PubMed

Front Plant Sci. 2023 May 9;14:1147145. doi: 10.3389/fpls.2023.1147145. eCollection 2023.ABSTRACTSitophilus zeamais (maize weevil) is one of the most destructive pests that seriously affects the quantity and quality of wheat (Triticum aestivum L.). However, little is known about the constitutive defense mechanism of wheat kernels against maize weevils. In this study, we obtained a highly resistant variety RIL-116 and a highly susceptible variety after two years of screening. The morphological observations and germination rates of wheat kernels after feeding ad libitum showed that the degree of infection in RIL-116 was far less than that in RIL-72. The combined analysis of metabolome and transcriptome of RIL-116 and RIL-72 wheat kernels revealed differentially accumulated metabolites were mainly enriched in flavonoids biosynthesis-related pathway, followed by glyoxylate and dicarboxylate metabolism, and benzoxazinoid biosynthesis. Several flavonoids metabolites were significantly up-accumulated in resistant variety RIL-116. In addition, the expression of structural genes and transcription factors (TFs) related to flavonoids biosynthesis were up-regulated to varying degrees in RIL-116 than RIL-72. Taken together, these results indicated that the biosynthesis and accumulation of flavonoids contributes the most to wheat kernels defense against maize weevils. This study not only provides insights into the constitutive defense mechanism of wheat kernels against maize weevils, but may also play an important role in the breeding of resistant varieties.PMID:37229118 | PMC:PMC10204651 | DOI:10.3389/fpls.2023.1147145

Front Immunol. 2023 May 9;14:1144224. doi: 10.3389/fimmu.2023.1144224. eCollection 2023.ABSTRACTBACKGROUND: Deep metabolomic, proteomic and immunologic phenotyping of patients suffering from an infection with severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) have matched a wide diversity of clinical symptoms with potential biomarkers for coronavirus disease 2019 (COVID-19). Several studies have described the role of small as well as complex molecules such as metabolites, cytokines, chemokines and lipoproteins during infection and in recovered patients. In fact, after an acute SARS-CoV-2 viral infection almost 10-20% of patients experience persistent symptoms post 12 weeks of recovery defined as long-term COVID-19 syndrome (LTCS) or long post-acute COVID-19 syndrome (PACS). Emerging evidence revealed that a dysregulated immune system and persisting inflammation could be one of the key drivers of LTCS. However, how these biomolecules altogether govern pathophysiology is largely underexplored. Thus, a clear understanding of how these parameters within an integrated fashion could predict the disease course would help to stratify LTCS patients from acute COVID-19 or recovered patients. This could even allow to elucidation of a potential mechanistic role of these biomolecules during the disease course.METHODS: This study comprised subjects with acute COVID-19 (n=7; longitudinal), LTCS (n=33), Recov (n=12), and no history of positive testing (n=73). 1H-NMR-based metabolomics with IVDr standard operating procedures verified and phenotyped all blood samples by quantifying 38 metabolites and 112 lipoprotein properties. Univariate and multivariate statistics identified NMR-based and cytokine changes.RESULTS: Here, we report on an integrated analysis of serum/plasma by NMR spectroscopy and flow cytometry-based cytokines/chemokines quantification in LTCS patients. We identified that in LTCS patients lactate and pyruvate were significantly different from either healthy controls (HC) or acute COVID-19 patients. Subsequently, correlation analysis in LTCS group only among cytokines and amino acids revealed that histidine and glutamine were uniquely attributed mainly with pro-inflammatory cytokines. Of note, triglycerides and several lipoproteins (apolipoproteins Apo-A1 and A2) in LTCS patients demonstrate COVID-19-like alterations compared with HC. Interestingly, LTCS and acute COVID-19 samples were distinguished mostly by their phenylalanine, 3-hydroxybutyrate (3-HB) and glucose concentrations, illustrating an imbalanced energy metabolism. Most of the cytokines and chemokines were present at low levels in LTCS patients compared with HC except for IL-18 chemokine, which tended to be higher in LTCS patients.CONCLUSION: The identification of these persisting plasma metabolites, lipoprotein and inflammation alterations will help to better stratify LTCS patients from other diseases and could help to predict ongoing severity of LTCS patients.PMID:37228606 | PMC:PMC10203989 | DOI:10.3389/fimmu.2023.1144224

