorsalis and for developing IR-specific regulatory guidelines under MA environments.PMID:38535372 | DOI:10.3390/insects15030177

Matrix- and Surface-Assisted Laser Desorption/Ionization Mass Spectrometry Methods for Urological Cancer Biomarker Discovery-Metabolomics and Lipidomics Approaches

Wed, 27/03/2024 - 11:00
Metabolites. 2024 Mar 20;14(3):173. doi: 10.3390/metabo14030173.ABSTRACTUrinary tract cancers, including those of the bladder, the kidneys, and the prostate, represent over 12% of all cancers, with significant global incidence and mortality rates. The continuous challenge that these cancers present necessitates the development of innovative diagnostic and prognostic methods, such as identifying specific biomarkers indicative of cancer. Biomarkers, which can be genes, proteins, metabolites, or lipids, are vital for various clinical purposes including early detection and prognosis. Mass spectrometry (MS), particularly soft ionization techniques such as electrospray ionization (ESI) and laser desorption/ionization (LDI), has emerged as a key tool in metabolic profiling for biomarker discovery, due to its high resolution, sensitivity, and ability to analyze complex biological samples. Among the LDI techniques, matrix-assisted laser desorption/ionization (MALDI) and surface-assisted laser desorption/ionization (SALDI) should be mentioned. While MALDI methodology, which uses organic compounds as matrices, is effective for larger molecules, SALDI, based on the various types of nanoparticles and nanostructures, is preferred for smaller metabolites and lipids due to its reduced spectral interference. This study highlights the application of LDI techniques, along with mass spectrometry imaging (MSI), in identifying potential metabolic and lipid biomarkers for urological cancers, focusing on the most common bladder, kidney, and prostate cancers.PMID:38535333 | DOI:10.3390/metabo14030173

Application of Clinical Blood Metabogram to Type 2 Diabetes Mellitus

Wed, 27/03/2024 - 11:00
Metabolites. 2024 Mar 18;14(3):168. doi: 10.3390/metabo14030168.ABSTRACTThe clinical blood metabogram (CBM) was developed to match a tailored analysis of the blood metabolome to the time, cost, and reproducibility constraints of clinical laboratory testing. By analyzing the main blood metabolite groups, CBM offers clinically relevant information about the intake of low-molecular substances into the organism, humoral regulation, liver function, amino acid level, and the lipid and carbohydrate metabolism. The purpose of this work was to investigate the relevance of using the CBM in patients with diabetes mellitus. For this, a CBM was obtained for 18 healthy individuals, 12 individuals with prediabetes, and 64 individuals with type 2 diabetes mellitus, separated into groups according to fasting blood glucose and oral glucose tolerance tests. The results showed that the CBM reveals diabetes-associated metabolic alterations in the blood, including changes in the levels of carbohydrates, ketone bodies, eicosanoids, phospholipids, and amino acids, which are consistent with the scientific data available to date. The CBM enabled the separation of diabetic patients according to their metabolic metabotypes, providing both a general overview of their metabolic alterations and detailing their individual metabolic characteristics. It was concluded that the CBM is a precise and clinically applicable test for assessing an individual's metabolic status in diabetes mellitus for diagnostic and treatment purposes.PMID:38535328 | DOI:10.3390/metabo14030168

Metabolomics and Lipidomics Analyses Aid Model Classification of Type 2 Diabetes in Non-Human Primates

