PubMed

Biochimie. 2023 Oct 14:S0300-9084(23)00255-9. doi: 10.1016/j.biochi.2023.10.001. Online ahead of print.ABSTRACTA high-salt diet is known to increase serum cholesterol levels; however, the underlying mechanism of salt-induced dyslipidemia in patients with salt-sensitivity remains poorly understood. We aimed to investigate whether high-salt diet (HSD) can induce dyslipidemia and elucidate the underlying mechanism of salt-induced dyslipidemia in Dahl salt-sensitive (SS) rats. Metabolomic and biochemical analyses revealed that the consumption of an HSD (8 % NaCl) significantly increased the serum levels of total cholesterol (TC) and low-density lipoprotein cholesterol (LDL-C) in SS rats. The enzyme-linked immunosorbent assay demonstrated an increase in circulating proprotein convertase subtilisin/kexin type 9 (PCSK9) levels, accompanied by a decrease in hepatic low-density lipoprotein receptor (LDLR) levels due to HSD consumption. Reverse transcription-quantitative polymerase chain reaction (RT-qPCR) and Western blot analysis revealed that HSD consumption activated sterol regulatory element-binding protein-2 (SREBP2) expression in the liver and kidney, resulting in upregulation of PCSK9 at the transcriptional level in the liver and at the translational level in the kidney, ultimately increasing circulating PCSK9 levels. The combined effects of HSD on the liver and kidney contributed to the development of hypercholesterolemia. Furthermore, an in vitro assay confirmed that high-salt exposure led to an increase in the protein expression of SREBP2 and PCSK9 secretion, thereby reducing low-density lipoprotein (LDL) uptake. This study, for the first time, shows that an HSD induces dyslipidemia through activation of the SREBP2/PCSK9 pathway, providing new insights into the prevention and treatment of dyslipidemia in patients with salt sensitivity.PMID:37844755 | DOI:10.1016/j.biochi.2023.10.001

Chemosphere. 2023 Oct 14:140398. doi: 10.1016/j.chemosphere.2023.140398. Online ahead of print.ABSTRACTChlorella vulgaris (C. vulgaris) can provide the means to fix CO2 from complicated flue gas, treat wastewater and reach a sustainable production of petrochemical substitutes simultaneously. However, a prerequisite to achieving this goal is to promote C. vulgaris growth and improve the CO2-to-fatty acids conversion efficiency under different conditions of flue gas and wastewater. Thus, the addition of indole-3-acetic acid (IAA) in C. vulgaris cultivation was proposed. Results showed that C. vulgaris were more easily inhibited by 100 ppm NO and 200 ppm SO2 under low nitrogen (N) condition. NO and SO2 decreased the carbon (C) fixation; but increased N and sulfur (S) fixation. IAA adjusted the content of superoxide dismutase (SOD) and malondialdehyde (MDA), improved the expression of psbA, rbcL, and accD, attenuated the toxicity of NO and SO2 on C. vulgaris, and ultimately improved cell growth (2014.64-2458.16 mgdw·L-1) and restored CO2 fixation rate (170.98-220.92 mg CO2·L-1·d-1). Moreover, wastewater was found to have a high treatment efficiency because C. vulgaris grew well in all treatments, and the maximal removal rates of both N and phosphorus (P) reached 100%. Metabonomic analysis showed that IAA, "NO and SO2" were involved in the down-regulated and up-regulated expression of multiple metabolites, such as fatty acids, amino acids, and carbohydrates. IAA was beneficial for improving lipid accumulation with 24584.21-27634.23 μg g-1, especially monounsaturated fatty acids (MUFAs) dominated by 16-18 C fatty acids, in C. vulgaris cells. It was concluded that IAA enhanced the CO2 fixation, fatty acids production of C. vulgaris and its nutrients removal rate.PMID:37844705 | DOI:10.1016/j.chemosphere.2023.140398

