PubMed

J Clin Invest. 2023 Nov 16:e170397. doi: 10.1172/JCI170397. Online ahead of print.ABSTRACTWhile the poor prognosis of glioblastoma arises from the invasion of a subset of tumor cells, little is known of the metabolic alterations within these cells that fuel invasion. We integrated spatially addressable hydrogel biomaterial platforms, patient site-directed biopsies, and multi-omics analyses to define metabolic drivers of invasive glioblastoma cells. Metabolomics and lipidomics revealed elevations in the redox buffers cystathionine, hexosylceramides, and glucosyl ceramides in the invasive front of both hydrogel-cultured tumors and patient site-directed biopsies, with immunofluorescence indicating elevated reactive oxygen species (ROS) markers in invasive cells. Transcriptomics confirmed upregulation of ROS-producing and response genes at the invasive front in both hydrogel models and patient tumors. Amongst oncologic ROS, H2O2 specifically promoted glioblastoma invasion in 3D hydrogel spheroid cultures. A CRISPR metabolic gene screen revealed cystathionine gamma-lyase (CTH), which converts cystathionine to the non-essential amino acid cysteine in the transsulfuration pathway, to be essential for glioblastoma invasion. Correspondingly, supplementing CTH knockdown cells with exogenous cysteine rescued invasion. Pharmacologic CTH inhibition suppressed glioblastoma invasion, while CTH knockdown slowed glioblastoma invasion in vivo. Our studies highlight the importance of ROS metabolism in invasive glioblastoma cells and support further exploration of the transsulfuration pathway as a mechanistic and therapeutic target.PMID:37971886 | DOI:10.1172/JCI170397

Ann Hematol. 2023 Nov 16. doi: 10.1007/s00277-023-05533-7. Online ahead of print.ABSTRACTOBJECTIVES: This study aimed to investigate the incidence rate and spectrum of gene mutations of Glucose-6-phosphate dehydrogenase (G6PD) deficiency in the Huizhou city of southern China to provide a scientific basis for disease prevention and control in the area.METHODS: From March 2003 to December 2022, newborn screening for G6PD enzyme activity was carried out in Huizhou city using the fluorescence quantitative method. Infants who tested positive during the initial screening were diagnosed using the nitroblue tetrazolium ratio method, while a subset of infants received further gene mutation analysis using the multicolor probe melting curve analysis method.RESULTS: A total of 1,291,274 newborns were screened and the screening rate has increased from 20.39% to almost 100%. In the 20-year period, 57,217 (4.43%) infants testing positive during the initial screening. Out of these infants, 49,779 (87%) were recalled for confirmatory testing. G6PD deficiency was confirmed in 39,261 of the recalled infants, indicating a positive predictive value of 78.87%. The estimated incidence rate of G6PD deficiency in the region was 3.49%, which was significantly higher than the average incidence rate of 2.1% in southern China. On the other hand, seven pathogenic G6PD variants were identified in the analysis of the 99 diagnosed infants with the most common being c.1388 G > A (48.5%), followed by c.95 A > G (19.2%), c.1376 G > T (15.2%), c.871 G > A (9.1%), c.1360 C > T (3.0%), c.392 G > T (3.0%), and c.487 G > A (1.0%).CONCLUSION: The incidence of G6PD deficiency in newborns in the Huizhou city was higher than the southern China average level, while the types and frequencies of gene mutations were found to vary slightly from other regions. Our findings suggested that free government screening and nearby diagnosis strategies could reduce the incidence of G6PD deficiency in the area.PMID:37971548 | DOI:10.1007/s00277-023-05533-7

Nucleic Acids Res. 2023 Nov 16:gkad1045. doi: 10.1093/nar/gkad1045. Online ahead of print.ABSTRACTMetaboLights is a global database for metabolomics studies including the raw experimental data and the associated metadata. The database is cross-species and cross-technique and covers metabolite structures and their reference spectra as well as their biological roles and locations where available. MetaboLights is the recommended metabolomics repository for a number of leading journals and ELIXIR, the European infrastructure for life science information. In this article, we describe the continued growth and diversity of submissions and the significant developments in recent years. In particular, we highlight MetaboLights Labs, our new Galaxy Project instance with repository-scale standardized workflows, and how data public on MetaboLights are being reused by the community. Metabolomics resources and data are available under the EMBL-EBI's Terms of Use at https://www.ebi.ac.uk/metabolights and under Apache 2.0 at https://github.com/EBI-Metabolights.PMID:37971328 | DOI:10.1093/nar/gkad1045

