PubMed

J Genet. 2023;102:13.ABSTRACTDuchenne muscular dystrophy (DMD) is the most common form of progressive childhood muscular dystrophy associated with weakness of limbs, loss of ambulation, heart weakness and early death. The mutations causing either loss-of-expression or function of the full-length protein dystrophin (Dp427) from the DMD gene are responsible for the disease pathology. Dp427 forms a part of the large dystroglycan complex, called DAPC, in the sarcolemma, and its absence derails muscle contraction. Muscle biopsies from DMD patients show an overactivation of excitation-contraction-coupling (ECC) activable calcium incursion, sarcolemmal ROS production, NHE1 activation, IL6 secretion, etc. The signalling pathways, like Akt/PBK, STAT3, p38MAPK, and ERK1/2, are also hyperactive in DMD. These pathways are responsible for post-mitotic trophic growth and metabolic adaptation, in response to exercise in healthy muscles, but cause atrophy and cell death in dystrophic muscles. We hypothesize that the metabolic background of repressed glycolysis in DMD, as opposed to excess glycolysis seen in cancers or healthy contracting muscles, changes the outcome of these 'growth pathways'. The reduced glycolysis has been considered a secondary outcome of the cytoskeletal disruptions seen in DMD. Given the cytoskeleton-crosslinking ability of the glycolytic enzymes, we hypothesize that the failure of glycogenolytic and glycolytic enzymes to congregate is the primary pathology, which then affects the subsarcolemmal cytoskeletal organization in costameres and initiates the pathophysiology associated with DMD, giving rise to the tissue-specific differences in disease progression between muscle, heart and brain. The lacunae in the regulation of the key components of the hypothesized metabolome, and the limitations of this theory are deliberated. The considerations for developing future therapies based on known pathological processes are also discussed.PMID:36814107

Nature. 2023 Feb 22. doi: 10.1038/s41586-023-05728-y. Online ahead of print.ABSTRACTPancreatic ductal adenocarcinoma (PDAC) is expected to be the second most deadly cancer by 2040, owing to the high incidence of metastatic disease and limited responses to treatment1,2. Less than half of all patients respond to the primary treatment for PDAC, chemotherapy3,4, and genetic alterations alone cannot explain this5. Diet is an environmental factor that can influence the response to therapies, but its role in PDAC is unclear. Here, using shotgun metagenomic sequencing and metabolomic screening, we show that the microbiota-derived tryptophan metabolite indole-3-acetic acid (3-IAA) is enriched in patients who respond to treatment. Faecal microbiota transplantation, short-term dietary manipulation of tryptophan and oral 3-IAA administration increase the efficacy of chemotherapy in humanized gnotobiotic mouse models of PDAC. Using a combination of loss- and gain-of-function experiments, we show that the efficacy of 3-IAA and chemotherapy is licensed by neutrophil-derived myeloperoxidase. Myeloperoxidase oxidizes 3-IAA, which in combination with chemotherapy induces a downregulation of the reactive oxygen species (ROS)-degrading enzymes glutathione peroxidase 3 and glutathione peroxidase 7. All of this results in the accumulation of ROS and the downregulation of autophagy in cancer cells, which compromises their metabolic fitness and, ultimately, their proliferation. In humans, we observed a significant correlation between the levels of 3-IAA and the efficacy of therapy in two independent PDAC cohorts. In summary, we identify a microbiota-derived metabolite that has clinical implications in the treatment of PDAC, and provide a motivation for considering nutritional interventions during the treatment of patients with cancer.PMID:36813961 | DOI:10.1038/s41586-023-05728-y

Nat Commun. 2023 Feb 22;14(1):980. doi: 10.1038/s41467-023-36659-x.NO ABSTRACTPMID:36813812 | DOI:10.1038/s41467-023-36659-x