Wed, 27/03/2024 - 11:00
Metabolites. 2024 Mar 9;14(3):159. doi: 10.3390/metabo14030159.ABSTRACTType 2 diabetes (T2D) is a global public health issue characterized by excess weight, abdominal obesity, dyslipidemia, hyperglycemia, and a progressive increase in insulin resistance. Human population studies of T2D development and its effects on systemic metabolism are confounded by many factors that cannot be controlled, complicating the interpretation of results and the identification of early biomarkers. Aged, sedentary, and overweight/obese non-human primates (NHPs) are one of the best animal models to mimic spontaneous T2D development in humans. We sought to identify and distinguish a set of plasma and/or fecal metabolite biomarkers, that have earlier disease onset predictability, and that could be evaluated for their predictability in subsequent T2D studies in human cohorts. In this study, a single plasma and fecal sample was collected from each animal in a colony of 57 healthy and dysmetabolic NHPs and analyzed for metabolomics and lipidomics. The samples were comprehensively analyzed using untargeted and targeted LC/MS/MS. The changes in each animal's disease phenotype were monitored using IVGTT, HbA1c, and other clinical metrics, and correlated with their metabolic profile. The plasma and fecal lipids, as well as bile acid profiles, from Healthy, Dysmetabolic (Dys), and Diabetic (Dia) animals were compared. Following univariate and multivariate analyses, including adjustments for weight, age, and sex, several plasma lipid species were identified to be significantly different between these animal groups. Medium and long-chain plasma phosphatidylcholines (PCs) ranked highest at distinguishing Healthy from Dys animals, whereas plasma triglycerides (TG) primarily distinguished Dia from Dys animals. Random Forest (RF) analysis of fecal bile acids showed a reduction in the secondary bile acid glycoconjugate, GCDCA, in diseased animals (AUC 0.76[0.64, 0.89]). Moreover, metagenomics results revealed several bacterial species, belonging to the genera Roseburia, Ruminococcus, Clostridium, and Streptococcus, to be both significantly enriched in non-healthy animals and associated with secondary bile acid levels. In summary, our results highlight the detection of several elevated circulating plasma PCs and microbial species associated with fecal secondary bile acids in NHP dysmetabolic states. The lipids and metabolites we have identified may help researchers to differentiate individual NHPs more precisely between dysmetabolic and overtly diabetic states. This could help assign animals to study groups that are more likely to respond to potential therapies where a difference in efficacy might be anticipated between early vs. advanced disease.PMID:38535319 | DOI:10.3390/metabo14030159

Integrative Multiomics Approach to Skin: The Sinergy between Individualised Medicine and Futuristic Precision Skin Care?

Wed, 27/03/2024 - 11:00
Metabolites. 2024 Mar 7;14(3):157. doi: 10.3390/metabo14030157.ABSTRACTThe skin is a complex ecosystem colonized by millions of microorganisms, the skin microbiota, which are crucial in regulating not only the physiological functions of the skin but also the metabolic changes underlying the onset of skin diseases. The high microbial colonization together with a low diversity at the phylum level and a high diversity at the species level of the skin is very similar to that of the gastrointestinal tract. Moreover, there is an important communication pathway along the gut-brain-skin axis, especially associated with the modulation of neurotransmitters by the microbiota. Therefore, it is evident that the high complexity of the skin system, due not only to the genetics of the host but also to the interaction of the host with resident microbes and between microbe and microbe, requires a multi-omics approach to be deeply understood. Therefore, an integrated analysis, with high-throughput technologies, of the consequences of microbial interaction with the host through the study of gene expression (genomics and metagenomics), transcription (transcriptomics and meta-transcriptomics), and protein production (proteomics and meta-proteomics) and metabolite formation (metabolomics and lipidomics) would be useful. Although to date very few studies have integrated skin metabolomics data with at least one other 'omics' technology, in the future, this approach will be able to provide simple and fast tests that can be routinely applied in both clinical and cosmetic settings for the identification of numerous skin diseases and conditions. It will also be possible to create large archives of multi-omics data that can predict individual responses to pharmacological treatments and the efficacy of different cosmetic products on individual subjects by means of specific allotypes, with a view to increasingly tailor-made medicine. In this review, after analyzing the complexity of the skin ecosystem, we have highlighted the usefulness of this emerging integrated omics approach for the analysis of skin problems, starting with one of the latest 'omics' sciences, metabolomics, which can photograph the expression of the genome during its interaction with the environment.PMID:38535317 | DOI:10.3390/metabo14030157