Nucleic Acids Res. 2023 Nov 16:gkad1046. doi: 10.1093/nar/gkad1046. Online ahead of print.ABSTRACTThe Bioinformation and DNA Data Bank of Japan (DDBJ) Center (https://www.ddbj.nig.ac.jp) provides database archives that cover a wide range of fields in life sciences. As a founding member of the International Nucleotide Sequence Database Collaboration (INSDC), DDBJ accepts and distributes nucleotide sequence data as well as their study and sample information along with the National Center for Biotechnology Information in the United States and the European Bioinformatics Institute (EBI). Besides INSDC databases, the DDBJ Center provides databases for functional genomics (GEA: Genomic Expression Archive), metabolomics (MetaboBank) and human genetic and phenotypic data (JGA: Japanese Genotype-phenotype Archive). These database systems have been built on the National Institute of Genetics (NIG) supercomputer, which is also open for domestic life science researchers to analyze large-scale sequence data. This paper reports recent updates on the archival databases and the services of the DDBJ Center, highlighting the newly redesigned MetaboBank. MetaboBank uses BioProject and BioSample in its metadata description making it suitable for multi-omics large studies. Its collaboration with MetaboLights at EBI brings synergy in locating and reusing public data.PMID:37971299 | DOI:10.1093/nar/gkad1046

Microbiol Spectr. 2023 Nov 16:e0331223. doi: 10.1128/spectrum.03312-23. Online ahead of print.ABSTRACTHeat stress is one of the main causes of economic losses in the dairy industry worldwide; however, the mechanisms associated with the metabolic and microbial changes in heat stress remain unclear. Here, we characterized both the changes in metabolites, rumen microbial communities, and their functional potential indices derived from rumen fluid and serum samples from cows at different growth stages and under different climates. This study highlights that the rumen microbe may be involved in the regulation of lipid metabolism by modulating the fatty acyl metabolites. Under heat stress, the changes in the metabolic status of growing heifers, heifers, and lactating cows were closely related to arachidonic acid metabolism, fatty acid biosynthesis, and energy metabolism. Moreover, this study provides new markers for further research to understand the effects of heat stress on the physiological metabolism of Holstein cows and the time-dependent changes associated with growth stages.PMID:37971264 | DOI:10.1128/spectrum.03312-23

J Proteome Res. 2023 Nov 16. doi: 10.1021/acs.jproteome.3c00548. Online ahead of print.ABSTRACTProbiotics are live microorganisms that confer health benefits when administered in adequate amounts. They are used to promote gut health and alleviate various disorders. Recently, there has been an increasing interest in the potential effects of probiotics on human physiology. In the presented study, the effects of probiotic treatment on the metabolic profiles of human urine and serum using a nuclear magnetic resonance (NMR)-based metabonomic approach were investigated. Twenty-one healthy volunteers were enrolled in the study, and they received two different dosages of probiotics for 8 weeks. During the study, urine and serum samples were collected from volunteers before and during probiotic supplementation. The results showed that probiotics had a significant impact on the urinary and serum metabolic profiles without altering their phenotypes. This study demonstrated the effects of probiotics in terms of variations of metabolite levels resulting also from the different probiotic posology. Overall, the results suggest that probiotic administration may affect both urine and serum metabolomes, although more research is needed to understand the mechanisms and clinical implications of these effects. NMR-based metabonomic analysis of biofluids is a powerful tool for monitoring host-gut microflora dynamic interaction as well as for assessing the individual response to probiotic treatment.PMID:37970754 | DOI:10.1021/acs.jproteome.3c00548