Nat Commun. 2023 Feb 22;14(1):995. doi: 10.1038/s41467-023-36350-1.ABSTRACTThe rising incidence of non-ST-segment elevation myocardial infarction (NSTEMI) and associated long-term high mortality constitutes an urgent clinical issue. Unfortunately, the study of possible interventions to treat this pathology lacks a reproducible pre-clinical model. Indeed, currently adopted small and large animal models of MI mimic only full-thickness, ST-segment-elevation (STEMI) infarcts, and hence cater only for an investigation into therapeutics and interventions directed at this subset of MI. Thus, we develop an ovine model of NSTEMI by ligating the myocardial muscle at precise intervals parallel to the left anterior descending coronary artery. Upon histological and functional investigation to validate the proposed model and comparison with STEMI full ligation model, RNA-seq and proteomics show the distinctive features of post-NSTEMI tissue remodelling. Transcriptome and proteome-derived pathway analyses at acute (7 days) and late (28 days) post-NSTEMI pinpoint specific alterations in cardiac post-ischaemic extracellular matrix. Together with the rise of well-known markers of inflammation and fibrosis, NSTEMI ischaemic regions show distinctive patterns of complex galactosylated and sialylated N-glycans in cellular membranes and extracellular matrix. Identifying such changes in molecular moieties accessible to infusible and intra-myocardial injectable drugs sheds light on developing targeted pharmacological solutions to contrast adverse fibrotic remodelling.PMID:36813782 | DOI:10.1038/s41467-023-36350-1

Phytochem Anal. 2023 Feb 22. doi: 10.1002/pca.3216. Online ahead of print.ABSTRACTINTRODUCTION: Flavonoids are active substances in many herbal medicines, and Areca catechu fruit (AF), an important component in traditional Chinese medicine (TCM), is rich in flavonoids. Different parts of AF, Pericarpium Arecae (PA) and Semen Arecae (SA), have different medicinal effects in prescription of TCM.OBJECTIVE: To understand flavonoid biosynthesis and regulation in AF.METHODOLOGY: The metabolomic based on liquid chromatography-tandem mass spectrometry (LC-MS/MS) and the transcriptome based on high-throughput sequencing technology were combined to comprehensively analyse PA and SA.RESULTS: From the metabolite dataset, we found that 148 flavonoids showed significant differences between PA and SA. From the transcriptomic dataset, we identified 30 genes related to the flavonoid biosynthesis pathway which were differentially expressed genes in PA and SA. The genes encoding the key enzymes in the flavonoid biosynthesis pathway, chalcone synthase and chalcone isomerase (AcCHS4/6/7 and AcCHI1/2/3), were significantly higher expressed in SA than in PA, reflecting the high flavonoid concentration in SA.CONCLUSIONS: Taken together, our research acquired the key genes, including AcCHS4/6/7 and AcCHI1/2/3, which regulated the accumulation of flavonol in AF. This new evidence may reveal different medicinal effects of PA and SA. This study lays a foundation for investigating the biosynthesis and regulation of flavonoid biosynthesis in areca and provides the reference for the production and consumption of betel nut.PMID:36813748 | DOI:10.1002/pca.3216

J Clin Pathol. 2023 Feb 22:jcp-2023-208790. doi: 10.1136/jcp-2023-208790. Online ahead of print.ABSTRACTAIMS: Identification and characterisation of monoclonal gammopathies of renal significance (MGRS) is critical for therapeutic purposes. Amyloidosis represents one of the most common forms of MGRS, and renal biopsy remains the gold standard for their classification, although mass spectrometry has shown greater sensitivity in this area.METHODS: In the present study, a new in situ proteomic technique, matrix-assisted laser desorption/ionisation mass spectrometry imaging (MALDI-MSI), is investigated as an alternative to conventional laser capture microdissection MS for the characterisation of amyloids. MALDI-MSI was performed on 16 cases (3 lambda light chain amyloidosis (AL), 3 AL kappa, 3 serum amyloid A amyloidosis (SAA), 2 lambda light chain deposition disease (LCDD), 2 challenging amyloid cases and 3 controls). Analysis began with regions of interest labelled by the pathologist, and then automatic segmentation was performed.RESULTS: MALDI-MSI correctly identified and typed cases with known amyloid type (AL kappa, AL lambda and SAA). A 'restricted fingerprint' for amyloid detection composed of apolipoprotein E, serum amyloid protein and apolipoprotein A1 showed the best automatic segmentation performance (area under the curve >0.7).CONCLUSIONS: MALDI-MSI correctly assigned minimal/challenging cases of amyloidosis to the correct type (AL lambda) and identified lambda light chains in LCDD cases, highlighting the promising role of MALDI-MSI for amyloid typing.PMID:36813560 | DOI:10.1136/jcp-2023-208790