Integrating Genome Sequencing and Untargeted Metabolomics in Monozygotic Twins with a Rare Complex Neurological Disorder

Wed, 27/03/2024 - 11:00
Metabolites. 2024 Mar 4;14(3):152. doi: 10.3390/metabo14030152.ABSTRACTMulti-omics approaches, which integrate genomics, transcriptomics, proteomics, and metabolomics, have emerged as powerful tools in the diagnosis of rare diseases. We used untargeted metabolomics and whole-genome sequencing (WGS) to gain a more comprehensive understanding of a rare disease with a complex presentation affecting female twins from a consanguineous family. The sisters presented with polymicrogyria, a Dandy-Walker malformation, respiratory distress, and multiorgan dysfunctions. Through WGS, we identified two rare homozygous variants in both subjects, a pathogenic variant in ADGRG1(p.Arg565Trp) and a novel variant in CNTNAP1(p.Glu910Val). These genes have been previously associated with autosomal recessive polymicrogyria and hypomyelinating neuropathy with/without contractures, respectively. The twins exhibited symptoms that overlapped with both of these conditions. The results of the untargeted metabolomics analysis revealed significant metabolic perturbations relating to neurodevelopmental abnormalities, kidney dysfunction, and microbiome. The significant metabolites belong to essential pathways such as lipids and amino acid metabolism. The identification of variants in two genes, combined with the support of metabolic perturbation, demonstrates the rarity and complexity of this phenotype and provides valuable insights into its underlying mechanisms.PMID:38535312 | DOI:10.3390/metabo14030152

Advancing Personalized Medicine by Analytical Means: Selection of Three Metabolites That Allows Discrimination between Glaucoma, Diabetes, and Controls

Wed, 27/03/2024 - 11:00
Metabolites. 2024 Feb 29;14(3):149. doi: 10.3390/metabo14030149.ABSTRACTThis paper aimed at devising an intelligence-based method to select compounds that can distinguish between open-angle glaucoma patients, type 2 diabetes patients, and healthy controls. Taking the concentration of 188 compounds measured in the aqueous humour (AH) of patients and controls, linear discriminant analysis (LDA) was used to identify the right combination of compounds that could lead to accurate diagnosis. All possibilities, using the leave-one-out approach, were considered through ad hoc programming and in silico massive data production and statistical analysis. Our proof of concept led to the selection of four molecules: acetyl-ornithine (Ac-Orn), C3 acyl-carnitine (C3), diacyl C42:6 phosphatidylcholine (PC aa C42:6), and C3-DC (C4-OH) acyl-carnitine (C3-DC (C4-OH)) that, taken in combination, would lead to a 95% discriminative success. 100% success was obtained with a non-linear combination of the concentration of three of these four compounds. By discarding younger controls to adjust by age, results were similar although one control was misclassified as a diabetes patient. Methods based on the consideration of individual clinical chemical parameters have limitations in the ability to make a reliable diagnosis, stratify patients, and assess disease progression. Leveraging human AH metabolomic data, we developed a procedure that selects a minimal number of metabolites (3-5) and designs algorithms that maximize the overall accuracy evaluating both positive predictive (PPV) and negative predictive (NPV) values. Our approach of simultaneously considering the levels of a few metabolites can be extended to any other body fluid and has potential to advance precision medicine. Artificial intelligence is expected to use algorithms that use the concentration of three to five molecules to correctly diagnose diseases, also allowing stratification of patients and evaluation of disease progression. In addition, this significant advance shifts focus from a single-molecule biomarker approach to that of an appropriate combination of metabolites.PMID:38535309 | DOI:10.3390/metabo14030149

Diagnostic and Prognostic Performance of Metabolic Signatures in Pancreatic Ductal Adenocarcinoma: The Clinical Application of Quantitative NextGen Mass Spectrometry