J Chromatogr A. 2023 Sep 29;1710:464425. doi: 10.1016/j.chroma.2023.464425. Online ahead of print.ABSTRACTThe technological advances of analytical instrumentation and techniques has laid the ground for the rapid expansion of metabolomics or in a wider sense, untargeted analysis applied to life sciences themes. However, the objective of identifying all existing metabolites within organisms remains a daunting challenge. All analytical techniques exhibit varying degrees of sensitivity and versatility for the detection of metabolites and none of the existing analytical platforms can be expected to be ideal for exhaustive chemical profiling. Planar liquid chromatography, and in particular, high performance thin layer chromatography (HPTLC), has been used for chemical profiling of natural products in conjunction with metabolomics. HPTLC has specific advantages which include its ability to generate reliable chemical fingerprinting data and facilitate preparative work for metabolite isolation during later stages of metabolomics analysis. In this study, we investigated the chemical profiles of four commercially available basil cultivars, namely Dolly, Emily, Keira, and Rosie. We used HPTLC as the primary analytical tool for the separation of basil cultivars based on detected metabolites, and then compared the results with those obtained with other analytical platforms. We identified the characteristic marker compounds of each basil cultivar from the HPTLC plates and validated their potential using LC-MS and GC-MS analyses as a metabolomics tool. Firstly, we compared the HPTLC data of the four cultivars, obtained with two systems that used silica gel 60 and two mobile phases composed of toluene-EtOAc (8:2, v/v) and EtOAc-formic acid-acetic acid-water (100:11:11:27, v/v), with 1H NMR data to evaluate their separation power. Despite providing lower resolution and detecting fewer compounds, the HPTLC separation power was comparable, and in some cases even better than that of 1H NMR. Additionally, we investigated the potential of HPTLC as a tool for chemical fingerprinting and demonstrated its suitability for preparative purposes that are essential for identifying metabolites in mixture analysis. Metabolites were easily isolated from sample mixtures, and identified with the assistance of GC-MS, LC-MS, and TLC-densitometry.. Several marker compounds were thus identified, including 2,4 di-tertbutylphenol, palmitic acid, hexadecanamide, 9-octadecenamide, squalene, hentriacontane, methyl 3-(3,5-ditert‑butyl‑4-hydroxyphenyl)propanoic acid, sagerinic acid, and cyanidin-3-O-sophoroside.PMID:37844367 | DOI:10.1016/j.chroma.2023.464425

Parkinsonism Relat Disord. 2023 Sep 15;116:105847. doi: 10.1016/j.parkreldis.2023.105847. Online ahead of print.ABSTRACTINTRODUCTION: Progressive Supranuclear Palsy (PSP) is a neurodegenerative tauopathy and, to date, the pathophysiological mechanisms in PSP that lead to Tau hyperphosphorylation and neurodegeneration are not clear. In some brain areas, Tau pathology in glial cells appears to precede Tau aggregation in neurons. The development of a model using astrocyte cell lines derived from patients has the potential to identify molecules and pathways that contribute to early events of neurodegeneration. We developed a model of induced pluripotent stem cells (iPSC)-derived astrocytes to investigate the pathophysiology of PSP, particularly early events that might contribute to Tau hyperphosphorylation, applying omics approach to detect differentially expressed genes, metabolites, and proteins, including those from the secretome.METHODS: Skin fibroblasts from PSP patients (without MAPT mutations) and controls were reprogrammed to iPSCs, further differentiated into neuroprogenitor cells (NPCs) and astrocytes. In the 5th passage, astrocytes were harvested for total RNA sequencing. Intracellular and secreted proteins were processed for proteomics experiments. Metabolomics profiling was obtained from supernatants only.RESULTS: We identified hundreds of differentially expressed genes. The main networks were related to cell cycle re-activation in PSP. Several proteins were found exclusively secreted by the PSP group. The cellular processes related to the cell cycle and mitotic proteins, TriC/CCT pathway, and redox signaling were enriched in the secretome of PSP. Moreover, we found distinct sets of metabolites between PSP and controls.CONCLUSION: Our iPSC-derived astrocyte model can provide distinct molecular signatures for PSP patients and it is useful to elucidate the initial stages of PSP pathogenesis.PMID:37844348 | DOI:10.1016/j.parkreldis.2023.105847