Handb Clin Neurol. 2023;194:251-257. doi: 10.1016/B978-0-12-821751-1.00006-3.ABSTRACTThe mitochondrial disease group consists of different disorders with unprecedented variability of clinical manifestations and tissue-specific symptoms. Their tissue-specific stress responses vary depending on the patients' age and type of dysfunction. These responses include secretion of metabolically active signal molecules to systemic circulation. Such signals-metabolites or metabokines-can be also utilized as biomarkers. During the past 10 years, metabolite and metabokine biomarkers have been described for mitochondrial disease diagnosis and follow-up, to complement the conventional blood biomarkers lactate, pyruvate and alanine. These new tools include metabokines FGF21 and GDF15; cofactors (NAD-forms); sets of metabolites (multibiomarkers) and the full metabolome. FGF21 and GDF15 are messengers of mitochondrial integrated stress response that together outperform the conventional biomarkers in specificity and sensitivity for muscle-manifesting mitochondrial diseases. Metabolite or metabolomic imbalance (e.g., NAD+ deficiency) is a secondary consequence to the primary cause in some diseases, but relevant as a biomarker and a potential indicator of therapy targets. For therapy trials, the optimal biomarker set needs to be tailored to match the disease of interest. The new biomarkers have increased the value of blood samples in mitochondrial disease diagnosis and follow-up, enabling prioritization of patients to different diagnostic paths and having crucial roles in follow-up of therapy effect.PMID:36813317 | DOI:10.1016/B978-0-12-821751-1.00006-3

Handb Clin Neurol. 2023;194:167-172. doi: 10.1016/B978-0-12-821751-1.00012-9.ABSTRACTClinical variability and substantial overlap between mitochondrial disorders and other genetic disorders and inborn errors make the clinical and metabolic diagnosis of mitochondrial disorders quite challenging. Evaluating specific laboratory markers is essential in the diagnostic process, but mitochondrial disease can be present in the absence of any abnormal metabolic markers. In this chapter, we share the current consensus guidelines for metabolic investigations, including investigations in blood, urine, and the cerebral spinal fluid and discuss different diagnostic approaches. As personal experience might significantly vary and there are different recommendations published as diagnostic guidelines, the Mitochondrial Medicine Society developed a consensus approach based on literature review for metabolic diagnostics in a suspected mitochondrial disease. According to the guidelines, the work-up should include the assessment of complete blood count, creatine phosphokinase, transaminases, albumin, postprandial lactate and pyruvate (lactate/pyruvate ratio when the lactate level is elevated), uric acid, thymidine, amino acids, acylcarnitines in blood, and urinary organic acids (especially screening for 3-methylglutaconic acid). Urine amino acid analysis is recommended in mitochondrial tubulopathies. CSF metabolite analysis (lactate, pyruvate, amino acids, and 5-methyltetrahydrofolate) should be included in the presence of central nervous system disease. We also suggest a diagnostic strategy based on the mitochondrial disease criteria (MDC) scoring system in mitochondrial disease diagnostics; evaluating muscle-, neurologic-, and multisystem involvement, and the presence of metabolic markers and abnormal imaging. The consensus guideline encourages a primary genetic approach in diagnostics and only suggests a more invasive diagnostic approach with tissue biopsies (histology, OXPHOS measurements, etc.) after nonconclusive genetic testing.PMID:36813311 | DOI:10.1016/B978-0-12-821751-1.00012-9

