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

Early IGF-1 receptor inhibition in mice mimics preterm human brain disorders and reveals a therapeutic target

Fri, 01/03/2024 - 12:00
Sci Adv. 2024 Mar;10(9):eadk8123. doi: 10.1126/sciadv.adk8123. Epub 2024 Mar 1.ABSTRACTBesides recent advances in neonatal care, preterm newborns still develop sex-biased behavioral alterations. Preterms fail to receive placental insulin-like growth factor-1 (IGF-1), a major fetal growth hormone in utero, and low IGF-1 serum levels correlate with preterm poor neurodevelopmental outcomes. Here, we mimicked IGF-1 deficiency of preterm newborns in mice by perinatal administration of an IGF-1 receptor antagonist. This resulted in sex-biased brain microstructural, functional, and behavioral alterations, resembling those of ex-preterm children, which we characterized performing parallel mouse/human behavioral tests. Pharmacological enhancement of GABAergic tonic inhibition by the U.S. Food and Drug Administration-approved drug ganaxolone rescued functional/behavioral alterations in mice. Establishing an unprecedented mouse model of prematurity, our work dissects the mechanisms at the core of abnormal behaviors and identifies a readily translatable therapeutic strategy for preterm brain disorders.PMID:38427732 | DOI:10.1126/sciadv.adk8123

High-Throughput Lipidomic and Metabolomic Profiling for Brain Tissue and Biofluid Samples in Neurodegenerative Disorders

Fri, 01/03/2024 - 12:00
Methods Mol Biol. 2024;2785:221-260. doi: 10.1007/978-1-0716-3774-6_14.ABSTRACTRecent research has revealed the potential of lipidomics and metabolomics in identifying new biomarkers and mechanistic insights for neurodegenerative disorders. To contribute to this promising area, we present a detailed protocol for conducting an integrated lipidomic and metabolomic profiling of brain tissue and biofluid samples. In this method, a single-phase methanol extraction is employed for extracting both nonpolar and highly polar lipids and metabolites from each biological sample. The extracted samples are then subjected to liquid chromatography-mass spectrometry-based assays to provide relative or semiquantitative measurements for hundreds of selected lipids and metabolites per sample. This high-throughput approach enables the generation of new hypotheses regarding the mechanistic and functional significance of lipid and metabolite alterations in neurodegenerative disorders while also facilitating the discovery of new biomarkers to support drug development.PMID:38427197 | DOI:10.1007/978-1-0716-3774-6_14

Mass Spectrometry-Based Metabolomics Multi-platform for Alzheimer's Disease Research

Fri, 01/03/2024 - 12:00
Methods Mol Biol. 2024;2785:75-86. doi: 10.1007/978-1-0716-3774-6_6.ABSTRACTThe integration of complementary analytical platforms is nowadays the most common strategy for comprehensive metabolomics analysis of complex biological systems. In this chapter, we describe methods and tips for the application of a mass spectrometry multi-platform in Alzheimer's disease research, based on the combination of direct mass spectrometry and orthogonal hyphenated approaches, namely, reversed-phase ultrahigh-performance liquid chromatography and gas chromatography. These procedures have been optimized for the analysis of multiple biological samples from human patients and transgenic animal models, including blood serum, various brain regions (e.g., hippocampus, cortex, cerebellum, striatum, olfactory bulbs), and other peripheral organs (e.g., liver, kidney, spleen, thymus).PMID:38427189 | DOI:10.1007/978-1-0716-3774-6_6

An exploratory investigation of the CSF metabolic profile of HIV in a South African paediatric cohort using GCxGC-TOF/MS

