PubMed

Nat Rev Immunol. 2023 Oct 13. doi: 10.1038/s41577-023-00949-8. Online ahead of print.ABSTRACTAlthough there is little direct evidence supporting that stress affects cancer incidence, it does influence the evolution, dissemination and therapeutic outcomes of neoplasia, as shown in human epidemiological analyses and mouse models. The experience of and response to physiological and psychological stressors can trigger neurological and endocrine alterations, which subsequently influence malignant (stem) cells, stromal cells and immune cells in the tumour microenvironment, as well as systemic factors in the tumour macroenvironment. Importantly, stress-induced neuroendocrine changes that can regulate immune responses have been gradually uncovered. Numerous stress-associated immunomodulatory molecules (SAIMs) can reshape natural or therapy-induced antitumour responses by engaging their corresponding receptors on immune cells. Moreover, stress can cause systemic or local metabolic reprogramming and change the composition of the gastrointestinal microbiota which can indirectly modulate antitumour immunity. Here, we explore the complex circuitries that link stress to perturbations in the cancer-immune dialogue and their implications for therapeutic approaches to cancer.PMID:37833492 | DOI:10.1038/s41577-023-00949-8

J Comp Physiol B. 2023 Oct 13. doi: 10.1007/s00360-023-01518-0. Online ahead of print.ABSTRACTMelatonin is a multifunctional bioactive molecule present in almost all organisms and has been gradually used in the aquaculture industry in recent years. Energy metabolism is an essential process for individuals to maintain their life activities; however, the process through which melatonin regulates energy metabolism in aquatic animals remains unclear. The present study aimed to conduct a comprehensive analysis of the regulatory mechanism of melatonin for energy metabolism in Cherax destructor by combining metabolomics analysis with the detection of the key substance content, enzymatic activity, and gene expression levels in the energy metabolism process after culturing with dietary melatonin supplementation for 8 weeks. Our results showed that dietary melatonin increased the content of glycogen, triglycerides, and free fatty acids; decreased lactate levels; and promoted the enzymatic activity of pyruvate kinase (PK), malate dehydrogenase (MDH), and acetyl-CoA carboxylase. The results of gene expression analysis showed that dietary melatonin also increased the expression levels of hexokinase, PK, MDH, lactate dehydrogenase, lipase, and fatty acid synthase genes. The results of metabolomics analysis showed that differentially expressed metabolites were significantly enriched in lysine degradation and glycerophospholipid metabolism. In conclusion, our study demonstrates that dietary melatonin increased oxidative phosphorylation, improved glucose utilization, and promoted storage of glycogen and lipids in C. destructor. These lipids are used not only for energy storage but also to maintain the structure and function of cell membranes. Our results further add to the understanding of the mechanisms of energy regulation by melatonin in crustaceans.PMID:37833417 | DOI:10.1007/s00360-023-01518-0

Sci Rep. 2023 Oct 13;13(1):17396. doi: 10.1038/s41598-023-44526-4.ABSTRACTIn the field of applied microbiology, reproducibility and experimental variability are important factors that influence both basic research as well as process development for industrial applications. Experimental reproducibility and accuracy depend not only on culture conditions such as temperature and aeration but also on raw materials and procedures used for media preparation. The M9 minimal medium is one of the most common synthetic media for culturing Escherichia coli and other bacteria. This synthetic medium can be used to observe and evaluate the physiological activity of microbes under minimal nutritional requirements and determine the limiting factor for the desired phenotype. Although one of the advantages using the M9 medium is that its composition can be modulated, it is difficult to control presence of trace components and impurities from the reagents for preparing this medium. Herein, we showed that trace ingredients present in the reagents used for M9 media preparation affect the bacterial physiological activities (e.g., cell growth, substrate consumption, and byproduct formation). Additionally, we systematically identified the trace ingredient that influenced phenotypic differences. Our results showed that the selection of reagents and accuracy during reagent preparation is important for experimental reproducibility in the field of bio-engineering and systems biology focused on the systematic and continuous development of biomolecular systems (e.g., biorefinery, metabolic engineering, and synthetic biology).PMID:37833342 | DOI:10.1038/s41598-023-44526-4