Explor Target Antitumor Ther. 2023;4(5):812-849. doi: 10.37349/etat.2023.00170. Epub 2023 Sep 28.ABSTRACTFrom attributing mutations to cancers with the advent of cutting-edge genetic technology in recent decades, to re-searching the age-old theory of intrinsic metabolic shift of cancers (Warburg's glycolysis), the quest for a precise panacea for mainly the metastatic cancers, remains incessant. This review delineates the advanced glycation end product (AGE)-receptor for AGE (RAGE) pathway driven intricate oncogenic cues, budding from the metabolic (glycolytic) reliance of tumour cells, branching into metastatic emergence of malignancies. Strong AGE-RAGE concomitance in metastasis, chemo-resistance and cancer resurgence adversely incite disease progression and patient mortality. At the conjunction of metabolic and metastatic shift of cancers, are the "glycolytically" generated AGEs and AGE-activated RAGE, instigating aberrant molecular pathways, culminating in aggressive malignancies. AGEs as by-products of metabolic insurgence, modify the metabolome, epigenome and microbiome, besides coercing the inter-, intra- and extra-cellular micro-milieu conducive for oncogenic events like epithelial-mesenchymal transition (EMT). AGE-RAGE synergistically elicit ATP surge for surplus energy, autophagy for apoptotic evasion and chemo-resistance, insulin-like growth factor 1 (IGF-1) for meta-inflammation and angiogenesis, high mobility group box-1 (HMGB1) for immune tolerance, S100 proteins for metastasis, and p53 protein attenuation for tumour suppression. AGEs are pronouncedly reported in invasive forms of breast, prostate, colon and pancreatic cancers, higher in patients with cancer than healthy counterparts, and higher in advanced stage than localized phase. Hence, the investigation of person-specific presence of AGEs, soluble RAGE and AGE-activated RAGE can be advocated as impending bio-markers for diagnostic, prognostic and therapeutic purposes, to predict cancer risk in patients with diabetes, obesity, metabolic syndrome as well as general population, to monitor prognosis and metastasis in patients with cancer, and to reckon complications in cancer survivors. Furthermore, clinical reports of exogenous (dietary) and endogenous (internally formed) AGEs in cancer patients, and contemporary clinical trials involving AGE-RAGE axis in cancer are underlined with theranostic implications.PMID:37970208 | PMC:PMC10645465 | DOI:10.37349/etat.2023.00170

Chin J Cancer Res. 2023 Oct 30;35(5):550-562. doi: 10.21147/j.issn.1000-9604.2023.05.11.ABSTRACTOBJECTIVE: As an important part of metabolomics analysis, untargeted metabolomics has become a powerful tool in the study of tumor mechanisms and the discovery of metabolic markers with high-throughput spectrometric data which also poses great challenges to data analysis, from the extraction of raw data to the identification of differential metabolites. To date, a large number of analytical tools and processes have been developed and constructed to serve untargeted metabolomics research. The different selection of analytical tools and parameter settings lead to varied results of untargeted metabolomics data. Our goal is to establish an easily operated platform and obtain a repeatable analysis result.METHODS: We used the R language basic environment to construct the preprocessing system of the original data and the LAMP (Linux+Apache+MySQL+PHP) architecture to build a cloud mass spectrum data analysis system.RESULTS: An open-source analysis software for untargeted metabolomics data (openNAU) was constructed. It includes the extraction of raw mass data and quality control for the identification of differential metabolic ion peaks. A reference metabolomics database based on public databases was also constructed.CONCLUSIONS: A complete analysis system platform for untargeted metabolomics was established. This platform provides a complete template interface for the addition and updating of the analysis process, so we can finish complex analyses of untargeted metabolomics with simple human-computer interactions. The source code can be downloaded from https://github.com/zjuRong/openNAU.PMID:37969962 | PMC:PMC10643343 | DOI:10.21147/j.issn.1000-9604.2023.05.11

J Biomol Tech. 2023 Aug 7;34(3):3fc1f5fe.a058bad4. doi: 10.7171/3fc1f5fe.a058bad4. eCollection 2023 Sep 30.ABSTRACTMetaproteomics research using mass spectrometry data has emerged as a powerful strategy to understand the mechanisms underlying microbiome dynamics and the interaction of microbiomes with their immediate environment. Recent advances in sample preparation, data acquisition, and bioinformatics workflows have greatly contributed to progress in this field. In 2020, the Association of Biomolecular Research Facilities Proteome Informatics Research Group launched a collaborative study to assess the bioinformatics options available for metaproteomics research. The study was conducted in 2 phases. In the first phase, participants were provided with mass spectrometry data files and were asked to identify the taxonomic composition and relative taxa abundances in the samples without supplying any protein sequence databases. The most challenging question asked of the participants was to postulate the nature of any biological phenomena that may have taken place in the samples, such as interactions among taxonomic species. In the second phase, participants were provided a protein sequence database composed of the species present in the sample and were asked to answer the same set of questions as for phase 1. In this report, we summarize the data processing methods and tools used by participants, including database searching and software tools used for taxonomic and functional analysis. This study provides insights into the status of metaproteomics bioinformatics in participating laboratories and core facilities.PMID:37969874 | PMC:PMC10644979 | DOI:10.7171/3fc1f5fe.a058bad4