Fri, 01/03/2024 - 12:00
Metabolomics. 2024 Mar 1;20(2):33. doi: 10.1007/s11306-024-02098-y.ABSTRACTINTRODUCTION: Because cerebrospinal fluid (CSF) samples are difficult to obtain for paediatric HIV, few studies have attempted to profile neurometabolic dysregulation.AIM AND OBJECTIVE: The aim of this exploratory study was to profile the neurometabolic state of CSF from a South African paediatric cohort using GCxGC-TOF/MS. The study included 54 paediatric cases (< 12 years), 42 HIV-negative controls and 12 HIV-positive individuals.RESULTS: The results revealed distinct metabolic alterations in the HIV-infected cohort. In the PLS-DA model, 18 metabolites significantly discriminated between HIV-infected and control groups. In addition, fold-change analysis, Mann-Whitney U tests, and effect size measurements verified these findings. Notably, lactose, myo-inositol, and glycerol, although not significant by p-value alone, demonstrated practical significance based on the effect size.CONCLUSIONS: This study provided valuable insights on the impact of HIV on metabolic pathways, including damage to the gut and blood-brain barrier, disruption of bioenergetics processes, gliosis, and a potential marker for antiretroviral therapy. Nevertheless, the study recognized certain constraints, notably a limited sample size and the absence of a validation cohort. Despite these limitations, the rarity of the study's focus on paediatric HIV research underscores the significance and unique contributions of its findings.PMID:38427142 | DOI:10.1007/s11306-024-02098-y

Research progress on the multi-omics and survival status of circulating tumor cells

Fri, 01/03/2024 - 12:00
Clin Exp Med. 2024 Mar 1;24(1):49. doi: 10.1007/s10238-024-01309-z.ABSTRACTIn the dynamic process of metastasis, circulating tumor cells (CTCs) emanate from the primary solid tumor and subsequently acquire the capacity to disengage from the basement membrane, facilitating their infiltration into the vascular system via the interstitial tissue. Given the pivotal role of CTCs in the intricate hematogenous metastasis, they have emerged as an essential resource for a deeper comprehension of cancer metastasis while also serving as a cornerstone for the development of new indicators for early cancer screening and new therapeutic targets. In the epoch of precision medicine, as CTC enrichment and separation technologies continually advance and reach full fruition, the domain of CTC research has transcended the mere straightforward detection and quantification. The rapid advancement of CTC analysis platforms has presented a compelling opportunity for in-depth exploration of CTCs within the bloodstream. Here, we provide an overview of the current status and research significance of multi-omics studies on CTCs, including genomics, transcriptomics, proteomics, and metabolomics. These studies have contributed to uncovering the unique heterogeneity of CTCs and identifying potential metastatic targets as well as specific recognition sites. We also review the impact of various states of CTCs in the bloodstream on their metastatic potential, such as clustered CTCs, interactions with other blood components, and the phenotypic states of CTCs after undergoing epithelial-mesenchymal transition (EMT). Within this context, we also discuss the therapeutic implications and potential of CTCs.PMID:38427120 | DOI:10.1007/s10238-024-01309-z

Metabolic effect of adrenaline infusion in people with type 1 diabetes and healthy individuals

Fri, 01/03/2024 - 12:00
Diabetologia. 2024 Mar 1. doi: 10.1007/s00125-024-06116-5. Online ahead of print.ABSTRACTAIMS/HYPOTHESIS: As a result of early loss of the glucagon response, adrenaline is the primary counter-regulatory hormone in type 1 diabetes. Diminished adrenaline responses to hypoglycaemia due to counter-regulatory failure are common in type 1 diabetes, and are probably induced by exposure to recurrent hypoglycaemia, however, the metabolic effects of adrenaline have received less research attention, and also there is conflicting evidence regarding adrenaline sensitivity in type 1 diabetes. Thus, we aimed to investigate the metabolic response to adrenaline and explore whether it is modified by prior exposure to hypoglycaemia.METHODS: Eighteen participants with type 1 diabetes and nine healthy participants underwent a three-step ascending adrenaline infusion during a hyperinsulinaemic-euglycaemic clamp. Continuous glucose monitoring data obtained during the week before the study day were used to assess the extent of hypoglycaemia exposure.RESULTS: While glucose responses during the clamp were similar between people with type 1 diabetes and healthy participants, plasma concentrations of NEFAs and glycerol only increased in the group with type 1 diabetes (p<0.001). Metabolomics revealed an increase in the most common NEFAs (p<0.01). Other metabolic responses were generally similar between participants with type 1 diabetes and healthy participants. Exposure to hypoglycaemia was negatively associated with the NEFA response; however, this was not statistically significant.CONCLUSIONS/INTERPRETATION: In conclusion, individuals with type 1 diabetes respond with increased lipolysis to adrenaline compared with healthy participants by mobilising the abundant NEFAs in plasma, whereas other metabolic responses were similar. This may suggest that the metabolic sensitivity to adrenaline is altered in a pathway-specific manner in type 1 diabetes.TRIAL REGISTRATION: ClinicalTrials.gov NCT05095259.PMID:38427076 | DOI:10.1007/s00125-024-06116-5