PNAS Nexus. 2023 May 23;2(5):pgad137. doi: 10.1093/pnasnexus/pgad137. eCollection 2023 May.ABSTRACTHeat alters biology from molecular to ecological levels, but may also have unknown indirect effects. This includes the concept that animals exposed to abiotic stress can induce stress in naive receivers. Here, we provide a comprehensive picture of the molecular signatures of this process, by integrating multiomic and phenotypic data. In individual zebrafish embryos, repeated heat peaks elicited both a molecular response and a burst of accelerated growth followed by a growth slowdown in concert with reduced responses to novel stimuli. Metabolomes of the media of heat treated vs. untreated embryos revealed candidate stress metabolites including sulfur-containing compounds and lipids. These stress metabolites elicited transcriptomic changes in naive receivers related to immune response, extracellular signaling, glycosaminoglycan/keratan sulfate, and lipid metabolism. Consequently, non-heat-exposed receivers (exposed to stress metabolites only) experienced accelerated catch-up growth in concert with reduced swimming performance. The combination of heat and stress metabolites accelerated development the most, mediated by apelin signaling. Our results prove the concept of indirect heat-induced stress propagation toward naive receivers, inducing phenotypes comparable with those resulting from direct heat exposure, but utilizing distinct molecular pathways. Group-exposing a nonlaboratory zebrafish line, we independently confirm that the glycosaminoglycan biosynthesis-related gene chs1 and the mucus glycoprotein gene prg4a, functionally connected to the candidate stress metabolite classes sugars and phosphocholine, are differentially expressed in receivers. This hints at the production of Schreckstoff-like cues in receivers, leading to further stress propagation within groups, which may have ecological and animal welfare implications for aquatic populations in a changing climate.PMID:37228511 | PMC:PMC10205475 | DOI:10.1093/pnasnexus/pgad137

ERJ Open Res. 2023 May 9;9(3):00026-2023. doi: 10.1183/23120541.00026-2023. eCollection 2023 May.ABSTRACTEnormous progress has been made on the epic journey towards implementation of lung cancer screening in Europe. A breakthrough for lung health has been achieved with the EU proposal for a Council recommendation on cancer screening. https://bit.ly/3J4O0Jb.PMID:37228272 | PMC:PMC10204812 | DOI:10.1183/23120541.00026-2023

Clin Transl Med. 2023 May;13(5):e1274. doi: 10.1002/ctm2.1274.ABSTRACTAs omics technologies, including genomics, epigenomics, transcriptomics, T cell receptor-repertorie profiling, proteomics, metabolomics and microbiomics, have provided valuable insights into CAR T cell therapy, in our recent review, we discuss these multidimensional profiling technologies in CAR T cell research, and their potential to identify tumor-specific antigens and molecular characteristics associated with anti-tumour effects and toxicities.PMID:37228183 | DOI:10.1002/ctm2.1274

Langmuir. 2023 May 25. doi: 10.1021/acs.langmuir.3c00602. Online ahead of print.ABSTRACTWater reclamation is the most effective way to continuously provide clean water to combat catastrophic global water scarcity. However, current technology for water purification is not conducive to sustainability due to the high energy consumption and negative environmental impact. Here, we introduce an innovative method by utilizing the hierarchical microstructure of bamboo for water purification. Natural bamboo was delignified followed by freeze-drying to obtain a bamboo aerogel with a porosity of 72.0%; then, the bamboo aerogel was coated with silver nanoparticles to form a hierarchical bamboo/silver nanoparticle composite. The scanning electron microscopy images and energy-dispersive X-ray spectroscopy results indicated that the silver nanoparticles were uniformly attached to the parenchyma cell surface. By physical adsorption and catalytic reduction, the bamboo/silver nanoparticle composite was able to degrade methylene blue by more than 96.7%, which is mainly attributed to the large specific surface area of the bamboo providing more space for the purification reaction. This composite can be potentially used for board applications with its high porosity, mechanical reliability, and sustainability.PMID:37228013 | DOI:10.1021/acs.langmuir.3c00602