Gastroenterology. 2023 Feb 20:S0016-5085(23)00144-0. doi: 10.1053/j.gastro.2023.02.010. Online ahead of print.ABSTRACTBACKGROUND & AIMS: Aberrant epigenetic events mediated by histone methyltransferases and demethylases contributes to malignant progression of colorectal cancer (CRC). However, the role of the histone demethylase ubiquitously transcribed tetratricopeptide repeat on chromosome X (UTX) in CRC remains poorly understood.METHODS: UTX conditional knock-out mice and UTX-silenced MC38 cells were used to investigate UTX function in tumorigenesis and development of CRC. We performed Time of Flight Mass Cytometry to clarify the functional role of UTX in remodeling immune microenvironment of CRC. To investigate metabolic interaction between myeloid-derived suppressor cells (MDSCs) and CRC, we analyzed metabolomics data to identify metabolites secreted by UTX-deficient cancer cells and taken up by MDSCs.RESULTS: We unraveled a tyrosine-mediated metabolic symbiosis between MDSC and UTX-deficient CRC. Loss of UTX in CRC resulted in methylation of phenylalanine hydroxylase, preventing its degradation and subsequently increasing tyrosine synthesis and secretion. Tyrosine taken up by MDSCs was metabolized to homogentisic acid (HGA) by hydroxyphenylpyruvate dioxygenase (HPD). HGA modified PIAS3 via carbonylation of Cys 176, and relieved the inhibitory effect of PIAS3 on STAT5 transcriptional activity. This in turn, promoted MDSCs survival and accumulation, enabling CRC cells to acquire invasive and metastatic traits.CONCLUSIONS: Collectively, these findings highlight HPD as a metabolic checkpoint to restrict immunosuppressive MDSCs and to counteract malignant progression of UTX-deficient CRC.PMID:36813208 | DOI:10.1053/j.gastro.2023.02.010

Sci Total Environ. 2023 Feb 20:162327. doi: 10.1016/j.scitotenv.2023.162327. Online ahead of print.ABSTRACTThe spread of heavy metal(loid)s at soil-food crop interfaces has become a threat to sustainable agricultural productivity, food security, and human health. The potential eco-toxic effects of heavy metals on food crops can be manifested through reactive oxygen species that have the potential to disturb seed germination, normal growth, photosynthesis, cellular metabolism, and homeostasis. This review provides a critical overview of stress tolerance mechanisms in food crops/hyperaccumulator plants against heavy metals and arsenic (HM-As). The HM-As antioxidative stress tolerance in food crops is associated with changes in metabolomics (physico-biochemical/lipidomics) and genomics (molecular level). Furthermore, HM-As stress tolerance occurs through plant-microbe, phytohormone, antioxidant, and signal molecule interactions. Information regarding the avoidance, tolerance, and stress resilience of HM-As should help pave the way to minimize food chain contamination, eco-toxicity, and health risks. Advanced biotechnological approaches (e.g., genome modification with CRISPR-Cas9 gene editing) in concert with traditional sustainable biological methods are useful options to develop 'pollution safe designer cultivars' with increased climate change resilience and public health risks mitigation. Last, the usage of HM-As tolerant hyperaccumulator biomass in biorefineries (e.g., environmental remediation, value added chemicals, and bioenergy) is advocated to realize the synergy between biotechnological research and socio-economic policy frameworks, which are inextricably linked with environmental sustainability. The biotechnological innovations in 'cleaner climate smart phytotechnologies' and evolving HM-As stress resilient food crops should serve as an effective tool to achieve sustainable development goals (SDGs) and a circular bioeconomy.PMID:36813200 | DOI:10.1016/j.scitotenv.2023.162327