Wed, 27/03/2024 - 11:00
Metabolites. 2024 Feb 29;14(3):148. doi: 10.3390/metabo14030148.ABSTRACTWith 64,050 new diagnoses and 50,550 deaths in the US in 2023, pancreatic ductal adenocarcinoma (PDAC) is among the most lethal of all human malignancies. Early detection and improved prognostication remain critical unmet needs. We applied next-generation metabolomics, using quantitative tandem mass spectrometry on plasma, to develop biochemical signatures that identify PDAC. We first compared plasma from 10 PDAC patients to 169 samples from healthy controls. Using metabolomic algorithms and machine learning, we identified ratios that incorporate amino acids, biogenic amines, lysophosphatidylcholines, phosphatidylcholines and acylcarnitines that distinguished PDAC from normal controls. A confirmatory analysis then applied the algorithms to 30 PDACs compared with 60 age- and sex-matched controls. Metabolic signatures were then analyzed to compare survival, measured in months, from date of diagnosis to date of death that identified metabolite ratios that stratified PDACs into distinct survival groups. The results suggest that metabolic signatures could provide PDAC diagnoses earlier than tumor markers or radiographic measures and offer insights into disease severity that could allow more judicious use of therapy by stratifying patients into metabolic-risk subgroups.PMID:38535308 | DOI:10.3390/metabo14030148

Unraveling Metabolic Changes following Stroke: Insights from a Urinary Metabolomics Analysis

Wed, 27/03/2024 - 11:00
Metabolites. 2024 Feb 28;14(3):145. doi: 10.3390/metabo14030145.ABSTRACTThe neuropathological sequelae of stroke and subsequent recovery are incompletely understood. Here, we investigated the metabolic dynamics following stroke to advance the understanding of the pathophysiological mechanisms orchestrating stroke recovery. Using a nuclear magnetic resonance (NMR)-driven metabolomic profiling approach for urine samples obtained from a clinical group, the objective of this research was to (1) identify novel biomarkers indicative of severity and recovery following stroke, and (2) uncover the biochemical pathways underlying repair and functional recovery after stroke. Urine samples and clinical stroke assessments were collected during the acute (2-11 days) and chronic phases (6 months) of stroke. Using a 700 MHz 1H NMR spectrometer, metabolomic profiles were acquired followed by a combination of univariate and multivariate statistical analyses, along with biological pathway analysis and clinical correlations. The results revealed changes in phenylalanine, tyrosine, tryptophan, purine, and glycerophospholipid biosynthesis and metabolism during stroke recovery. Pseudouridine was associated with a change in post-stroke motor recovery. Thus, NMR-based metabolomics is able to provide novel insights into post-stroke cellular functions and establish a foundational framework for future investigations to develop targeted therapeutic interventions, advance stroke diagnosis and management, and enhance overall quality of life for individuals with stroke.PMID:38535305 | DOI:10.3390/metabo14030145

Metabolomic Analysis Reveals Association between Decreased Ovarian Reserve and In Vitro Fertilization Outcomes

Wed, 27/03/2024 - 11:00
Metabolites. 2024 Feb 27;14(3):143. doi: 10.3390/metabo14030143.ABSTRACTIn vitro fertilization (IVF) is a highly effective treatment for infertility; however, it poses challenges for women with decreased ovarian reserve (DOR). Despite the importance of understanding the impact of DOR on IVF outcomes, limited research has explored this relationship, particularly using omics approaches. Hence, we conducted a study to investigate the association between DOR and IVF outcomes, employing a metabolomic approach. We analyzed serum samples from 207 women undergoing IVF treatment, including 89 with DOR and 118 with normal ovarian reserve (NOR). Our findings revealed that DOR was significantly associated with unfavorable IVF outcomes, characterized by a reduced oocyte count, lower embryo quality, and decreased rates of pregnancy and live births. Furthermore, we identified 82 metabolites that displayed significant alterations in DOR patients, impacting diverse metabolic pathways. Notably, a distinct panel of metabolites, including palmitic acid, stearic acid, LysoPC(9:0(CHO)/0:0), PC(18:0/9:0(CHO)), and PC(16:0/9:0(CHO)), exhibited discriminatory power between the DOR and NOR groups, showcasing a strong correlation with IVF outcomes. These findings emphasize the crucial role of metabolomic disruptions in influencing IVF outcomes among women with DOR.PMID:38535303 | DOI:10.3390/metabo14030143