JCI Insight. 2023 May 25:e169135. doi: 10.1172/jci.insight.169135. Online ahead of print.ABSTRACTTherapeutic strategies targeting complement have revolutionized the treatment of myasthenia gravis (MG). However, a deeper understanding of complement modulation in the human system is required to improve treatment responses and identify "off-target effects" shaping long-term outcomes. For this purpose, we studied a cohort of MG patients treated with either eculizumab (n = 10) or azathioprine (n = 10) as well as treatment-naïve (n = 10) patients using a combined proteomics and metabolomics approach. This strategy confirmed known effects of eculizumab on the terminal complement cascade. Beyond that, eculizumab modulated the serum proteometabolome as distinct pathways were altered in eculizumab-treated patients including the oxidative stress response, mitogen-activated protein kinase signaling and lipid metabolism with particular emphasis on arachidonic acid signaling. We detected reduced levels of arachidonate 5-lipoxygenase (ALOX5) and leukotriene A4 (LTA4) in eculizumab-treated patients. Mechanistically, ligation of the C5a receptor (C5aR) is needed for ALOX5 metabolism and generation of downstream leukotrienes. As eculizumab prevents cleavage of C5 into C5a, decreased engagement of C5aR may inhibit ALOX5-mediated synthesis of pro-inflammatory leukotrienes. These findings indicate distinct "off-target effects" induced by eculizumab, illuminating potential mechanisms of action that may be harnessed to improve treatment outcomes.PMID:37227781 | DOI:10.1172/jci.insight.169135

Microbiol Spectr. 2023 May 25:e0351922. doi: 10.1128/spectrum.03519-22. Online ahead of print.ABSTRACTSaccharomyces kudriavzevii is a cold-tolerant species identified as a good alternative for industrial winemaking. Although S. kudriavzevii has never been found in winemaking, its co-occurrence with Saccharomyces cerevisiae in Mediterranean oaks is well documented. This sympatric association is believed to be possible due to the different growth temperatures of the two yeast species. However, the mechanisms behind the cold tolerance of S. kudriavzevii are not well understood. In this work, we propose the use of a dynamic genome-scale model to compare the metabolic routes used by S. kudriavzevii at two temperatures, 25°C and 12°C, to decipher pathways relevant to cold tolerance. The model successfully recovered the dynamics of biomass and external metabolites and allowed us to link the observed phenotype with exact intracellular pathways. The model predicted fluxes that are consistent with previous findings, but it also led to novel results which we further confirmed with intracellular metabolomics and transcriptomic data. The proposed model (along with the corresponding code) provides a comprehensive picture of the mechanisms of cold tolerance that occur within S. kudriavzevii. The proposed strategy offers a systematic approach to explore microbial diversity from extracellular fermentation data at low temperatures. IMPORTANCE Nonconventional yeasts promise to provide new metabolic pathways for producing industrially relevant compounds and tolerating specific stressors such as cold temperatures. The mechanisms behind the cold tolerance of S. kudriavzevii or its sympatric relationship with S. cerevisiae in Mediterranean oaks are not well understood. This study proposes a dynamic genome-scale model to investigate metabolic pathways relevant to cold tolerance. The predictions of the model would indicate the ability of S. kudriavzevii to produce assimilable nitrogen sources from extracellular proteins present in its natural niche. These predictions were further confirmed with metabolomics and transcriptomic data. This finding suggests that not only the different growth temperature preferences but also this proteolytic activity may contribute to the sympatric association with S. cerevisiae. Further exploration of these natural adaptations could lead to novel engineering targets for the biotechnological industry.PMID:37227304 | DOI:10.1128/spectrum.03519-22