Adv Exp Med Biol. 2023;1439:225-248. doi: 10.1007/978-3-031-41741-2_9.ABSTRACTSince the discovery of penicillin, microbial metabolites have been extensively investigated for drug discovery purposes. In the last decades, microbial derived compounds have gained increasing attention in different fields from pharmacognosy to industry and agriculture. Microbial metabolites in microbiomes present specific functions and can be associated with the maintenance of the natural ecosystems. These metabolites may exhibit a broad range of biological activities of great interest to human purposes. Samples from either microbial isolated cultures or microbiomes consist of complex mixtures of metabolites and their analysis are not a simple process. Mass spectrometry-based metabolomics encompass a set of analytical methods that have brought several improvements to the microbial natural products field. This analytical tool allows the comprehensively detection of metabolites, and therefore, the access of the chemical profile from those biological samples. These analyses generate thousands of mass spectra which is challenging to analyse. In this context, bioinformatic metabolomics tools have been successfully employed to accelerate and facilitate the investigation of specialized microbial metabolites. Herein, we describe metabolomics tools used to provide chemical information for the metabolites, and furthermore, we discuss how they can improve investigation of microbial cultures and interactions.PMID:37843811 | DOI:10.1007/978-3-031-41741-2_9

Adv Exp Med Biol. 2023;1439:185-224. doi: 10.1007/978-3-031-41741-2_8.ABSTRACTThe incessant search for new natural molecules with biological activities has forced researchers in the field of chemistry of natural products to seek different approaches for their prospection studies. In particular, researchers around the world are turning to approaches in metabolomics to avoid high rates of re-isolation of certain compounds, something recurrent in this branch of science. Thanks to the development of new technologies in the analytical instrumentation of spectroscopic and spectrometric techniques, as well as the advance in the computational processing modes of the results, metabolomics has been gaining more and more space in studies that involve the prospection of natural products. Thus, this chapter summarizes the precepts and good practices in the metabolomics of microbial natural products using mass spectrometry and nuclear magnetic resonance spectroscopy, and also summarizes several examples where this approach has been applied in the discovery of bioactive molecules.PMID:37843810 | DOI:10.1007/978-3-031-41741-2_8

Adv Exp Med Biol. 2023;1439:149-183. doi: 10.1007/978-3-031-41741-2_7.ABSTRACTMicrobial metabolomics has gained significant interest as it reflects the physiological state of microorganisms. Due to the great variability of biological organisms, in terms of physicochemical characteristics and variable range of concentration of metabolites, the choice of sample preparation methods is a crucial step in the metabolomics workflow and will reflect on the quality and reliability of the results generated. The procedures applied to the preparation of microbial samples will vary according to the type of microorganism studied, the metabolomics approach (untargeted or targeted), and the analytical platform of choice. This chapter aims to provide an overview of the sample preparation workflow for microbial metabolomics, highlighting the pre-analytical factors associated with cultivation, harvesting, metabolic quenching, and extraction. Discussions focus on obtaining intracellular and extracellular metabolites. Finally, we introduced advanced sample preparation methods based on automated systems.PMID:37843809 | DOI:10.1007/978-3-031-41741-2_7

Adv Exp Med Biol. 2023;1439:123-147. doi: 10.1007/978-3-031-41741-2_6.ABSTRACTConfidently, nuclear magnetic resonance (NMR) is the most informative technique in analytical chemistry and its use as an analytical platform in metabolomics is well proven. This chapter aims to present NMR as a viable tool for microbial metabolomics discussing its fundamental aspects and applications in metabolomics using some chosen examples.PMID:37843808 | DOI:10.1007/978-3-031-41741-2_6