Food Sci Anim Resour. 2023 Nov;43(6):1044-1054. doi: 10.5851/kosfa.2023.e54. Epub 2023 Nov 1.ABSTRACTGrowing evidence indicates a crucial role of the gut microbiota in physiological functions. Gut-brain axis imbalance has also been associated with neuropsychiatric and neurodegenerative disorders. Studies have suggested that probiotics regulate the stress response and alleviate mood-related symptoms. In this study, we investigated the effects of the probiotic Lacticaseibacillus rhamnosus IDCC3201 (L3201) on the behavioral response and fecal metabolite content in an unpredictable chronic mild stress (UCMS) mouse model. Our study shows that chronic stress in mice for three weeks resulted in significant changes in behavior, including lower locomotor activity, higher levels of anxiety, and depressive-like symptoms, compared to the control group. Metabolomic analysis demonstrated that disrupted fecal metabolites associated with aminoacyl-tRNA biosynthesis and valine, leucine, and isoleucine biosynthesis by UCMS were restored with the administration of L3201. Oral administration of the L3201 ameliorated the observed changes and improved the behavioral alterations along with fecal metabolites, suggesting that probiotics play a neuroprotective role.PMID:37969325 | PMC:PMC10636227 | DOI:10.5851/kosfa.2023.e54

Food Sci Anim Resour. 2023 Nov;43(6):1067-1086. doi: 10.5851/kosfa.2023.e63. Epub 2023 Nov 1.ABSTRACTWith rapid advances in meat science in recent decades, changes in meat quality during the pre-slaughter phase of muscle growth and the post-slaughter process from muscle to meat have been investigated. Commonly used techniques have evolved from early physicochemical indicators such as meat color, tenderness, water holding capacity, flavor, and pH to various omic tools such as genomics, transcriptomics, proteomics, and metabolomics to explore fundamental molecular mechanisms and screen biomarkers related to meat quality and taste characteristics. This review highlights the application of omics and integrated multi-omics in meat quality and taste characteristics studies. It also discusses challenges and future perspectives of multi-omics technology to improve meat quality and taste. Consequently, multi-omics techniques can elucidate the molecular mechanisms responsible for changes of meat quality at transcriptome, proteome, and metabolome levels. In addition, the application of multi-omics technology has great potential for exploring and identifying biomarkers for meat quality and quality control that can make it easier to optimize production processes in the meat industry.PMID:37969318 | PMC:PMC10636221 | DOI:10.5851/kosfa.2023.e63

Acta Neuropsychiatr. 2023 Nov 16:1-50. doi: 10.1017/neu.2023.52. Online ahead of print.ABSTRACTOBJECTIVE: We aimed to answer the questions of whether early-life (perinatal and/or juvenile) exercise can induce antidepressant-like effects in a validated rodent model of depression, and whether such early-life intervention could prevent or reverse the adverse effects of early-life stress in their offspring.METHODS: Male and female FSL rats born to a dam that exercised during gestation, or not, were either maternally separated between PND02 and 16 and weaned on PND17, or not. Half of these animals then underwent a fourteen-day low intensity exercise regimen from PND22. Baseline depressive-like behaviour was assessed on PND21 and then reassessed on PND36, whereafter hippocampal monoamine levels, redox state markers and metabolic markers, relevant to mitochondrial function were measured.RESULTS: Prepubertal exercise was identified as the largest contributing factor to the observed effects, where it decreased immobility time in the FST by 6%, increased time spent in the open arms of the EPM by 9%. Hippocampal serotonin and norepinephrine levels were also increased by 35 and 26%, respectively, whilst nicotinic acid was significantly decreased.CONCLUSION: These findings suggests that prepubertal low intensity exercise induces beneficial biological alterations that could translate into antidepressant behaviour in genetically susceptible individuals.PMID:37969008 | DOI:10.1017/neu.2023.52