Trends Parasitol. 2023 Oct 11:S1471-4922(23)00232-5. doi: 10.1016/j.pt.2023.09.011. Online ahead of print.ABSTRACTEmerging resistance against artemisinin (ART) poses a major challenge in controlling malaria. Parasites with mutations in PfKelch13, the major marker for ART resistance, are known to reduce hemoglobin endocytosis, induce unfolded protein response (UPR), elevate phosphatidylinositol-3-phosphate (PI3P) levels, and stimulate autophagy. Nonetheless, PfKelch13-independent resistance is also reported, indicating extensive complementation by reconfiguration in the parasite metabolome and transcriptome. These findings implicate that there may not be a single 'universal identifier' of ART resistance. This review sheds light on the molecular, transcriptional, and metabolic pathways associated with ART resistance, while also highlighting the interplay between cellular heterogeneity, environmental stress, and ART sensitivity.PMID:37833166 | DOI:10.1016/j.pt.2023.09.011

Chemosphere. 2023 Oct 11:140354. doi: 10.1016/j.chemosphere.2023.140354. Online ahead of print.ABSTRACTCyanide extraction dominates the gold smelting industry, which leads to the generation of large amounts of cyanide-containing wastewater. In this study, Aneurinibacillus tyrosinisolvens strain named JK-1 was used for cyanide wastewater biodegradation. First, we tested the performance of JK-1 in degrading cyanide under different conditions. Then, we screened metabolic compounds and pathways associated with cyanide degradation by JK-1. Finally, we explored the potential JK-1-mediated cyanide degradation pathway. Our results showed that the optimal pH and temperature for cyanide biodegradation were 7.0 and 30 °C, respectively; under these conditions, a degradation rate of >98% was achieved within 48 h. Untargeted metabolomics results showed that increased cyanide concentration decreased the abundance of metabolic compounds by 71.1% but upregulated 32 metabolic pathways. The Kyoto Encyclopedia of Genes and Genomes enrichment results revealed significant changes in amino acid metabolism pathways during cyanide degradation by JK-1, including cyanoamino acid metabolism, β-alanine metabolism, and glutamate metabolism. Differential metabolic compounds included acetyl-CoA, l-asparagine, l-glutamic acid, l-phenylalanine, and l-glutamine. These results confirmed that cyanide degradation by JK-1 occurs through amino acid assimilation. This study provides new insights into the mechanism of cyanide biodegradation, which can be applied in the treatment of cyanide wastewater or tailings.PMID:37832879 | DOI:10.1016/j.chemosphere.2023.140354

J Peripher Nerv Syst. 2023 Oct 13. doi: 10.1111/jns.12600. Online ahead of print.ABSTRACTBACKGROUND: Distal symmetric sensorimotor polyneuropathy (DSPN) is a common neurologic complication of type 2 diabetes mellitus (T2DM), but the underlying mechanisms and changes in serum metabolites remain largely undefined. This study aimed to characterize the plasma metabolite profiles of participants with T2DM using targeted metabolomics analysis and identify potential biomarkers for DSPN.METHODS: A combined liquid chromatography MS/MS and direct flow injection were used to quantify plasma metabolite obtained from 63 participants with T2DM, 81 with DSPN, and 33 non-diabetic control participants. A total of 130 metabolites, including amino acids, biogenic amines, sphingomyelins (SM), phosphatidylcholines, carnitines, and hexose were analyzed.RESULTS: A total of 16 plasma metabolites and 3 cholesterol-related laboratory parameters were found to have variable importance in the projection score > 1.0 and false discovery rate <5.0% between control, T2DM, and DSPN. Among these variables, 5 serum metabolites including phenylalanine (AUC = 0.653), alanine (AUC = 0.630), lysine (AUC = 0.622) tryptophan (AUC = 0.620), and SM C16:0 (AUC = 0.630) are potential biomarkers (all p<0.05) in distinguishing T2DM with DSPN from those without (AUC = 0.720).CONCLUSIONS: In this cross-sectional study, derangement of several metabolites in the plasma was observed in T2DM with and without DSPN, and these metabolites may be potential biomarkers for predicting DSPN. Longitudinal studies are warranted. This article is protected by copyright. All rights reserved.PMID:37831393 | DOI:10.1111/jns.12600