Cell Host Microbe. 2023 Feb 13:S1931-3128(23)00042-2. doi: 10.1016/j.chom.2023.01.017. Online ahead of print.ABSTRACTThe molecular understanding of host-pathogen interactions in the gastrointestinal (GI) tract of superspreader hosts is incomplete. In a mouse model of chronic, asymptomatic Salmonella enterica serovar Typhimurium (S. Tm) infection, we performed untargeted metabolomics on the feces of mice and found that superspreader hosts possess distinct metabolic signatures compared with non-superspreaders, including differential levels of L-arabinose. RNA-seq on S. Tm from superspreader fecal samples showed increased expression of the L-arabinose catabolism pathway in vivo. By combining bacterial genetics and diet manipulation, we demonstrate that diet-derived L-arabinose provides S. Tm a competitive advantage in the GI tract, and expansion of S. Tm in the GI tract requires an alpha-N-arabinofuranosidase that liberates L-arabinose from dietary polysaccharides. Ultimately, our work shows that pathogen-liberated L-arabinose from the diet provides a competitive advantage to S. Tm in vivo. These findings propose L-arabinose as a critical driver of S. Tm expansion in the GI tracts of superspreader hosts.PMID:36812913 | DOI:10.1016/j.chom.2023.01.017

Anal Chem. 2023 Feb 22. doi: 10.1021/acs.analchem.2c04396. Online ahead of print.ABSTRACTMetabolism plays a fundamental role in regulating cellular functions and fate decisions. Liquid chromatography-mass spectrometry (LC-MS)-based targeted metabolomic approaches provide high-resolution insights into the metabolic state of a cell. However, the typical sample size is in the order of 105-107 cells and thus not compatible with rare cell populations, especially in the case of a prior flow cytometry-based purification step. Here, we present a comprehensively optimized protocol for targeted metabolomics on rare cell types, such as hematopoietic stem cells and mast cells. Only 5000 cells per sample are required to detect up to 80 metabolites above background. The use of regular-flow liquid chromatography allows for robust data acquisition, and the omission of drying or chemical derivatization avoids potential sources of error. Cell-type-specific differences are preserved while the addition of internal standards, generation of relevant background control samples, and targeted metabolite with quantifiers and qualifiers ensure high data quality. This protocol could help numerous studies to gain thorough insights into cellular metabolic profiles and simultaneously reduce the number of laboratory animals and the time-consuming and costly experiments associated with rare cell-type purification.PMID:36812587 | DOI:10.1021/acs.analchem.2c04396

Mol Biol Evol. 2023 Feb 22:msad045. doi: 10.1093/molbev/msad045. Online ahead of print.ABSTRACTThe mutualistic ectomycorrhizal (ECM) fungal genus Pisolithus comprises 19 species defined to date which colonize the roots of >50 hosts worldwide suggesting that substantial genomic and functional evolution occurred during speciation. To better understand this intra-genus variation, we undertook a comparative multi-omic study of nine Pisolithus species sampled from North America, South America, Asia, and Australasia. We found that there was a small core set of genes common to all species (13%), and that these genes were more likely to be significantly regulated during symbiosis with a host than accessory or species-specific genes. Thus, the genetic 'toolbox' foundational to the symbiotic lifestyle in this genus is small. Transposable elements were located significantly closer to gene classes including effector-like small secreted proteins (SSPs). Poorly conserved SSPs were more likely to be induced by symbiosis, suggesting that they may be a class of protein that tune host specificity. The Pisolithus gene repertoire is characterized by divergent CAZyme profiles when compared to other fungi, both symbiotic and saprotrophic. This was driven by differences in enzymes associated with symbiotic sugar processing, although metabolomic analysis suggest that neither copy number nor expression of these genes is sufficient to predict sugar capture from a host plant or its metabolism in fungal hyphae. Our results demonstrate that intra-genus genomic and functional diversity within ectomycorrhizal fungi is greater than previously thought, underlining the importance of continued comparative studies within the fungal tree of life to refine our focus on pathways and evolutionary processes foundational to this symbiotic lifestyle.PMID:36811946 | DOI:10.1093/molbev/msad045