Am J Physiol Renal Physiol. 2023 May 25. doi: 10.1152/ajprenal.00269.2022. Online ahead of print.ABSTRACTHistamine is involved in the immune response, vasodilation, neurotransmission, and gastric acid secretion. Although elevated histamine levels and increased expression of histamine metabolizing enzymes have been reported in renal disease, there is gap in knowledge regarding the mechanisms of histamine-related pathways in the kidney. We report here that all four histamine receptors, as well as enzymes responsible for metabolism of histamine are expressed in human and rat kidney tissues. In this study, we hypothesized that the histaminergic system plays a role in salt-induced kidney damage in Dahl Salt-Sensitive (DSS) rat, a model characterized with inflammation-driven renal lesions. To induce renal damage related to salt-sensitivity, DSS rats were challenged with a 21 days of high salt diet (HS, 4% NaCl); normal salt diet (NS, 0.4% NaCl) fed rats were used as a control. We observed lower histamine decarboxylase (HDC), and higher histamine N-methyltransferase (HNMT) levels in HS diet-fed rats, indicative of a shift in the histaminergic tone; metabolomics showed higher histamine and histidine levels in the kidneys HS diet-fed rats, while plasma levels for both compounds were lower. Acute systemic inhibition of histamine receptor 2 (HR2) in the DSS rat revealed that it lowered vasopressin receptor 2 and AQP2 abundance in the kidney. In summary, we established here the existence of the local histaminergic system, revealed a shift in the renal histamine balance during salt-induced kidney damage, and provided evidence that blockage of HR2 in the DSS rat affects water balance and urine concentrating mechanisms.PMID:37227223 | DOI:10.1152/ajprenal.00269.2022

Biofactors. 2023 May 25. doi: 10.1002/biof.1974. Online ahead of print.ABSTRACTWe aimed to evaluate whether improving maternal diet during lactation in diet-induced obese rats reverts the impact of western diet (WD) consumption on the metabolome of milk and offspring plasma, as well as to identify potential biomarkers of these conditions. Three groups of dams were followed: control-dams (CON-dams), fed with standard diet (SD); WD-dams, fed with WD prior and during gestation and lactation; and reversion-dams (REV-dams), fed as WD-dams but moved to SD during lactation. Metabolomic analysis was performed in milk at lactation days 5, 10, and 15, and in plasma from their male and female offspring at postnatal day 15. Milk of WD-dams presented, throughout lactation and compared to CON-dams, altered profiles of amino acids and of the carnitine pool, accompanied by changes in other polar metabolites, being stachydrine, N-acetylornithine, and trimethylamine N-oxide the most relevant and discriminatory metabolites between groups. The plasma metabolome profile was also altered in the offspring of WD-dams in a sex-dependent manner, and stachydrine, ergothioneine and the acylcarnitine C12:1 appeared as the top three most discriminating metabolites in both sexes. Metabolomic changes were largely normalized to control levels both in the milk of REV-dams and in the plasma of their offspring. We have identified a set of polar metabolites in maternal milk and in the plasma of the offspring whose alterations may indicate maternal intake of an unbalanced diet during gestation and lactation. Levels of these metabolites may also reflect the beneficial effects of implementing a healthier diet during lactation.PMID:37227188 | DOI:10.1002/biof.1974