Adv Exp Med Biol. 2023;1439:101-122. doi: 10.1007/978-3-031-41741-2_5.ABSTRACTHighly selective and sensitive analytical techniques are necessary for microbial metabolomics due to the complexity of the microbial sample matrix. Hence, mass spectrometry (MS) has been successfully applied in microbial metabolomics due to its high precision, versatility, sensitivity, and wide dynamic range. The different analytical tools using MS have been employed in microbial metabolomics investigations and can contribute to the discovery or accelerate the search for bioactive substances. The coupling with chromatographic and electrophoretic separation techniques has resulted in more efficient technologies for the analysis of microbial compounds occurring in trace levels. This book chapter describes the current advances in the application of mass spectrometry-based metabolomics in the search for new biologically active agents from microbial sources; the development of new approaches for in silico annotation of natural products; the different technologies employing mass spectrometry imaging to deliver more comprehensive analysis and elucidate the metabolome involved in ecological interactions as they enable visualization of the spatial dispersion of small molecules. We also describe other ambient ionization techniques applied to the fingerprint of microbial natural products and modern techniques such as ion mobility mass spectrometry used to microbial metabolomic analyses and the dereplication of natural microbial products through MS.PMID:37843807 | DOI:10.1007/978-3-031-41741-2_5

Adv Exp Med Biol. 2023;1439:71-100. doi: 10.1007/978-3-031-41741-2_4.ABSTRACTFor many years, several studies have explored the molecular mechanisms involved in the infection of bacteria by their specific phages to understand the main infection strategies and the host defense strategies. The modulation of the mechanisms involved in the infection, as well as the expression of key substances in the development of the different life cycles of phages, function as a natural source of strategies capable of promoting the control of different pathogens that are harmful to human and animal health. Therefore, this chapter aims to provide an overview of the mechanisms involved in virus-bacteria interaction to explore the main compounds produced or altered as a chemical survival strategy and the metabolism modulation when occurring a host-phage interaction. In this context, emphasis will be given to the chemistry of peptides/proteins and enzymes encoded by bacteriophages in the control of pathogenic bacteria and the use of secondary metabolites recently reported as active participants in the mechanisms of phage-bacteria interaction. Finally, metabolomics strategies developed to gain new insights into the metabolism involved in the phage-host interaction and the metabolomics workflow in host-phage interaction will be presented.PMID:37843806 | DOI:10.1007/978-3-031-41741-2_4

Adv Exp Med Biol. 2023;1439:51-70. doi: 10.1007/978-3-031-41741-2_3.ABSTRACTMicroorganisms are ubiquitous in diverse habitats and studying their chemical interactions with the environment and comprehend its complex relations with both hosts and environment, are crucial for the development of strategies to control microbial diseases. This chapter discusses the importance of studying microorganisms with agricultural benefits, using specialized metabolites as examples. Herein we highlight the challenges and opportunities in utilizing microorganisms as alternatives to synthetic pesticides and fertilizers in agriculture. Genome-guided investigations and improved analytical methodologies are necessary to characterize diverse and complex biomolecules produced by microorganisms. Predicting and isolating bioproducts based on genetic information have become a focus for researchers, aided by tools like antiSMASH, BiG-SCAPE, PRISM, and others. However, translating genomic data into practical applications can be complex. Therefore, integrating genomics, transcriptomics, and metabolomics enhances chemical characterization, aiding in discovering new metabolic pathways and specialized metabolites. Additionally, elicitation is one promising strategy to enhance beneficial metabolite production. Finally, identify and characterize microbial secondary metabolites remain challenging due to their low production, complex chemical structure characterization and different environmental factors necessary for metabolite in vitro production.PMID:37843805 | DOI:10.1007/978-3-031-41741-2_3

Adv Exp Med Biol. 2023;1439:21-49. doi: 10.1007/978-3-031-41741-2_2.ABSTRACTThe biological and chemical diversity of Cyanobacteria is remarkable. These ancient prokaryotes are widespread in nature and can be found in virtually every habitat on Earth where there is light and water. They are producers of an array of secondary metabolites with important ecological roles, toxic effects, and biotechnological applications. The investigation of cyanobacterial metabolites has benefited from advances in analytical tools and bioinformatics that are employed in metabolomic analyses. In this chapter, we review selected articles highlighting the use of targeted and untargeted metabolomics in the analyses of secondary metabolites produced by cyanobacteria. Here, cyanobacterial secondary metabolites have been didactically divided into toxins and natural products according to their relevance to toxicological studies and drug discovery, respectively. This review illustrates how metabolomics has improved the chemical analysis of cyanobacteria in terms of speed, sensitivity, selectivity, and/or coverage, allowing for broader and more complex scientific questions.PMID:37843804 | DOI:10.1007/978-3-031-41741-2_2