Chem Biodivers. 2023 Oct 13:e202300980. doi: 10.1002/cbdv.202300980. Online ahead of print.ABSTRACTDendrobium huoshanense is an important Traditional Chinese medicine that thickens the stomach and intestines. Its active ingredient Dendrobium huoshanense polysaccharide (DHP), was revealed to relieve the symptoms of liver injury. However, its mechanism of action remains poorly understood. This study aimed to investigate the mechanism of DHP in protecting the liver. The effects of DHP on lipid levels, liver function, and intestinal barrier function were investigated in mice with high-fat diet-induced liver damage. Changes in the gut flora and their metabolites were analyzed using 16S rRNA sequencing and metabolomics. The results showed that DHP reduced lipid levels, liver injury, and intestinal permeability. DHP altered the intestinal flora structure and increased the relative abundance of Bifidobacterium animalis and Clostridium disporicum. Furthermore, fecal metabolomics revealed that DHP altered fecal metabolites and significantly increased levels of gut-derived metabolites, spermidine, and indole, which have been reported to inhibit liver injury and improve lipid metabolism and the intestinal barrier. Correlation analysis showed that spermidine and indole levels were significantly negatively correlated with liver injury-related parameters and positively correlated with the intestinal species B. animalis enriched by DHP. Overall, this study confirmed that DHP prevented liver injury by regulating intestinal microbiota dysbiosis and fecal metabolites.PMID:37831331 | DOI:10.1002/cbdv.202300980

mSystems. 2023 Oct 13:e0075823. doi: 10.1128/msystems.00758-23. Online ahead of print.ABSTRACTThe use of combination antibiotics has been useful in the treatment of multidrug-resistant bacterial infections. The synergistic effect of amoxicillin/clavulanate and aztreonam combination against Escherichia coli carrying New Delhi metallo-β-lactamase (NDM) was primarily due to clavulanate inhibiting aztreonam degradation. In the present study, we employed metabolomic analysis to investigate the downstream changes in E. coli after treatment with aztreonam and clavulanate. E. coli metabolomes were compared at 1 and 24 h following treatments with clavulanate (4 µg/mL) and aztreonam (4 µg/mL) alone and in combination. Excluding false positives, 198 metabolites were identified to be affected by antibiotic treatment. Aztreonam/clavulanate combination inhibited cell wall synthesis more aggressively at 1 h and 24 h than aztreonam alone. The purine and pyrimidine metabolism, the central carbon metabolism, and the amino acid metabolism were also disrupted resulting in a prolonged bactericidal effect. This study reveals the synergistic killing mechanism of clavulanate and aztreonam combination against E. coli harboring NDM and provides a theoretical basis for the combined use of aztreonam/clavulanate in the treatment of multidrug-resistant E. coli infection. IMPORTANCE Multidrug-resistant Escherichia coli is a major threat to the health care system and is associated with poor outcomes in infected patients. The combined use of antibiotics has become an important treatment method for multidrug-resistant bacteria. However, the mechanism for their synergism has yet to be explored.PMID:37830827 | DOI:10.1128/msystems.00758-23

Cells. 2023 Sep 27;12(19):2367. doi: 10.3390/cells12192367.ABSTRACTHepatocellular carcinoma (HCC) is the third leading cause of cancer-related death worldwide. In metabolic dysfunction-associated steatohepatitis (MASH)-related HCC, cellular redox imbalance from metabolic disturbances leads to dysregulation of the α1-subunit of the Na/K-ATPase (ATP1A1) signalosome. We have recently reported that the normalization of this pathway exhibited tumor suppressor activity in MASH-HCC. We hypothesized that dysregulated signaling from the ATP1A1, mediated by cellular metabolic stress, promotes aberrant epigenetic modifications including abnormal post-translational histone modifications and dysfunctional autophagic activity, leading to HCC development and progression. Increased H3K9 acetylation (H3K9ac) and H3K9 tri-methylation (H3K9me3) were observed in human HCC cell lines, HCC-xenograft and MASH-HCC mouse models, and epigenetic changes were associated with decreased cell autophagy in HCC cell lines. Inhibition of the pro-autophagic transcription factor FoxO1 was associated with elevated protein carbonylation and decreased levels of reduced glutathione (GSH). In contrast, normalization of the ATP1A1 signaling significantly decreased H3K9ac and H3K9me3, in vitro and in vivo, with concomitant nuclear localization of FoxO1, heightening cell autophagy and cancer-cell apoptotic activities in treated HCC cell lines. Our results showed the critical role of the ATP1A1 signalosome in HCC development and progression through epigenetic modifications and impaired cell autophagy activity, highlighting the importance of the ATP1A1 pathway as a potential therapeutic target for HCC.PMID:37830582 | DOI:10.3390/cells12192367