Characterizing Metabolic Heterogeneity of Hepatocellular Carcinoma with Hyperpolarized <sup>13</sup>C Pyruvate MRI and Mass Spectrometry

Fri, 01/03/2024 - 12:00
Radiol Imaging Cancer. 2024 Mar;6(2):e230056. doi: 10.1148/rycan.230056.ABSTRACTPurpose To characterize the metabolomic profiles of two hepatocellular carcinoma (HCC) rat models, track evolution of these profiles to a stimulated tumor state, and assess their effect on lactate flux with hyperpolarized (HP) carbon 13 (13C) MRI. Materials and Methods Forty-three female adult Fischer rats were implanted with N1S1 or McA-RH7777 HCC tumors. In vivo lactate-to-pyruvate ratio (LPR) was measured with HP 13C MRI at 9.4 T. Ex vivo mass spectrometry was used to measure intratumoral metabolites, and Ki67 labeling was used to quantify proliferation. Tumors were first compared with three normal liver controls. The tumors were then compared with stimulated variants via off-target hepatic thermal ablation treatment. All comparisons were made using the Mann-Whitney test. Results HP 13C pyruvate MRI showed greater LPR in N1S1 tumors compared with normal liver (mean [SD], 0.564 ± 0.194 vs 0.311 ± 0.057; P < .001 [n = 9]), but not for McA-RH7777 (P = .44 [n = 8]). Mass spectrometry confirmed that the glycolysis pathway was increased in N1S1 tumors and decreased in McA-RH7777 tumors. The pentose phosphate pathway was also decreased only in McA-RH7777 tumors. Increased proliferation in stimulated N1S1 tumors corresponded to a net increase in LPR (six stimulated vs six nonstimulated, 0.269 ± 0.148 vs 0.027 ± 0.08; P = .009), but not in McA-RH7777 (eight stimulated vs six nonstimulated, P = .13), despite increased proliferation and metastases. Mass spectrometry demonstrated relatively increased lactate production with stimulation in N1S1 tumors only. Conclusion Two HCC subtypes showed divergent glycolytic dependency at baseline and during transformation to a high proliferation state. This metabolic heterogeneity in HCC should be considered with use of HP 13C MRI for diagnosis and tracking. Keywords: Molecular Imaging-Probe Development, Liver, Abdomen/GI, Oncology, Hepatocellular Carcinoma © RSNA, 2024 See also commentary by Ohliger in this issue.PMID:38426887 | DOI:10.1148/rycan.230056