Adv Exp Med Biol. 2023;1439:1-20. doi: 10.1007/978-3-031-41741-2_1.ABSTRACTMetabolomics has been extensively used in clinical studies in the search for new biomarkers of human diseases. However, this approach has also been highlighted in agriculture and biological sciences, once metabolomics studies have been assisting researchers to deduce new chemical mechanisms involved in biological interactions that occur between microorganisms and plants. In this sense, the knowledge of the biological role of each metabolite (virulence factors, signaling compounds, antimicrobial metabolites, among others) and the affected biochemical pathways during the interaction contribute to a better understand of different ecological relationships established in nature. The current chapter addresses five different applications of the metabolomics approach in fungal-plant interactions research: (1) Discovery of biomarkers in pathogen-host interactions, (2) plant diseases diagnosis, (3) chemotaxonomy, (4) plant defense, and (5) plant resistance; using mass spectrometry and/or nuclear magnetic resonance spectroscopy, which are the techniques most used in metabolomics.PMID:37843803 | DOI:10.1007/978-3-031-41741-2_1

Mol Neurobiol. 2023 Oct 16. doi: 10.1007/s12035-023-03666-4. Online ahead of print.ABSTRACTCerebrospinal fluid (CSF) is a metabolically diverse biofluid and a key specimen for exploring biochemical changes in neurodegenerative diseases. Detecting lipid species in CSF using mass spectrometry (MS)-based techniques remains challenging because lipids are highly complex in structure, and their concentrations span over a broad dynamic range. This work aimed to develop a robust lipidomics and metabolomics method based on commonly used two-phase extraction systems from human CSF samples. Prioritizing lipid detection, biphasic extraction methods, Folch, Bligh and Dyer (B&D), Matyash, and acidified Folch and B&D (aFolch and aB&D) were compared using 150 μL of human CSF samples for the simultaneous extraction of lipids and metabolites with a wide range of polarity. Multiple chromatographical separation approaches, including reversed-phase liquid chromatography (RPLC), hydrophilic interaction liquid chromatography (HILIC), and gas chromatography (GC), were utilized to characterize human CSF metabolome. The aB&D method was found as the most reproducible technique (RSD < 15%) for lipid extraction. The aB&D and B&D yielded the highest peak intensities for targeted lipid internal standards and displayed superior extracting power for major endogenous lipid classes. A total of 674 unique metabolites with a wide polarity range were annotated in CSF using, combining RPLC-MS/MS lipidomics (n = 219), HILIC-MS/MS (n = 304), and GC-quadrupole time of flight (QTOF) MS (n = 151). Overall, our findings show that the aB&D extraction method provided suitable lipid coverage, reproducibility, and extraction efficiency for global lipidomics profiling of human CSF samples. In combination with RPLC-MS/MS lipidomics, complementary screening approaches enabled a comprehensive metabolite signature that can be employed in an array of clinical studies.PMID:37843799 | DOI:10.1007/s12035-023-03666-4

Kidney Int. 2023 Oct 5:S0085-2538(23)00565-3. doi: 10.1016/j.kint.2023.08.006. Online ahead of print.ABSTRACTDiabetic nephropathy (DN) is characterized by abnormal kidney energy metabolism, but its causes and contributions to DN pathogenesis are not clear. To examine this issue, we carried out targeted metabolomics profiling in a mouse model of DN that develops kidney disease resembling the human disorder. We found a distinct profile of increased lactate levels and impaired energy metabolism in kidneys of mice with DN, and treatment with an angiotensin-receptor blocker (ARB) reduced albuminuria, attenuated kidney pathology and corrected many metabolic abnormalities, restoring levels of lactate toward normal while increasing kidney ATP content. We also found enhanced expression of lactate dehydrogenase isoforms in DN. Expression of both the LdhA and LdhB isoforms were significantly increased in kidneys of mice, and treatment with ARB significantly reduced their expression. Single-cell sequencing studies showed specific up-regulation of LdhA in the proximal tubule, along with enhanced expression of oxidative stress pathways. There was a significant correlation between albuminuria and lactate in mice, and also in a Southeast Asian patient cohort consisting of individuals with type 2 diabetes and impaired kidney function. In the individuals with diabetes, this association was independent of ARB and angiotensin-converting enzyme inhibitor use. Furthermore, urinary lactate levels predicted the clinical outcomes of doubling of serum creatinine or development of kidney failure, and there was a significant correlation between urinary lactate levels and biomarkers of tubular injury and epithelial stress. Thus, we suggest that kidney metabolic disruptions leading to enhanced generation of lactate contribute to the pathogenesis of DN and increased urinary lactate levels may be a potential biomarker for risk of kidney disease progression.PMID:37843477 | DOI:10.1016/j.kint.2023.08.006