Expert Rev Proteomics. 2023 Oct 13. doi: 10.1080/14789450.2023.2267756. Online ahead of print.ABSTRACTINTRODUCTION: Bipolar disorder (BD) is a complex psychiatric disease characterized by alternating mood episodes. As for any other psychiatric illness, currently there is no biochemical test that is able to support diagnosis or therapeutic decisions for BD. In this context, the discovery and validation of biomarkers are interesting strategies that can be achieved through proteomics and metabolomics.AREAS COVERED: In this descriptive review, a literature search including original articles and systematic reviews published in the last decade was performed with the objective to discuss the results of BD proteomic and metabolomic profiling analyses and indicate proteins and metabolites (or metabolic pathways) with potential clinical value.EXPERT OPINION: A large number of proteins and metabolites have been reported as potential BD biomarkers; however, most studies do not reach biomarker validation stages. An effort from the scientific community should be directed toward the validation of biomarkers and the development of simplified bioanalytical techniques or protocols to determine them in biological samples, in order to translate proteomics and metabolomics findings into clinical routine assays.PMID:37830362 | DOI:10.1080/14789450.2023.2267756

J Am Soc Mass Spectrom. 2023 Oct 13. doi: 10.1021/jasms.3c00239. Online ahead of print.ABSTRACTSingle-cell metabolomics has the potential to reveal unique insights into intracellular mechanisms and biological processes. However, the detection of metabolites from individual cells is challenging due to their versatile chemical properties and concentrations. Here, we demonstrate a tapered probe for pneumatically assisted nanospray desorption electrospray ionization (PA nano-DESI) mass spectrometry that enables both chemical imaging of larger cells and global metabolomics of smaller 15 μm cells. Additionally, by depositing cells in predefined arrays, we show successful metabolomics from three individual INS-1 cells per minute, which enabled the acquisition of data from 479 individual cells. Several cells were used to optimize analytical conditions, and 93 or 97 cells were used to monitor metabolome alterations in INS-1 cells after exposure to a low or high glucose concentration, respectively. Our analytical approach offers insights into cellular heterogeneity and provides valuable information about cellular processes and responses in individual cells.PMID:37830184 | DOI:10.1021/jasms.3c00239

R Soc Open Sci. 2023 Oct 11;10(10):230825. doi: 10.1098/rsos.230825. eCollection 2023 Oct.ABSTRACTPlasmonic colorimetric sensors have emerged as powerful analytical tools in biochemistry due to their localized surface plasmon resonance extinction in the visible range. Here, we describe the feasibility of NAD(P)/NAD(P)H as redox agents in enzymatic plasmonic gold nanostar (AuNS) assays for galactose quantification using three model enzymes, GalDH, AR and GalOx, immobilized separately on polyvinylpyrrolidone-capped AuNS scaffolds. These highly specific, sensitive and selective bioassays induce the transformation of AuNS into quasi-spherical nanoparticles during the biorecognition of galactose in water and synthetic blood matrices. As a result, using our inexpensive and simple AuNS plasmon bioassays, the presence of galactose may be detected spectrophotometrically and by the naked eye.PMID:37830025 | PMC:PMC10565372 | DOI:10.1098/rsos.230825