Am J Clin Nutr. 2022 Dec 20:S0002-9165(22)10526-5. doi: 10.1016/j.ajcnut.2022.10.015. Online ahead of print.ABSTRACTBACKGROUND: Periodic prolonged fasting (PF) extends lifespan in model organisms and ameliorates multiple disease states both clinically and experimentally owing, in part, to its ability to modulate the immune system. However, the relationship between metabolic factors, immunity, and longevity during PF remains poorly characterized especially in humans.OBJECTIVE: This study aimed to observe the effects of PF in human subjects on the clinical and experimental markers of metabolic and immune health and uncover underlying plasma-borne factors that may be responsible for these effects.METHODS: In this rigorously controlled pilot study (ClinicalTrial.gov identifier, NCT03487679), 20 young males and females participated in a 3-d study protocol including assessments of 4 distinct metabolic states: 1) overnight fasted baseline state, 2) 2-h postprandial fed state, 3) 36-h fasted state, and 4) final 2-h postprandial re-fed state 12 h after the 36-h fasting period. Clinical and experimental markers of immune and metabolic health were assessed for each state along with comprehensive metabolomic profiling of participant plasma. Bioactive metabolites identified to be upregulated in circulation after 36 h of fasting were then assessed for their ability to mimic the effects of fasting in isolated human macrophage as well as the ability to extend lifespan in Caenorhabditis elegans.RESULTS: We showed that PF robustly altered the plasma metabolome and conferred beneficial immunomodulatory effects on human macrophages. We also identified 4 bioactive metabolites that were upregulated during PF (spermidine, 1-methylnicotinamide, palmitoylethanolamide, and oleoylethanolamide) that could replicate these immunomodulatory effects. Furthermore, we found that these metabolites and their combination significantly extended the median lifespan of C. elegans by as much as 96%.CONCLUSIONS: The results of this study reveal multiple functionalities and immunological pathways affected by PF in humans, identify candidates for the development of fasting mimetic compounds, and uncover targets for investigation in longevity research.PMID:36811567 | DOI:10.1016/j.ajcnut.2022.10.015

Am J Clin Nutr. 2023 Jan 7:S0002-9165(23)00002-3. doi: 10.1016/j.ajcnut.2023.01.001. Online ahead of print.ABSTRACTBACKGROUND: Elevated BCAA levels are strongly associated with diabetes, but how diabetes affects BCAA, branched-chain ketoacids (BCKAs), and the broader metabolome after a meal is not well known.OBJECTIVE: To compare quantitative BCAA and BCKA levels in a multiracial cohort with and without diabetes after a mixed meal tolerance test (MMTT) as well as to explore the kinetics of additional metabolites and their associations with mortality in self-identified African Americans.METHODS: We administered an MMTT to 11 participants without obesity or diabetes and 13 participants with diabetes (treated with metformin only) and measured the levels of BCKAs, BCAAs, and 194 other metabolites at 8 time points across 5 h. We used mixed models for repeated measurements to compare between group metabolite differences at each timepoint with adjustment for baseline. We then evaluated the association of top metabolites with different kinetics with all-cause mortality in the Jackson Heart Study (JHS) (N = 2441).RESULTS: BCAA levels, after adjustment for baseline, were similar at all timepoints between groups, but adjusted BCKA kinetics were different between groups for α-ketoisocaproate (P = 0.022) and α-ketoisovalerate (P = 0.021), most notably diverging at 120 min post-MMTT. An additional 20 metabolites had significantly different kinetics across timepoints between groups, and 9 of these metabolites-including several acylcarnitines-were significantly associated with mortality in JHS, irrespective of diabetes status. The highest quartile of a composite metabolite risk score was associated with higher mortality (HR:1.57; 1.20, 2.05, P = 0.00094) than the lowest quartile.CONCLUSIONS: BCKA levels remained elevated after an MMTT among participants with diabetes, suggesting that BCKA catabolism may be a key dysregulated process in the interaction of BCAA and diabetes. Metabolites with different kinetics after an MMTT may be markers of dysmetabolism and associated with increased mortality in self-identified African Americans.PMID:36811472 | DOI:10.1016/j.ajcnut.2023.01.001