J Clin Invest. 2023 Oct 16;133(20):e174015. doi: 10.1172/JCI174015.ABSTRACTEnabling the early detection and prevention of diabetic kidney damage has potential to substantially reduce the global burden of kidney failure. There is a critical need for identification of mechanistic biomarkers that can predict progression and serve as therapeutic targets. In this issue of the JCI, Sharma and colleagues used an integrated multiomics approach to identify the metabolite adenine as a noninvasive biomarker of progression in early diabetic kidney disease (DKD). The highest tertile of urine adenine/creatinine ratio (UAdCR) was associated with higher risk for end-stage kidney disease and mortality across independent cohorts, including participants with early DKD without macroalbuminuria. Spatial metabolomics, single-cell transcriptomics, and experimental studies localized adenine to regions of tubular pathology and implicated the mTOR pathway in adenine-mediated tissue fibrosis. Inhibition of endogenous adenine production was protective in a diabetic model. These findings exemplify the potential for multiomics to uncover mechanistic biomarkers and targeted therapies in DKD.PMID:37843281 | DOI:10.1172/JCI174015

J Anim Sci. 2023 Oct 16:skad308. doi: 10.1093/jas/skad308. Online ahead of print.ABSTRACTThe adverse effects of chronic heat stress (CHS)-induced fatty liver syndrome (FLS) on laying hens during the egg-producing stages have been wildly documented. However, until nowadays, the CHS responses of growing laying hens as well as its alleviating effects of vitamin C is rarely reported. In this study, 12-week-old laying hens were subjected to CHS at 36 °C for 10 h/d for 3 weeks with or without dietary supplementation of 300 mg/kg vitamin C. Results showed that CHS significantly impaired the growth performances and the liver functions of birds, as characterized by reduced feed intake and body weight, increased hepatic lipid accumulation and serum concentrations of TG, ALT and AST, as well as the abnormal expression patterns of the lipid metabolism-related genes. Vitamin C supplementation successfully mitigated the lipid accumulation, while showed no alleviating effect on the serum contents of ALT or AST, which are two key indicators of the liver functions. Metabolomic analysis based on UPLC-Q-TOF/MS identified 173 differential metabolites from the HS and HSV group samples, and they are mainly enriched in the pathways related to the cellular components, vitamin and amino acid metabolism and the energy substance metabolism. The results indicate that CHS-induced hepatic lipid deposition in growing laying hens is effectively alleviated by dietary supplementation of vitamin C, which is probably resulted from the alterations of hepatocellular metabolic patterns.PMID:37843035 | DOI:10.1093/jas/skad308

J Proteome Res. 2023 Oct 16. doi: 10.1021/acs.jproteome.3c00356. Online ahead of print.ABSTRACTLung cancer (LC) is a leading cause of mortality, claiming more than 1.8 million deaths per year worldwide. Surgery is one of the most effective treatments when the disease is in its early stages. The study of metabolic alterations after surgical intervention with curative intent could be used to assess the response to treatment or the detection of cancer recurrence. In this study, we have evaluated the metabolomic profile of serum samples (n = 110) from preoperative (PRE) and postoperative (POST) LC patients collected at two different time points (1 month, A; 3-6 months, B) with respect to healthy people. An untargeted metabolomic platform based on reversed phase (RP) and hydrophilic interaction chromatography (HILIC), using ultra-high performance liquid chromatography (UHPLC) and mass spectrometry (MS), was applied (MassIVE ID MSV000092213). Twenty-two altered metabolites were annotated by comparing all the different studied groups. DG(14,0/22:1), stearamide, proline, and E,e-carotene-3,3'-dione were found altered in PRE, and their levels returned to those of a baseline control group 3-6 months after surgery. Furthermore, 3-galactosyllactose levels remained altered after intervention in some patients. This study provides unique insights into the metabolic profiles of LC patients after surgery at two different time points by combining complementary analytical methods.PMID:37843028 | DOI:10.1021/acs.jproteome.3c00356