RSC Adv. 2023 Oct 11;13(42):29784-29800. doi: 10.1039/d3ra00201b. eCollection 2023 Oct 4.ABSTRACTSilver nanoparticles (AgNPs) are one of the widely studied nanomaterials for diverse biomedical applications, in particular, as antimicrobial agents to kill bacteria, fungi, and viruses. In this report, AgNPs were synthesized using a geranium (Pelargonium x hortorum) leaves extract and tested for their antimicrobial and cytotoxic activity and reactive oxygen species (ROS) production. Using green biosynthesis, the leaves extract was employed as a reducing and stabilizing agent. Synthesis parameters like reaction time and precursor (silver nitrate AgNO3) volume final were modified, and the products were tested against Streptococcus mutans. For the first time, the metabolomic analysis of extract, we have identified more than 50 metabolites. The UV-Vis analysis showed a peak ranging from 410-430 nm, and TEM confirmed their nearly spherical morphology for all NPs. The antimicrobial activity of the NPs revealed a minimum inhibitory concentration (MIC) of 10 μg mL-1. Concerning cytotoxicity, a dose-time-dependent effect was observed with a 50% cellular cytotoxicity concentration (CC50) of 4.51 μg mL-1 at 24 h. Interestingly, the cell nuclei were visualized using fluorescence microscopy, and no significant changes were observed. These results suggest that synthesized spherical AgNPs are promising potential candidates for medical applications.PMID:37829709 | PMC:PMC10565737 | DOI:10.1039/d3ra00201b

Front Microbiol. 2023 Sep 27;14:1214845. doi: 10.3389/fmicb.2023.1214845. eCollection 2023.ABSTRACTThe present crisis at hand revolves around the need to enhance plant resilience to various environmental stresses, including abiotic and biotic stresses, to ensure sustainable agriculture and mitigate the impact of climate change on crop production. One such promising approach is the utilization of plant growth-promoting rhizobacteria (PGPR) to mediate plant resilience to these stresses. Plants are constantly exposed to various stress factors, such as drought, salinity, pathogens, and nutrient deficiencies, which can significantly reduce crop yield and quality. The PGPR are beneficial microbes that reside in the rhizosphere of plants and have been shown to positively influence plant growth and stress tolerance through various mechanisms, including nutrient solubilization, phytohormone production, and induction of systemic resistance. The review comprehensively examines the various mechanisms through which PGPR promotes plant resilience, including nutrient acquisition, hormonal regulation, and defense induction, focusing on recent research findings. The advancements made in the field of PGPR-mediated resilience through multi-omics approaches (viz., genomics, transcriptomics, proteomics, and metabolomics) to unravel the intricate interactions between PGPR and plants have been discussed including their molecular pathways involved in stress tolerance. Besides, the review also emphasizes the importance of continued research and implementation of PGPR-based strategies to address the pressing challenges facing global food security including commercialization of PGPR-based bio-formulations for sustainable agricultural.PMID:37829451 | PMC:PMC10565232 | DOI:10.3389/fmicb.2023.1214845

Front Pharmacol. 2023 Sep 27;14:1275832. doi: 10.3389/fphar.2023.1275832. eCollection 2023.ABSTRACTMale infertility occurs approximately in about 50% of all infertility cases and represents a serious concern worldwide. Traditional semen analysis alone is insufficient to diagnose male infertility. Over the past two decades, advances in omics technologies have led to the widespread application of metabolomics profiling as a valuable diagnostic tool for various diseases and disorders. Seminal plasma represents a rich and easily accessible source of metabolites surrounding spermatozoa, a milieu that provides several indispensable nutrients to sustain sperm motility and fertilization. Changes of metabolic profiles in seminal plasma reflect male reproductive tract disorders. Here, we performed seminal plasma metabolomics and lipidomics profiling to identify a new pattern of biomarkers of male infertility. Seminal plasma samples from unfertile subjects (n = 31) and fertile controls (n = 19) were analyzed using an untargeted metabolomics/lipidomics integrated approach, based on Ultra-High-Pressure Liquid Chromatography-tandem Mass Spectrometry. Partial Least Squares-Discriminant Analysis showed a distinct separation between healthy fertile men and infertile subjects. Among the 15 selected candidate biomarkers based on Variable Importance in Projection scores, phosphatidylethanolamine (PE) (18:1; 18:1) resulted with the highest score. In total, 40 molecular species showed statistically significant variations between fertile and infertile men. Heat-map and volcano plot analysis indicated that acylcarnitines, phosphatidylserine (PS) (40:2) and lactate were decreased, while PE (18:1; 18:1), Phosphatidic acid (PA) (O-19:2; 18:1), Lysophosphatidylethanolamine (LPE) (O-16:1) and Phosphatidylcholine (PC) (O-16:2; 18:1)-CH3 were increased in the infertile group. The present study is the first one to analyze the metabolomics/lipidomics dysregulation in seminal plasma between fertile and infertile individuals regardless of sub-infertility condition. Association of several metabolites/lipids dysregulation with male infertility reinforced data of previous studies performed with different approaches. In particular, we confirmed significantly decreased levels of PS and carnitines in infertile patients as well as the positive correlation with sperm motility and morphology. If validated on a larger prospective cohort, the metabolite biomarkers of infertility in seminal plasma we identified in the present study might inform novel strategies for diagnosis and interventions to overcome male infertility.PMID:37829298 | PMC:PMC10565040 | DOI:10.3389/fphar.2023.1275832