Neoplasma. 2023 Apr;70(2):260-271. doi: 10.4149/neo_2023_221126N1140.ABSTRACTMetabolic reprogramming is a common feature of glioblastoma (GBM) progression and metastasis. Altered lipid metabolism is one of the most prominent metabolic alterations in cancer. Understanding the links between phospholipid remodeling and GBM tumorigenesis may help develop new anticancer strategies and improve treatments to overcome drug resistance. We used metabolomic and transcriptomic analyses to systematically investigate metabolic and molecular changes in low-grade glioma (LGG) and GBM. We then re-established the reprogrammed metabolic flux and membrane lipid composition in GBM based on metabolomic and transcriptomic analyses. By inhibiting Aurora A kinase via RNA interference (RNAi) and inhibitor treatment, we investigated the effect of Aurora A kinase on phospholipid reprogramming LPCAT1 enzyme expression and GBM cell proliferation in vitro and in vivo. We found that GBM displayed aberrant glycerophospholipid and glycerolipid metabolism compared with LGG. Metabolic profiling indicated that fatty acid synthesis and uptake for phospholipid synthesis were significantly increased in GBM compared to LGG. The unsaturated phosphatidylcholine (PC) and phosphatidylethanolamine (PE) levels were significantly decreased in GBM compared to LGG. The expression level of LPCAT1, which is required for the synthesis of saturated PC and PE, was upregulated in GBM, and the expression of LPCAT4, which is required for the synthesis of unsaturated PC and PE, was downregulated in GBM. Notably, the inhibition of Aurora A kinase by shRNA knockdown and treatment with Aurora A kinase inhibitors such as Alisertib, AMG900, or AT9283 upregulated LPCAT1 mRNA and protein expression in vitro. In vivo, the inhibition of Aurora A kinase with Alisertib increased LPCAT1 protein expression. Phospholipid remodeling and a reduction in unsaturated membrane lipid components were found in GBM. Aurora A kinase inhibition increased LPCAT1 expression and suppressed GBM cell proliferation. The combination of Aurora kinase inhibition with LPCAT1 inhibition may exert promising synergistic effects on GBM.PMID:37226933 | DOI:10.4149/neo_2023_221126N1140

J Integr Plant Biol. 2023 May 25. doi: 10.1111/jipb.13536. Online ahead of print.ABSTRACTMulticellular organisms such as plants contain various cell types with specialized functions. Analyzing the characteristics of each cell type reveals specific cell functions and enhances our understanding of organization and function at the organismal level. Guard cells (GC) are specialized epidermal cells that regulate the movement of the stomata and gaseous exchange, and provide a model genetic system for analyzing cell fate, signaling and function. Several proteomics analyses of GC are available, but these are limited in depth. Here we used enzymatic isolation and flow cytometry to enrich for GC and mesophyll cell protoplasts and perform in-depth proteomics in these two major cell types in Arabidopsis leaves. We identified ~3,000 proteins not previously found in the GC proteome and more than 600 proteins that may be specific to GC. The depth of our proteomics enabled us to uncover a guard cell-specific kinase cascade whereby Raf15 and Snf1-related kinase2.6 (SnRK2.6)/OST1(open stomata 1) mediate abscisic acid (ABA)-induced stomatal closure. RAF15 directly phosphorylated SnRK2.6/OST1 at the conserved Ser175 residue in its activation loop and was sufficient to reactivate the inactive form of SnRK2.6/OST1. ABA-triggered SnRK2.6/OST1 activation and stomatal closure was impaired in raf15 mutants. We also showed enrichment of enzymes and flavone metabolism in GC, and consistent, dramatic accumulation of flavone metabolites. Our study answers the long-standing question of how ABA activates SnRK2.6/OST1 in guard cells and represents a resource potentially providing further insights into the molecular basis of GC and mesophyll cell development, metabolism, structure, and function. This article is protected by copyright. All rights reserved.PMID:37226855 | DOI:10.1111/jipb.13536

ACS Appl Mater Interfaces. 2023 May 25. doi: 10.1021/acsami.2c21485. Online ahead of print.ABSTRACTOsteosarcoma is prone to metastasis and has a low long-term survival rate. The drug treatment of osteosarcoma, side effects of treatment drugs, and prognosis of patients with lung metastasis continue to present significant challenges, and the efficacy of drugs used in the treatment of osteosarcoma remains low. The development of new therapeutic drugs is urgently needed. In this study, we successfully isolated Pinctada martensii mucilage exosome-like nanovesicles (PMMENs). Our findings demonstrated that PMMENs inhibited the viability and proliferation of 143B cells, induced apoptosis, and inhibited cell proliferation by suppressing the activation of the ERK1/2 and Wnt signaling pathways. Furthermore, PMMENs inhibited cell migration and invasion by downregulating N-cadherin, vimentin, and matrix metalloprotease-2 protein expression levels. Transcriptomic and metabolomic analyses revealed that differential genes were co-enriched with differential metabolites in cancer signaling pathways. These results suggest that PMMENs may exert anti-tumor activity by targeting the ERK1/2 and Wnt signaling pathways. Moreover, tumor xenograft model experiments showed that PMMENs can inhibit the growth of osteosarcoma in mice. Thus, PMMENs may be a potential anti-osteosarcoma drug.PMID:37226779 | DOI:10.1021/acsami.2c21485