Comparative Metabolomics of Ligulate and Tubular Flowers of Two Cultivars of Calendula officinalis L

Wed, 27/03/2024 - 11:00
Metabolites. 2024 Feb 26;14(3):140. doi: 10.3390/metabo14030140.ABSTRACTCalendula officinalis L. is a well-known plant widely used in traditional medicine due to the presence of various biologically active compounds. The main raw material for the production of medicinal preparations is the inflorescence, which consists of ligulate and tubular flowers. However, the characteristics of the metabolome of these flowers are not fully understood. This study identified and compared the levels of major metabolites in the ligulate and tubular flowers of two C. officinalis cultivars, 'Golden Sea' (GS) and 'Paradise Garden' (PG). The metabolome was analysed using ultra-performance liquid chromatography with photodiode array detection and a Q Exactive Orbitrap high-resolution mass spectrometer. It was found that the tubular flowers of both PG and GS cultivars had higher levels of lipids, phenolamides and caffeoylquinic acids and lower levels of triterpenoid glycosides than the ligulate flowers. It was also shown that the inflorescences of the GS, which had a 35% higher proportion of tubular flowers, contained 30% more phenolic compounds and 50% more lipids than the PG. Thus, the results obtained extend our understanding of the features in the metabolomes of ligulate and tubular flowers and suggest that the quality of inflorescences of C. officinalis cultivars, as a source of medicinal preparations, is strongly influenced by the proportion of ligulate and tubular flowers.PMID:38535300 | DOI:10.3390/metabo14030140

Effects of Different Feed Additives on Intestinal Metabolite Composition of Weaned Piglets

Wed, 27/03/2024 - 11:00
Metabolites. 2024 Feb 26;14(3):138. doi: 10.3390/metabo14030138.ABSTRACTTo study the effects of different feed additives on the weaning stress of Tibetan piglets, we selected 28 healthy, 30-day-old Tibetan weaned piglets and divided them into four groups, namely, the control group (basal feed without any antibiotic additions) (Nor), the group with the addition of the antibiotic lincomycin (Ant), the group with the addition of fifteen-flavor black pills of Tibetan medicine (Tib), and the group with the addition of fecal bacterial supernatant (Fec). We measured growth performance, blood physiological indexes, and metabolomics. The results showed that the Ant, Tib, and Fec groups significantly reduced the ratio of diarrhea to feed/weight (F/G) and increased the average daily gain (ADG) compared with the Nor group (p < 0.01). The Nor group had significantly lower leukocyte counts, hemoglobin levels, and erythrocyte counts compared with the other three groups at 21 d (p < 0.05). These physiological indexes tended to stabilize at 42 d. We found that there were beneficial metabolites and metabolic pathways for gastrointestinal function. Specifically, the porphyrin metabolic pathway was elevated in the Ant group, and the tryptophan metabolic pathway was significantly elevated in the Tib and Fec groups compared with the Nor group (p < 0.05). In conclusion, adding fecal bacterial supernatant and fifteen-flavor black pills of Tibetan medicine to the feed reduced the rate of diarrhea and improved the growth performance of the piglets. Moreover, it had an effect on the microorganisms and their metabolites and pathways in the gastrointestinal tract of the animals, which might be the main reason for influencing the diarrhea rate of weaned Tibetan piglets and the growth and development of the piglets. This study provides a new approach for anti-stress applications in weaned Tibetan piglets and the development of substitute anti-products.PMID:38535298 | DOI:10.3390/metabo14030138

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