Front Immunol. 2023 Sep 27;14:1254155. doi: 10.3389/fimmu.2023.1254155. eCollection 2023.ABSTRACTBACKGROUND: Chronic metabolic changes relevant to human immunodeficiency virus type 1 (HIV-1) infection and in response to antiretroviral therapy (ART) remain undetermined. Moreover, links between metabolic dysfunction caused by HIV and immunological inflammation in long-term treated individuals have been poorly studied.METHODS: Untargeted metabolomics and inflammatory cytokine levels were assessed in 47 HIV-infected individuals including 22 immunological responders (IRs) and 25 non-responders (INRs) before and after ART. The IRs and INRs were matched by age, gender, baseline viral load, and baseline CD4+T cell counts. Another 25 age-matched uninfected healthy individuals were also included as controls.RESULTS: Among the 770 plasma compounds detected in the current study, significant changes were identified in lipids, nucleotides, and biogenic amino acids between HIV-infected patients and healthy controls. Principal Component Analysis (PCA) and the Random Forest (RF) model suggested that levels of selected metabolites could differentiate HIV-infected patients clearly from healthy controls. However, the metabolite profiles identified in our patients were similar, and only three metabolites, maltotetraose, N, N-dimethyl-5-aminovalerate, and decadienedioic acid (C10:2-DC), were different between IRs and INRs following long-term ART. The pathway enrichment analysis results revealed that disturbances in pyrimidine metabolism, sphingolipid metabolism, and purine metabolism after HIV infection and these changes did not recover to normal levels in healthy controls even with suppressive ART. Correlation analysis of the metabolism-immune network indicated that interleukin (IL)-10, D-dimer, vascular cell adhesion molecule-1 (VCAM-1), intercellular cell adhesion molecule-1 (ICAM-1), and TNF-RII were positively correlated with most of the significantly changed lipid and amino acid metabolites but negatively correlated with metabolites in nucleotide metabolism.CONCLUSIONS: Significant changes in many metabolites were observed in HIV-infected individuals before and after ART regardless of their immunological recovery status. The disturbed metabolic profiles of lipids and nucleotides in HIV infection did not recover to normal levels even after long-term ART. These changes are correlated with modified cytokines and biomarkers of chronic non-AIDS events, warranting tryout of interventions other than ART.PMID:37828979 | PMC:PMC10565217 | DOI:10.3389/fimmu.2023.1254155

Front Plant Sci. 2023 Sep 27;14:1259229. doi: 10.3389/fpls.2023.1259229. eCollection 2023.ABSTRACTChrysanthemums are one of the top ten most well-known traditional famous flowers in China and one of the top four cut flowers worldwide, holding a significant position in landscape gardening. The cold temperatures of winter restrict the cultivation, introduction, and application of chrysanthemum, resulting in high costs for year-round production. This severely impacts the ornamental and economic value of chrysanthemum. Therefore, research on cold tolerance is of vital importance for guiding chrysanthemum production and application. With the development of genomics, transcriptomics, metabolomics, and other omics approaches, along with high-throughput molecular marker technologies, research on chrysanthemum cold tolerance has been continuously advancing. This article provides a comprehensive overview of the progress in cold tolerance research from various aspects, including chrysanthemum phenotype, physiological mechanisms, the forward genetics, molecular mechanisms, and breeding. The aim is to offer insights into the mechanisms of cold tolerance in chrysanthemum and provide reference for in-depth research and the development of new cold tolerance chrysanthemum varieties.PMID:37828931 | PMC:PMC10565118 | DOI:10.3389/fpls.2023.1259229