The timing of bacterial mesophyll infection shapes the leaf chemical landscape

Fri, 01/03/2024 - 12:00
Microbiol Spectr. 2024 Mar 1:e0413823. doi: 10.1128/spectrum.04138-23. Online ahead of print.ABSTRACTChemistry in eukaryotic intercellular spaces is shaped by both hosts and symbiotic microorganisms such as bacteria. Pathogenic microorganisms like barley-associated Xanthomonas translucens (Xt) swiftly overtake the inner leaf tissue becoming the dominant microbial community member during disease development. The dynamic metabolic changes due to Xt pathogenesis in the mesophyll spaces remain unknown. Genomic group I of Xt consists of two barley-infecting lineages: pathovar translucens (Xtt) and pathovar undulosa (Xtu). Xtu and Xtt, although genomically distinct, cause similar water-soaked lesions. To define the metabolic signals associated with inner leaf colonization, we used untargeted metabolomics to characterize Xtu and Xtt metabolism signatures associated with mesophyll growth. We found that mesophyll apoplast fluid from infected tissue yielded a distinct metabolic profile and shift from catabolic to anabolic processes over time compared to water-infiltrated control. The pathways with the most differentially expressed metabolites by time were glycolysis, tricarboxylic acid cycle, sucrose metabolism, pentose interconversion, amino acids, galactose, and purine metabolism. Hierarchical clustering and principal component analysis showed that metabolic changes were more affected by the time point rather than the individual colonization of the inner leaves by Xtt compared to Xtu. Overall, in this study, we identified metabolic pathways that explain carbon and nitrogen usage during host-bacterial interactions over time for mesophyll tissue colonization. This foundational research provides initial insights into shared metabolic strategies of inner leaf colonization niche occupation by related but phylogenetically distinct phyllosphere bacteria.IMPORTANCE: The phyllosphere is a habitat for microorganisms including pathogenic bacteria. Metabolic shifts in the inner leaf spaces for most plant-microbe interactions are unknown, especially for Xanthomonas species in understudied plants like barley (Hordeum vulgare). Xanthomonas translucens pv. translucens (Xtt) and Xanthomonas translucens pv. undulosa (Xtu) are phylogenomically distinct, but both colonize barley leaves for pathogenesis. In this study, we used untargeted metabolomics to shed light on Xtu and Xtt metabolic signatures. Our findings revealed a dynamic metabolic landscape that changes over time, rather than exhibiting a pattern associated with individual pathovars. These results provide initial insights into the metabolic mechanisms of X. translucens inner leaf pathogenesis.PMID:38426767 | DOI:10.1128/spectrum.04138-23

GC-MS-based Metabolomics Unravels Metabolites across Larval Development and Diapause of a Specialist Insect

Fri, 01/03/2024 - 12:00
Chem Biodivers. 2024 Mar 1:e202301779. doi: 10.1002/cbdv.202301779. Online ahead of print.ABSTRACTPlant-insect interactions are a driving force into ecosystem evolution and community dynamics. Many insect herbivores enter diapause, a developmental arrest stage in anticipation of adverse conditions, to survive and thrive through seasonal changes. Herein, we investigated the roles of medium- to non-polar metabolites during larval development and diapause in a specialist insect herbivore, Chlosyne lacinia, reared on Aldama robusta leaves. Varying metabolites were determined using gas chromatography-mass spectrometry (GC-MS)-based metabolomics. Sesquiterpenes and steroids were the main metabolites putatively identified in A. robusta leaves, whereas C. lacinia caterpillars were characterized by triterpenes, steroids, fatty acids, and long-chain alkanes. We found out that C. lacinia caterpillars biosynthesized most of the identified steroids and fatty acids from plant-derived ingested metabolites, as well as all triterpenes and long-chain alkanes. Steroids, fatty acids, and long-chain alkanes were detected across all C. lacinia instars and in diapausing caterpillars. Sesquiterpenes and triterpenes were also detected across larval development, yet they were not detected in diapausing caterpillars, which suggested that these metabolites were converted to other molecules prior to the diapause stage. Our findings shed light on the chemical content variation across C. lacinia development and diapause, providing insights into the roles of metabolites in plant-insect interactions.PMID:38426669 | DOI:10.1002/cbdv.202301779

Ion entropy and accurate entropy-based FDR estimation in metabolomics

Fri, 01/03/2024 - 12:00
Brief Bioinform. 2024 Jan 22;25(2):bbae056. doi: 10.1093/bib/bbae056.ABSTRACTAccurate metabolite annotation and false discovery rate (FDR) control remain challenging in large-scale metabolomics. Recent progress leveraging proteomics experiences and interdisciplinary inspirations has provided valuable insights. While target-decoy strategies have been introduced, generating reliable decoy libraries is difficult due to metabolite complexity. Moreover, continuous bioinformatics innovation is imperative to improve the utilization of expanding spectral resources while reducing false annotations. Here, we introduce the concept of ion entropy for metabolomics and propose two entropy-based decoy generation approaches. Assessment of public databases validates ion entropy as an effective metric to quantify ion information in massive metabolomics datasets. Our entropy-based decoy strategies outperform current representative methods in metabolomics and achieve superior FDR estimation accuracy. Analysis of 46 public datasets provides instructive recommendations for practical application.PMID:38426325 | DOI:10.1093/bib/bbae056