Probl Endokrinol (Mosk). 2023 Nov 11;69(5):45-54. doi: 10.14341/probl13278.ABSTRACTAgeing (as known as eldering, senescence) is a genetically and epigenetically programmed pathophysiological process. Velocity of biological ageing is defined as balance between alteration and reparation of body structures. According to last World Health Organization (WHO) highlights ageing still stays an extremely actual scientific, social and demographic problem: in 2020 total number of people older than 60 years and older was 1 billion people; in 2030 future number may be 1,4 billion people, in 2050 - 2,1 billion people. Absence of single universal theory of aging nowadays is reason for scientifical and clinical collaboration between biologists and doctors, including endocrinologists. Designing of potentially effective newest anti-ageing strategies (such as natural/synthetic telomerase regulators, mesenchymal stem cells etc.) is of interest to scientific community. The aim of present article is a review of modern omics (genomic, proteomic, metabolomic) ageing mechanisms, potential ways of targeted prevention and treatment of age-related disease according to conception of personalized medicine. Present review is narrative, it does not lead to systematic review, meta-analysis and does not aim to commercial advertisement. Review has been provided via PubMed article that have been published since 1979 until 2022.PMID:37968951 | DOI:10.14341/probl13278

J Dent Res. 2023 Nov 15:220345231203562. doi: 10.1177/00220345231203562. Online ahead of print.ABSTRACTSystemic metabolic signatures of oral diseases have been rarely investigated, and prospective studies do not exist. We analyzed whether signs of current or past infectious/inflammatory oral diseases are associated with circulating metabolites. Two study populations were included: the population-based Health-2000 (n = 6,229) and Parogene (n = 452), a cohort of patients with an indication to coronary angiography. Health-2000 participants (n = 4,116) provided follow-up serum samples 11 y after the baseline. Serum concentrations of 157 metabolites were determined with a nuclear magnetic resonance spectroscopy-based method. The associations between oral parameters and metabolite concentrations were analyzed using linear regression models adjusted for age, sex, number of teeth, smoking, presence of diabetes, and education (in Health-2000 only). The number of decayed teeth presented positive associations with low-density lipoprotein diameter and the concentrations of pyruvate and citrate. Negative associations were found between caries and the unsaturation degree of fatty acids (FA) and relative proportions of docosahexaenoic and omega-3 FAs. The number of root canal fillings was positively associated with very low-density lipoprotein parameters, such as diameter, cholesterol, triglycerides, and number of particles. Deepened periodontal pockets were positively associated with concentrations of cholesterol, triglycerides, pyruvate, leucine, valine, phenylalanine, and glycoprotein acetyls and negatively associated with high-density lipoprotein (HDL) diameter, FA unsaturation degree, and relative proportions of omega-6 and polyunsaturated FAs. Bleeding on probing (BOP) was associated with increased concentrations of triglycerides and glycoprotein acetyls, as well as decreased proportions of omega-3 and omega-6 FAs. Caries at baseline predicted alterations in apolipoprotein B-containing lipoproteins and HDL-related metabolites in the follow-up, and both caries and BOP were associated with changes in HDL-related metabolites and omega-3 FAs in the follow-up. Signs of current or past infectious/inflammatory oral diseases, especially periodontitis, were associated with metabolic profiles typical for inflammation. Oral diseases may represent a modifiable risk factor for systemic chronic inflammation and thus cardiometabolic disorders.PMID:37968796 | DOI:10.1177/00220345231203562

BMC Plant Biol. 2023 Nov 16;23(1):567. doi: 10.1186/s12870-023-04585-1.ABSTRACTBACKGROUND: Edgeworthia chrysantha, a deciduous shrub endemic to China, is known for its high ornamental value, extensive cultivation history, and wide-ranging applications. However, theoretical research on this plant is severely lacking. While its flowering process displays striking color transitions from green (S1) to yellow (S2) and then to white (S3), the scientific exploration of this phenomenon is limited, and the underlying regulatory mechanisms are yet to be elucidated.RESULTS: Correlation analysis between phenotypic measurements and pigment content revealed that carotenoids and chlorophyll are the key pigments responsible for the color changes. Metabolomic analysis of carotenoids demonstrated that lutein and β-carotene were present at higher levels in S1, while S2 exhibited increased diversity and quantity of carotenoids compared to other stages. Notably, antheraxanthin, zeaxanthin, lycopene, and α-cryptoxanthin showed significant increases. In S3, apart from the colorless phytoene, other carotenoid metabolites were significantly reduced to extremely low levels. Transcriptomic data indicated that PSY, Z-ISO, crtZ, ZEP, PDS and ZDS are key genes involved in carotenoid biosynthesis and accumulation, while NCED plays a crucial role in carotenoid degradation. SGR was identified as a key gene contributing to the progressive decline in chlorophyll content. Additionally, three transcription factors potentially regulating carotenoid metabolism were also identified.CONCLUSIONS: This study represents the first systematic investigation, spanning from phenotypic to molecular levels, of the color-changing phenomenon in E. chrysantha. The study elucidates the crucial pigments, metabolites, genes, and transcription factors responsible for flower color changes during the flowering process, thereby providing preliminary understanding of the intrinsic regulatory mechanisms. These findings establish a theoretical foundation for the genetic improvement of flower color in E. chrysantha.PMID:37968605 | DOI:10.1186/s12870-023-04585-1