EMBO Mol Med. 2023 May 25:e16758. doi: 10.15252/emmm.202216758. Online ahead of print.ABSTRACTFAM3C/ILEI is an important cytokine for tumor progression and metastasis. However, its involvement in inflammation remains elusive. Here, we show that ILEI protein is highly expressed in psoriatic lesions. Inducible keratinocyte-specific ILEI overexpression in mice (K5-ILEIind ) recapitulates many aspects of psoriasis following TPA challenge, primarily manifested by impaired epidermal differentiation and increased neutrophil recruitment. Mechanistically, ILEI triggers Erk and Akt signaling, which then activates STAT3 via Ser727 phosphorylation. Keratinocyte-specific ILEI deletion ameliorates TPA-induced skin inflammation. A transcriptomic ILEI signature obtained from the K5-ILEIind model shows enrichment in several signaling pathways also found in psoriasis and identifies urokinase as a targetable enzyme to counteract ILEI activity. Pharmacological inhibition of urokinase in TPA-induced K5-ILEIind mice results in significant improvement of psoriasiform symptoms by reducing ILEI secretion. The ILEI signature distinguishes psoriasis from healthy skin with uPA ranking among the top "separator" genes. Our study identifies ILEI as a key driver in psoriasis, indicates the relevance of ILEI-regulated genes for disease manifestation, and shows the clinical impact of ILEI and urokinase as novel potential therapeutic targets in psoriasis.PMID:37226685 | DOI:10.15252/emmm.202216758

Psychol Med. 2023 May 25:1-10. doi: 10.1017/S003329172300140X. Online ahead of print.ABSTRACTBACKGROUND: Major depression is associated with changes in plasma L-carnitine and acetyl-L-carnitine. But its association with acylcarnitines remains unclear. The aim of this study was to assess metabolomic profiles of 38 acylcarnitines in patients with major depression before and after treatment compared to healthy controls (HCs).METHODS: Metabolomic profiles of 38 plasma short-, medium-, and long-chain acylcarnitines were performed by liquid chromatography-mass spectrometry in 893 HCs from the VARIETE cohort and 460 depressed patients from the METADAP cohort before and after 6 months of antidepressant treatment.RESULTS: As compared to HCs, depressed patients had lower levels of medium- and long-chain acylcarnitines. After 6 months of treatment, increased levels of medium- and long-chain acyl-carnitines were observed that no longer differed from those of controls. Accordingly, several medium- and long-chain acylcarnitines were negatively correlated with depression severity.CONCLUSIONS: These medium- and long-chain acylcarnitine dysregulations argue for mitochondrial dysfunction through fatty acid β-oxidation impairment during major depression.PMID:37226550 | DOI:10.1017/S003329172300140X

Proteomics. 2023 May 24:e2200287. doi: 10.1002/pmic.202200287. Online ahead of print.ABSTRACTCellular communication is essential for cell-cell interactions, maintaining homeostasis and progression of certain disease states. While many studies examine extracellular proteins, the holistic extracellular proteome is often left uncaptured, leaving gaps in our understanding of how all extracellular proteins may impact communication and interaction. We used a cellular-based proteomics approach to more holistically profile both the intracellular and extracellular proteome of prostate cancer. Our workflow was generated in such a manner that multiple experimental conditions can be observed with the opportunity for high throughput integration. Additionally, this workflow is not limited to a proteomic aspect, as metabolomic and lipidomic studies can be integrated for a multi-omics workflow. Our analysis showed coverage of over 8000 proteins while also garnering insights into cellular communication in the context of prostate cancer development and progression. Identified proteins covered a variety of cellular processes and pathways, allowing for the investigation of multiple aspects into cellular biology. This workflow demonstrates advantages for integrating intra- and extracellular proteomic analyses as well as potential for multi-omics researchers. This approach possesses great value for future investigations into the systems biology aspects of disease development and progression.PMID:37226375 | DOI:10.1002/pmic.202200287