Metabolomic Association and Risk Prediction With Heart Failure in Older Adults

Fri, 01/03/2024 - 12:00
Circ Heart Fail. 2024 Mar 1:e010896. doi: 10.1161/CIRCHEARTFAILURE.123.010896. Online ahead of print.ABSTRACTBACKGROUND: Older adults have markedly increased risks of heart failure (HF), specifically HF with preserved ejection fraction (HFpEF). Identifying novel biomarkers can help in understanding HF pathogenesis and improve at-risk population identification. This study aimed to identify metabolites associated with incident HF, HFpEF, and HF with reduced ejection fraction and examine risk prediction in older adults.METHODS: Untargeted metabolomic profiling was performed in Black and White adults from the ARIC study (Atherosclerosis Risk in Communities) visit 5 (n=3719; mean age, 75 years). We applied Cox regressions to identify metabolites associated with incident HF and its subtypes. The metabolite risk score (MRS) was constructed and examined for associations with HF, echocardiographic measures, and HF risk prediction. Independent samples from visit 3 (n=1929; mean age, 58 years) were used for replication.RESULTS: Sixty metabolites (hazard ratios range, 0.79-1.49; false discovery rate, <0.05) were associated with incident HF after adjusting for clinical risk factors, eGFR, and NT-proBNP (N-terminal pro-B-type natriuretic peptide). Mannonate, a hydroxy acid, was replicated (hazard ratio, 1.36 [95% CI, 1.19-1.56]) with full adjustments. MRS was associated with an 80% increased risk of HF per SD increment, and the highest MRS quartile had 8.7× the risk of developing HFpEF than the lowest quartile. High MRS was also associated with unfavorable values of cardiac structure and function. Adding MRS over clinical risk factors and NT-proBNP improved 5-year HF risk prediction C statistics from 0.817 to 0.850 (∆C, 0.033 [95% CI, 0.017-0.047]). The association between MRS and incident HF was replicated after accounting for clinical risk factors (P<0.05).CONCLUSIONS: Novel metabolites associated with HF risk were identified, elucidating disease pathways, specifically HFpEF. An MRS was associated with HF risk and improved 5-year risk prediction in older adults, which may assist at at-risk population identification.PMID:38426319 | DOI:10.1161/CIRCHEARTFAILURE.123.010896

Metabolomic Insights in Risks of Developing Heart Failure: A New Frontier

Fri, 01/03/2024 - 12:00
Circ Heart Fail. 2024 Mar 1:e011482. doi: 10.1161/CIRCHEARTFAILURE.124.011482. Online ahead of print.NO ABSTRACTPMID:38426300 | DOI:10.1161/CIRCHEARTFAILURE.124.011482

Transforming Big Data into AI-ready data for nutrition and obesity research

Fri, 01/03/2024 - 12:00
Obesity (Silver Spring). 2024 Mar 1. doi: 10.1002/oby.23989. Online ahead of print.ABSTRACTOBJECTIVE: Big Data are increasingly used in obesity and nutrition research to gain new insights and derive personalized guidance; however, this data in raw form are often not usable. Substantial preprocessing, which requires machine learning (ML), human judgment, and specialized software, is required to transform Big Data into artificial intelligence (AI)- and ML-ready data. These preprocessing steps are the most complex part of the entire modeling pipeline. Understanding the complexity of these steps by the end user is critical for reducing misunderstanding, faulty interpretation, and erroneous downstream conclusions.METHODS: We reviewed three popular obesity/nutrition Big Data sources: microbiome, metabolomics, and accelerometry. The preprocessing pipelines, specialized software, challenges, and how decisions impact final AI- and ML-ready products were detailed.RESULTS: Opportunities for advances to improve quality control, speed of preprocessing, and intelligent end user consumption were presented.CONCLUSIONS: Big Data have the exciting potential for identifying new modifiable factors that impact obesity research. However, to ensure accurate interpretation of conclusions arising from Big Data, the choices involved in preparing AI- and ML-ready data need to be transparent to investigators and clinicians relying on the conclusions.PMID:38426232 | DOI:10.1002/oby.23989