Hepatology. 2023 Feb 23. doi: 10.1097/HEP.0000000000000341. Online ahead of print.ABSTRACTHepatocytes work in highly structured, repetitive hepatic lobules. Blood flow across the radial axis of the lobule generates oxygen, nutrient, and hormone gradients that result in zoned spatial variability and functional diversity. This large heterogeneity suggests that hepatocytes in different lobule zones may have distinct gene expression profiles, metabolic features, regenerative capacity, and susceptibility to damage. Here, we describe the principles of liver zonation, introduce metabolomic approaches to study the spatial heterogeneity of the liver, and highlight the possibility of exploring the spatial metabolic profile leading to a deeper understanding of the tissue metabolic organization. Spatial metabolomics can also reveal intercellular heterogeneity and its contribution to liver disease. These approaches facilitate the global characterization of liver metabolic function with high spatial resolution along physiological and pathological time scales. This review summarizes the state of the art for spatially resolved metabolomic analysis and the challenges that hinder the achievement of metabolome coverage at the single-cell level. We also discuss several major contributions to the understanding of liver spatial metabolism and conclude with our opinion on future developments and applications of these exciting new technologies.PMID:36811413 | DOI:10.1097/HEP.0000000000000341

Hepatology. 2023 Feb 23. doi: 10.1097/HEP.0000000000000316. Online ahead of print.ABSTRACTBACKGROUND AIMS: Patients with compensated cirrhosis with clinically significant portal hypertension (CSPH: HVPG >10 mmHg) have a high risk of decompensation. HVPG is, however, an invasive procedure not available in all centers. The present study aims to assess whether metabolomics can improve the capacity of clinical models in predicting clinical outcome in these compensated patients.APPROACH RESULTS: This is a nested study from the PREDESCI cohort (a RCT of non-selective beta blockers (NSBB) versus placebo in 201 patients with compensated cirrhosis and CSPH) including 167 patients for whom a blood sample was collected. A targeted metabolomic serum analysis, using UHPLC-MS, was performed. Metabolites underwent univariate time-to event cox regression analysis. Top ranked metabolites were selected using LogRank P-value to generate a stepwise cox model. Comparison between models was done using DeLong's test. Eighty-two patients with CSPH were randomized to NSBB and 85 to placebo. Thirty-three patients developed the main endpoint (decompensation/liver-related death). The model including HVPG, Child-Pugh and treatment received (HVPG/Clinical model) had a C-index of 0.748 [CI95% 0.664-0.827]. Addition of two metabolites, Ceramide (d18:1/22:0) and Methionine (HVPG/Clinical/Metabolite model) significantly improved model's performance (C-index of 0.808 [CI95% 0.735-0.882]; P=0.032). The combination of these two metabolites together with Child-Pugh and type of treatment received (Clinical/Metabolite model) had a C-Index of 0.785 [CI95% 0.710-0.860] not significantly different from the HVPG based models including or not metabolites.CONCLUSIONS: In patients with compensated cirrhosis and CSPH, metabolomics improves the capacity of clinical models and achieves similar predictive capacity than models including HVPG.PMID:36811400 | DOI:10.1097/HEP.0000000000000316

Cancer Rep (Hoboken). 2023 Feb 21:e1795. doi: 10.1002/cnr2.1795. Online ahead of print.ABSTRACTBACKGROUND: Oncogenic transformation alters intracellular metabolism and contributes to the growth of malignant cells. Metabolomics, or the study of small molecules, can reveal insight about cancer progression that other biomarker studies cannot. Number of metabolites involved in this process have been in spotlight for cancer detection, monitoring, and therapy.RECENT FINDINGS: In this review, the "Metabolomics" is defined in terms of current technology having both clinical and translational applications. Researchers have shown metabolomics can be used to discern metabolic indicators non-invasively using different analytical methods like positron emission tomography, magnetic resonance spectroscopic imaging etc. Metabolomic profiling is a powerful and technically feasible way to track changes in tumor metabolism and gauge treatment response across time. Recent studies have shown metabolomics can also predict individual metabolic changes in response to cancer treatment, measure medication efficacy, and monitor drug resistance. Its significance in cancer development and treatment is summarized in this review.CONCLUSION: Although in infancy, metabolomics can be used to identify treatment options and/or predict responsiveness to cancer treatments. Technical challenges like database management, cost and methodical knowhow still persist. Overcoming these challenges in near further can help in designing new treatment régimes with increased sensitivity and specificity.PMID:36811317 | DOI:10.1002/cnr2.1795