Brief Bioinform. 2023 May 23:bbad189. doi: 10.1093/bib/bbad189. Online ahead of print.ABSTRACTEnzymatic reactions are crucial to explore the mechanistic function of metabolites and proteins in cellular processes and to understand the etiology of diseases. The increasing number of interconnected metabolic reactions allows the development of in silico deep learning-based methods to discover new enzymatic reaction links between metabolites and proteins to further expand the landscape of existing metabolite-protein interactome. Computational approaches to predict the enzymatic reaction link by metabolite-protein interaction (MPI) prediction are still very limited. In this study, we developed a Variational Graph Autoencoders (VGAE)-based framework to predict MPI in genome-scale heterogeneous enzymatic reaction networks across ten organisms. By incorporating molecular features of metabolites and proteins as well as neighboring information in the MPI networks, our MPI-VGAE predictor achieved the best predictive performance compared to other machine learning methods. Moreover, when applying the MPI-VGAE framework to reconstruct hundreds of metabolic pathways, functional enzymatic reaction networks and a metabolite-metabolite interaction network, our method showed the most robust performance among all scenarios. To the best of our knowledge, this is the first MPI predictor by VGAE for enzymatic reaction link prediction. Furthermore, we implemented the MPI-VGAE framework to reconstruct the disease-specific MPI network based on the disrupted metabolites and proteins in Alzheimer's disease and colorectal cancer, respectively. A substantial number of novel enzymatic reaction links were identified. We further validated and explored the interactions of these enzymatic reactions using molecular docking. These results highlight the potential of the MPI-VGAE framework for the discovery of novel disease-related enzymatic reactions and facilitate the study of the disrupted metabolisms in diseases.PMID:37225420 | DOI:10.1093/bib/bbad189

J Environ Sci (China). 2023 Sep;131:141-150. doi: 10.1016/j.jes.2022.10.029. Epub 2022 Oct 30.ABSTRACTAdenosine triphosphate (ATP) generation of aquatic organisms is often subject to nanoparticles (NPs) stress, involving extensive reprogramming of gene expression and changes in enzyme activity accompanied by metabolic disturbances. However, little is known about the mechanism of energy supply by ATP to regulate the metabolism of aquatic organisms under NPs stress. Here, we selected extensively existing silver nanoparticles (AgNPs) to investigate their implications on ATP generation and relevant metabolic pathways in alga (Chlorella vulgaris). Results showed that ATP content significantly decreased by 94.2% of the control (without AgNPs) in the algal cells at 0.20 mg/L AgNPs, which was mainly attributed to the reduction of chloroplast ATPase activity (81.4%) and the downregulation of ATPase-coding genes atpB and atpH (74.5%-82.8%) in chloroplast. Molecular dynamics simulations demonstrated that AgNPs competed with the binding sites of substrates adenosine diphosphate and inorganic phosphate by forming a stable complex with ATPase subunit beta, potentially resulting in the reduced binding efficiency of substrates. Furthermore, metabolomics analysis proved that the ATP content positively correlated with the content of most differential metabolites such as D-talose, myo-inositol, and L-allothreonine. AgNPs remarkably inhibited ATP-involving metabolic pathways, including inositol phosphate metabolism, phosphatidylinositol signaling system, glycerophospholipid metabolism, aminoacyl-tRNA biosynthesis, and glutathione metabolism. These results could provide a deep understanding of energy supply in regulating metabolic disturbances under NPs stress.PMID:37225375 | DOI:10.1016/j.jes.2022.10.029