Liquid chromatography coupled to mass spectrometry metabolomic analysis of cerebrospinal fluid revealed the metabolic characteristics of moyamoya disease

Fri, 01/03/2024 - 12:00
Front Neurol. 2024 Feb 15;15:1298385. doi: 10.3389/fneur.2024.1298385. eCollection 2024.ABSTRACTOBJECTIVE: Metabolomics has found extensive applications in the field of neurological diseases, significantly contributing to their diagnosis and treatment. However, there has been limited research applying metabolomics to moyamoya disease (MMD). This study aims to investigate and identify differential metabolites associated with MMD.METHODS: We employed a liquid chromatography coupled with mass spectrometry (LC-MS) approach, complemented by univariate and multivariate analyses, to discern metabolic biomarkers in cerebrospinal fluid samples. We then compared these biomarkers between MMD patients and healthy controls (Ctl).RESULTS: Sixteen patients diagnosed with MMD via cerebral angiography and eight healthy controls were enrolled in this study. Comparative analyses, including univariate and multivariate analyses, correlation studies, heatmaps, Volcano Plots, and KEGG pathway enrichment, were performed between MMD patients and controls. As a result, we identified 129 significant differential metabolites in the cerebrospinal fluid between MMD patients and controls. These metabolic biomarkers are associated with various pathways, with notable involvement in purine and pyrimidine metabolism.CONCLUSION: Utilizing an LC-MS-based metabolomics approach holds promise for enhancing the clinical diagnosis of MMD. The identified biomarkers offer potential avenues for the development of novel diagnostic methods for MMD and offer fresh insights into the pathogenesis of the disease.PMID:38426176 | PMC:PMC10902010 | DOI:10.3389/fneur.2024.1298385

Effects of Caragana korshinskii tannin on fermentation, methane emission, community of methanogens, and metabolome of rumen in sheep

Fri, 01/03/2024 - 12:00
Front Microbiol. 2024 Feb 15;15:1334045. doi: 10.3389/fmicb.2024.1334045. eCollection 2024.ABSTRACTThe purpose of this research was to investigate the impact of dietary supplementation of Caragana korshinskii tannin (CKT) on rumen fermentation, methane emission, methanogen community and metabolome in rumen of sheep. A total of 15 crossbred sheep of the Dumont breed with similar body conditions, were divided into three groups (n = 5), which were fed with CKT addition at 0, 2 and 4%/kg DM. The study spanned a total of 74 days, with a 14-day period dedicated to adaptation and a subsequent 60-day period for conducting treatments. The results indicated that the levels of ammonia nitrogen (NH3-N) and acetate were reduced (p < 0.05) in rumen sheep fed with 2 and 4% CKT; The crude protein (CP) digestibility of sheep in 2 and 4% CKT groups was decreased(p < 0.05); while the neutral detergent fiber (NDF) digestibility was increased (p < 0.05) in 4% CKT group. Furthermore, the supplementation of CKT resulted in a decrease (p < 0.05) in daily CH4 emissions from sheep by reducing the richness and diversity of ruminal methanogens community, meanwhile decreasing (p < 0.05) concentrations of tyramine that contribute to methane synthesis and increasing (p < 0.05) concentrations of N-methy-L-glutamic acid that do not contribute to CH4 synthesis. However, CH4 production of DMI, OMI, NDFI and metabolic weight did not differ significantly across the various treatments. To sum up, the addition of 4% CKT appeared to be a viable approach for reducing CH4 emissions from sheep without no negative effects. These findings suggest that CKT hold promise in mitigating methane emissions of ruminant. Further investigation is required to evaluate it effectiveness in practical feeding strategies for livestock.PMID:38426060 | PMC:PMC10902071 | DOI:10.3389/fmicb.2024.1334045