Cardiovasc Res. 2023 Oct 16:cvad154. doi: 10.1093/cvr/cvad154. Online ahead of print.ABSTRACTAIMS: Mutation of the PRDM16 gene causes human dilated and non-compaction cardiomyopathy. The PRDM16 protein is a transcriptional regulator that affects cardiac development via Tbx5 and Hand1, thus regulating myocardial structure. The biallelic inactivation of Prdm16 induces severe cardiac dysfunction with post-natal lethality and hypertrophy in mice. The early pathological events that occur upon Prdm16 inactivation have not been explored.METHODS AND RESULTS: This study performed in-depth pathophysiological and molecular analyses of male and female Prdm16csp1/wt mice that carry systemic, monoallelic Prdm16 gene inactivation. We systematically assessed early molecular changes through transcriptomics, proteomics, and metabolomics. Kinetic modelling of cardiac metabolism was performed in silico with CARDIOKIN. Prdm16csp1/wt mice are viable up to 8 months, develop hypoplastic hearts, and diminished systolic performance that is more pronounced in female mice. Prdm16csp1/wt cardiac tissue of both sexes showed reductions in metabolites associated with amino acid as well as glycerol metabolism, glycolysis, and the tricarboxylic acid cycle. Prdm16csp1/wt cardiac tissue revealed diminished glutathione (GSH) and increased inosine monophosphate (IMP) levels indicating oxidative stress and a dysregulated energetics, respectively. An accumulation of triacylglycerides exclusively in male Prdm16csp1/wt hearts suggests a sex-specific metabolic adaptation. Metabolic modelling using CARDIOKIN identified a reduction in fatty acid utilization in males as well as lower glucose utilization in female Prdm16csp1/wt cardiac tissue. On the level of transcripts and protein expression, Prdm16csp1/wt hearts demonstrate an up-regulation of pyridine nucleotide-disulphide oxidoreductase domain 2 (Pyroxd2) and the transcriptional regulator pre-B-cell leukaemia transcription factor interacting protein 1 (Pbxip1). The strongest concordant transcriptional up-regulation was detected for Prdm16 itself, probably through an autoregulatory mechanism.CONCLUSIONS: Monoallelic, global Prdm16 mutation diminishes cardiac performance in Prdm16csp1/wt mice. Metabolic alterations and transcriptional dysregulation in Prdm16csp1/wt affect cardiac tissue. Female Prdm16csp1/wt mice develop a more pronounced phenotype, indicating sexual dimorphism at this early pathological window. This study suggests that metabolic dysregulation is an early event in the PRDM16 associated cardiac pathology.PMID:37842925 | DOI:10.1093/cvr/cvad154

Mol Syst Biol. 2023 Oct 16:e10571. doi: 10.15252/msb.202110571. Online ahead of print.ABSTRACTSpatial omics has emerged as a rapidly growing and fruitful field with hundreds of publications presenting novel methods for obtaining spatially resolved information for any omics data type on spatial scales ranging from subcellular to organismal. From a technology development perspective, spatial omics is a highly interdisciplinary field that integrates imaging and omics, spatial and molecular analyses, sequencing and mass spectrometry, and image analysis and bioinformatics. The emergence of this field has not only opened a window into spatial biology, but also created multiple novel opportunities, questions, and challenges for method developers. Here, we provide the perspective of technology developers on what makes the spatial omics field unique. After providing a brief overview of the state of the art, we discuss technological enablers and challenges and present our vision about the future applications and impact of this melting pot.PMID:37842805 | DOI:10.15252/msb.202110571