Alzheimers Dement. 2023 Feb 22. doi: 10.1002/alz.12969. Online ahead of print.ABSTRACTINTRODUCTION: Recent studies revealed the association of abnormal methylomic changes with Alzheimer's disease (AD) but there is a lack of systematic study of the impact of methylomic alterations over the molecular networks underlying AD.METHODS: We profiled genome-wide methylomic variations in the parahippocampal gyrus from 201 post mortem control, mild cognitive impaired, and AD brains.RESULTS: We identified 270 distinct differentially methylated regions (DMRs) associated with AD. We quantified the impact of these DMRs on each gene and each protein as well as gene and protein co-expression networks. DNA methylation had a profound impact on both AD-associated gene/protein modules and their key regulators. We further integrated the matched multi-omics data to show the impact of DNA methylation on chromatin accessibility, which further modulates gene and protein expression.DISCUSSION: The quantified impact of DNA methylation on gene and protein networks underlying AD identified potential upstream epigenetic regulators of AD.HIGHLIGHTS: A cohort of DNA methylation data in the parahippocampal gyrus was developed from 201 post mortem control, mild cognitive impaired, and Alzheimer's disease (AD) brains. Two hundred seventy distinct differentially methylated regions (DMRs) were found to be associated with AD compared to normal control. A metric was developed to quantify methylation impact on each gene and each protein. DNA methylation was found to have a profound impact on not only the AD-associated gene modules but also key regulators of the gene and protein networks. Key findings were validated in an independent multi-omics cohort in AD. The impact of DNA methylation on chromatin accessibility was also investigated by integrating the matched methylomic, epigenomic, transcriptomic, and proteomic data.PMID:36811307 | DOI:10.1002/alz.12969

APMIS. 2023 Feb 21. doi: 10.1111/apm.13302. Online ahead of print.ABSTRACTType 1 diabetes (T1D) is an autoimmune disease with rising incidence. Pre- and manifest T1D is associated with intestinal barrier dysfunction, skewed microbiota composition, and serum dyslipidemia. The intestinal mucus layer protects against pathogens and its structure and phosphatidylcholine (PC) lipid composition may be compromised in T1D, potentially contributing to barrier dysfunction. This study compared pre-diabetic Non-Obese Diabetic (NOD) mice to healthy C57BL/6 mice by analyzing the intestinal mucus PC profile by shotgun lipidomics, plasma metabolomics by mass spectrometry and nuclear magnetic resonance, intestinal mucus production by histology, and cecal microbiota composition by 16S rRNA sequencing. Jejunal mucus PC class levels were decreased in early pre-diabetic NOD vs C57BL/6 mice. In colonic mucus of NOD mice, the level of several PC species was reduced throughout pre-diabetes. In plasma, similar reductions of PC species were observed in early pre-diabetic NOD mice, where also increased beta-oxidation was prominent. No histological alterations were found in jejunal nor colonic mucus between the mouse strains. However, the β-diversity of the cecal microbiota composition differed between pre-diabetic NOD and C57BL/6 mice, and the bacterial species driving this difference were related to decreased short-chain fatty acid (SCFA)-production in the NOD mice. This study reports reduced levels of PCs in the intestinal mucus layer and plasma of pre-diabetic NOD mice as well as reduced proportions of SCFA-producing bacteria in cecal content at early pre-diabetes, possibly contributing to intestinal barrier dysfunction and T1D.PMID:36811202 | DOI:10.1111/apm.13302