Corrigendum: Functional metagenomic and metabolomics analysis of gut dysbiosis induced by hyperoxia

Fri, 01/03/2024 - 12:00
Front Microbiol. 2024 Feb 16;15:1382290. doi: 10.3389/fmicb.2024.1382290. eCollection 2024.ABSTRACT[This corrects the article DOI: 10.3389/fmicb.2023.1197970.].PMID:38426055 | PMC:PMC10904077 | DOI:10.3389/fmicb.2024.1382290

Biomarkers for assessing pain and pain relief in the neonatal intensive care unit

Fri, 01/03/2024 - 12:00
Front Pain Res (Lausanne). 2024 Feb 15;5:1343551. doi: 10.3389/fpain.2024.1343551. eCollection 2024.ABSTRACTNewborns admitted to the neonatal intensive care unit (NICU) regularly undergo painful procedures and may face various painful conditions such as postoperative pain. Optimal management of pain in these vulnerable preterm and term born neonates is crucial to ensure their comfort and prevent negative consequences of neonatal pain. This entails accurate and timely identification of pain, non-pharmacological pain treatment and if needed administration of analgesic therapy, evaluation of treatment effectiveness, and monitoring of adverse effects. Despite the widely recognized importance of pain management, pain assessment in neonates has thus far proven to be a challenge. As self-report, the gold standard for pain assessment, is not possible in neonates, other methods are needed. Several observational pain scales have been developed, but these often rely on snapshot and largely subjective observations and may fail to capture pain in certain conditions. Incorporation of biomarkers alongside observational pain scores holds promise in enhancing pain assessment and, by extension, optimizing pain treatment and neonatal outcomes. This review explores the possibilities of integrating biomarkers in pain assessment in the NICU.PMID:38426011 | PMC:PMC10902154 | DOI:10.3389/fpain.2024.1343551

Induced pluripotent stem cell-derived hepatocytes reveal TCA cycle disruption and the potential basis for triheptanoin treatment for malate dehydrogenase 2 deficiency

Fri, 01/03/2024 - 12:00
Mol Genet Metab Rep. 2024 Feb 23;39:101066. doi: 10.1016/j.ymgmr.2024.101066. eCollection 2024 Jun.ABSTRACTMitochondrial malate dehydrogenase 2 (MDH2) is crucial to cellular energy generation through direct participation in the tricarboxylic acid (TCA) cycle and the malate aspartate shuttle (MAS). Inherited MDH2 deficiency is an ultra-rare metabolic disease caused by bi-allelic pathogenic variants in the MDH2 gene, resulting in early-onset encephalopathy, psychomotor delay, muscular hypotonia and frequent seizures. Currently, there is no cure for this devastating disease. We recently reported symptomatic improvement of a three-year-old girl with MDH2 deficiency following treatment with the triglyceride triheptanoin. Here, we aimed to better characterize this disease and improve our understanding of the potential utility of triheptanoin treatment. Using fibroblasts derived from this patient, we generated induced pluripotent stem cells (hiPSCs) and differentiated them into hepatocytes (hiPSC-Heps). Characterization of patient-derived hiPSCs and hiPSC-Heps revealed significantly reduced MDH2 protein expression. Untargeted proteotyping of hiPSC-Heps revealed global dysregulation of mitochondrial proteins, including upregulation of TCA cycle and fatty acid oxidation enzymes. Metabolomic profiling confirmed TCA cycle and MAS dysregulation, and demonstrated normalization of malate, fumarate and aspartate following treatment with the triheptanoin components glycerol and heptanoate. Taken together, our results provide the first patient-derived hiPSC-Hep-based model of MDH2 deficiency, confirm altered TCA cycle function, and provide further evidence for the implementation of triheptanoin therapy for this ultra-rare disease.SYNOPSIS: This study reveals altered expression of mitochondrial pathways including the tricarboxylic acid cycle and changes in metabolite profiles in malate dehydrogenase 2 deficiency and provides the molecular basis for triheptanoin treatment in this ultra-rare disease.PMID:38425868 | PMC:PMC10900122 | DOI:10.1016/j.ymgmr.2024.101066