Anal Chim Acta. 2023 Jul 4;1263:341284. doi: 10.1016/j.aca.2023.341284. Epub 2023 Apr 25.ABSTRACTBACKGROUND: Adequately handling unbalanced groups remains one of the major challenges for the analysis of multivariate data collected from multifactorial experimental designs. While partial least squares-based methods, such as analysis of variance multiblock orthogonal partial least squares (AMOPLS), can offer better discrimination between factor levels, they can be more heavily affected by this issue, and unbalanced designs of experiments may lead to a substantial confusion of the effects. Even state-of-the-art analysis of variance (ANOVA) decomposition methodologies using general linear models (GLM) lack the ability to efficiently disentangle these sources of variation when combined with AMOPLS.RESULTS: A versatile solution developed as an extension of a prior rebalancing strategy is proposed for the first decomposition step based on ANOVA. This approach has the advantage of yielding an unbiased estimation of the parameters and retaining the within-group variation in the rebalanced design, while preserving the orthogonality of effect matrices, even in presence of unequal group sizes. This property is of utmost importance for model interpretation because it avoids mixing sources of variation related to the different effects in the design. A real case study involving metabolomic data from in vitro toxicological experiments was used to demonstrate the potential of this strategy to handle unequal group sizes using a supervised approach. Primary 3D rat neural cell cultures were exposed to trimethyltin following a multifactorial design of experiments involving three fixed effect factors.SIGNIFICANCE AND NOVELTY: The rebalancing strategy was demonstrated as a novel and potent solution to handle unbalanced experimental designs by offering unbiased parameter estimators and orthogonal submatrices, thus avoiding confusion of the effects and facilitating model interpretation. Moreover, it can be combined with any multivariate method used for the analysis of high-dimensional data collected from multifactorial designs.PMID:37225336 | DOI:10.1016/j.aca.2023.341284

Infect Genet Evol. 2023 May 22:105449. doi: 10.1016/j.meegid.2023.105449. Online ahead of print.ABSTRACTGonorrhea is an urgent antimicrobial resistance threat and its therapeutic options are continuously getting restricted. Moreover, no vaccine has been approved against it so far. Hence, the present study aimed to introduce novel immunogenic and drug targets against antibiotic-resistant Neisseria gonorrhoeae strains. In the first step, the core proteins of 79 complete genomes of N. gonorrhoeae were retrieved. Next, the surface-exposed proteins were evaluated from different aspects such as antigenicity, allergenicity, conservancy, and B-cell and T-cell epitopes to introduce promising immunogenic candidates. Then, the interactions with human Toll-like receptors (TLR-1, 2, and 4), and immunoreactivity to elicit humoral and cellular immune responses were simulated. On the other hand, to identify novel broad-spectrum drug targets, the cytoplasmic and essential proteins were detected. Then, the N. gonorrhoeae metabolome-specific proteins were compared to the drug targets of the DrugBank, and novel drug targets were retrieved. Finally, the protein data bank (PDB) file availability and prevalence among the ESKAPE group and common sexually transmitted infection (STI) agents were assessed. Our analyses resulted in the recognition of ten novel and putative immunogenic targets including murein transglycosylase A, PBP1A, Opa, NlpD, Azurin, MtrE, RmpM, LptD, NspA, and TamA. Moreover, four potential and broad-spectrum drug targets were identified including UMP kinase, GlyQ, HU family DNA-binding protein, and IF-1. Some of the shortlisted immunogenic and drug targets have confirmed roles in adhesion, immune evasion, and antibiotic resistance that can induce bactericidal antibodies. Other immunogenic and drug targets might be associated with the virulence of N. gonorrhoeae as well. Thus, further experimental studies and site-directed mutations are recommended to investigate the role of potential vaccine and drug targets in the pathogenesis of N. gonorrhoeae.PMID:37225067 | DOI:10.1016/j.meegid.2023.105449