Endocrinol Metab (Seoul). 2023 Oct 13. doi: 10.3803/EnM.2023.1820. Online ahead of print.ABSTRACTThe clinical characteristics and prognoses of acromegaly vary among patients. Assessment of current and novel predictors can lead to multilevel categorization of patients, allowing integration into new clinical guidelines and a reduction in the increased morbidity and mortality associated with acromegaly. Despite advances in the diagnosis and treatment of acromegaly, its pathophysiology remains unclear. Recent advancements in multiomics technologies, including genomics, transcriptomics, proteomics, metabolomics, and radiomics, have offered new opportunities to unravel the complex pathophysiology of acromegaly. This review comprehensively explores the emerging role of multiomics approaches in elucidating the molecular landscape of acromegaly. We discuss the potential implications of multiomics data integration in the development of novel diagnostic tools, identification of therapeutic targets, and the prospects of precision medicine in acromegaly management. By integrating diverse omics datasets, these approaches can provide valuable insights into disease mechanisms, facilitate the identification of diagnostic biomarkers, and identify potential therapeutic targets for precision medicine in the management of acromegaly.PMID:37828709 | DOI:10.3803/EnM.2023.1820

Anal Chim Acta. 2023 Oct 23;1279:341795. doi: 10.1016/j.aca.2023.341795. Epub 2023 Sep 9.ABSTRACTThe conserved region (Fc) of IgG antibodies dictates the interactions with designated receptors thus defining the immunological effector functions of IgG. Amino acid sequence variations in the Fc, recognized as subclasses and allotypes, as well as post-translational modifications (PTMs) modulate these interactions. Yet, the high similarity of Fc sequences hinders allotype-specific PTM analysis by state-of-the-art bottom-up methods and current subunit approaches lack sensitivity and face co-elution of near-isobaric allotypes. To circumvent these shortcomings, we present a nanoscale reversed-phase (RP) HPLC-MS workflow of intact Fc subunits for comprehensive characterization of Fc proteoforms in an allotype- and subclass-specific manner. Polyclonal IgGs were purified from individuals followed by enzymatic digestion releasing single chain Fc subunits (Fc/2) that were directly subjected to analysis. Chromatographic conditions were optimized to separate Fc/2 subunits of near-isobaric allotypes and subclasses allowing allotype and proteoform identification and quantification across all four IgG subclasses. The workflow was complemented by a semi-automated data analysis pipeline based on the open-source software Skyline followed by post-processing in R. The approach revealed pronounced differences in Fc glycosylation between donors, besides inter-subclass and inter-allotype variability within donors. Notably, partial occupancy of the N-glycosylation site in the CH3 domain of IgG3 was observed that is generally neglected by established approaches. The described method was benchmarked across several hundred runs and showed good precision and robustness. This methodology represents a first mature Fc subunit profiling approach allowing truly subclass- and allotype-specific Fc proteoform characterization beyond established approaches. The comprehensive information obtained paired with the high sensitivity provided by the miniaturization of the approach guarantees applicability to a broad range of research questions including clinically relevant (auto)antibody characterization or pharmacokinetics assessment of therapeutic IgGs.PMID:37827688 | DOI:10.1016/j.aca.2023.341795

Anal Chim Acta. 2023 Oct 23;1279:341791. doi: 10.1016/j.aca.2023.341791. Epub 2023 Sep 13.ABSTRACTMetabolomics is the study of small molecules, primarily metabolites, that are produced during metabolic processes. Analysis of the composition of an organism's metabolome can yield useful information about an individual's health status at any given time. In recent years, the development of large-scale, targeted metabolomic methods has allowed for the analysis of biological samples using analytical techniques such as LC-MS/MS. This paper presents a large-scale metabolomics method for analysis of biological samples, with a focus on quantification of metabolites found in blood plasma. The method comprises a 10-min chromatographic separation using HILIC and RP stationary phases combined with positive and negative electrospray ionization in order to maximize metabolome coverage. Complete analysis of a single sample can be achieved in as little as 40 min using the two columns and dual modes of ionization. With 540 metabolites and the inclusion of over 200 analytical standards, this method is comprehensive and quantitatively robust when compared to current targeted metabolomics methods. This study uses a large-scale evaluation of metabolite recovery from plasma that enables absolute quantification of metabolites by correcting for analyte loss throughout processes such as extraction, handling, or storage. In addition, the method was applied to plasma collected from adjuvant breast cancer patients to confirm the suitability of the method to clinical samples.PMID:37827685 | DOI:10.1016/j.aca.2023.341791