Time-restricted feeding restores metabolic flexibility in adult mice with excess adiposity

Fri, 01/03/2024 - 12:00
Front Nutr. 2024 Feb 15;11:1340735. doi: 10.3389/fnut.2024.1340735. eCollection 2024.ABSTRACTINTRODUCTION: Obesity is prevalent with the adult population in the United States. Energy-dense diets and erratic eating behavior contribute to obesity. Time-restricted eating is a dietary strategy in humans that has been advanced to reduce the propensity for obesity. We hypothesized that time-restricted feeding (TRF) would improve metabolic flexibility and normalize metabolic function in adult mice with established excess adiposity.METHODS: Male C57BL/6NHsd mice were initially fed a high-fat diet (HFD) for 12 weeks to establish excess body adiposity, while control mice were fed a normal diet. Then, the HFD-fed mice were assigned to two groups, either ad libitum HFD or TRF of the HFD in the dark phase (12 h) for another 12 weeks.RESULTS AND DISCUSSION: Energy intake and body fat mass were similar in TRF and HFD-fed mice. TRF restored rhythmic oscillations of respiratory exchange ratio (RER), which had been flattened by the HFD, with greater RER amplitude in the dark phase. Insulin sensitivity was improved and plasma cholesterol and hepatic triacylglycerol were decreased by TRF. When compared to HFD, TRF decreased transcription of circadian genes Per1 and Per2 and genes encoding lipid metabolism (Acaca, Fads1, Fads2, Fasn, Scd1, and Srebf1) in liver. Metabolomic analysis showed that TRF created a profile that was distinct from those of mice fed the control diet or HFD, particularly in altered amino acid profiles. These included aminoacyl-tRNA-biosynthesis, glutathione metabolism, and phenylalanine, tyrosine, and tryptophan biosynthesis pathways. In conclusion, TRF improved metabolic function in adult mice with excess adiposity. This improvement was not through a reduction in body fat mass but through the restoration of metabolic flexibility.PMID:38425486 | PMC:PMC10902009 | DOI:10.3389/fnut.2024.1340735

Association of tryptophan pathway metabolites with mortality and effectiveness of nutritional support among patients at nutritional risk: secondary analysis of a randomized clinical trial

Fri, 01/03/2024 - 12:00
Front Nutr. 2024 Feb 15;11:1335242. doi: 10.3389/fnut.2024.1335242. eCollection 2024.ABSTRACTTryptophan is an essential amino acid and is the precursor of many important metabolites and neurotransmitters. In malnutrition, the availability of tryptophan is reduced, potentially putting patients at increased risks. Herein, we investigated the prognostic implications of the tryptophan metabolism in a secondary analysis of the Effect of Early Nutritional Support on Frailty, Functional Outcomes, and Recovery of Malnourished Medical Inpatients Trial (EFFORT), a randomized, controlled trial comparing individualized nutritional support to usual care in patients at risk for malnutrition. Among 238 patients with available measurements, low plasma levels of metabolites were independently associated with 30-day mortality with adjusted hazard ratios (HR) of 1.77 [95% CI 1.05-2.99, p 0.034] for tryptophan, 3.49 [95% CI 1.81-6.74, p < 0.001] for kynurenine and 2.51 [95% CI 1.37-4.63, p 0.003] for serotonin. Nutritional support had more beneficial effects on mortality in patients with high tryptophan compared to patients with low tryptophan levels (adjusted HR 0.61 [95% CI 0.29-1.29] vs. HR 1.72 [95% CI 0.79-3.70], p for interaction 0.047). These results suggest that sufficient circulating levels of tryptophan might be a metabolic prerequisite for the beneficial effect of nutritional interventions in this highly vulnerable patient population.PMID:38425485 | PMC:PMC10902466 | DOI:10.3389/fnut.2024.1335242

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