Adv Biol (Weinh). 2023 Nov 15:e2300404. doi: 10.1002/adbi.202300404. Online ahead of print.ABSTRACTTrehalose is synthesized in insects through the trehalose 6-phosphate synthase and phosphatase (TPS/TPP) pathway. TPP dephosphorylates trehalose 6-phosphate to release trehalose. Trehalose is involved in metamorphosis, but its relation with body weight, size, and developmental timing is unexplored. The expression and activity of TPS/TPP fluctuate depending on trehalose demand. Thus, TPS/TPP inhibition can highlight the significance of trehalose in insect physiology. TPS/TPP transcript levels are elevated in the pre-pupal and pupal stages in Helicoverpa armigera. The inhibition of recombinantly expressed TPP by N-(phenylthio)phthalimide (NPP), is validated by in vitro assays. In vivo inhibition of trehalose synthesis reduces larval weight and size, hampers metamorphosis, and reduces its overall fitness. Insufficient trehalose leads to a shift in glucose flux, reduced energy, and dysregulated fatty acid oxidation. Metabolomics reaffirms the depletion of trehalose, glucose, glucose 6-phosphate, and suppressed tricarboxylic acid cycle. Reduced trehalose hampers the energy level affecting larval vitality. Through trehalose synthesis inhibition, the importance of trehalose in insect physiology and development is investigated. Also, in two other lepidopterans, TPP inhibition impedes physiology and survival. NPP is also found to be effective as an insecticidal formulation. Overall, trehalose levels affect the larval size, weight, and metabolic homeostasis for larval-pupal transition in lepidoptera.PMID:37968550 | DOI:10.1002/adbi.202300404

Stem Cell Res Ther. 2023 Nov 14;14(1):329. doi: 10.1186/s13287-023-03516-z.ABSTRACTBACKGROUND: Mesenchymal stem cells (MSCs) have immunomodulatory properties and therapeutic effects on autoimmune diseases through their secreted factors, referred to as the secretome. However, the specific key factors of the MSC secretome and their mechanisms of action in immune cells have not been fully determined. Most in vitro experiments are being performed using immune cells, but experiments using natural killer (NK) cells have been neglected, and a few studies using NK cells have shown discrepancies in results. NK cells are crucial elements of the immune system, and adjustment of their activity is essential for controlling various pathological conditions. The aim of this study was to elucidate the role of the adipose tissue-derived stem cell (ADSC) secretome on NK cell activity.METHODS: To obtain the ADSC secretome, we cultured ADSCs in medium and concentrated the culture medium using tangential flow filtration (TFF) capsules. We assessed NK cell viability and proliferation using CCK-8 and CFSE assays, respectively. We analyzed the effects of the ADSC secretome on NK cell activity and pathway-related proteins using a combination of flow cytometry, ELISA, cytotoxicity assay, CD107a assay, western blotting, and quantitative real-time PCR. To identify the composition of the ADSC secretome, we performed LC-MS/MS profiling and bioinformatics analysis. To elucidate the molecular mechanisms involved, we used mRNA sequencing to profile the transcriptional expression of human blood NK cells.RESULTS: The ADSC secretome was found to restrict IL-2-mediated effector function of NK cells while maintaining proliferative potency. This effect was achieved through the upregulation of the inhibitory receptor CD96, as well as downregulation of activating receptors and IL-2 receptor subunits IL-2Rα and IL-2Rγ. These changes were associated with attenuated JAK-STAT and AKT pathways in NK cells, which were achieved through the upregulation of cytokine-inducible SH2-containing protein (CIS, encoded by Cish) and dual specificity protein phosphatase 4 (DUSP4). Furthermore, proteomic analysis revealed twelve novel candidates associated with the immunomodulatory effects of MSCs.CONCLUSIONS: Our findings reveal a detailed cellular outcome and regulatory mechanism of NK cell activity by the ADSC secretome and suggest a therapeutic tool for treating NK-mediated inflammatory and autoimmune diseases using the MSC secretome.PMID:37964351 | PMC:PMC10648656 | DOI:10.1186/s13287-023-03516-z

J Appl Genet. 2023 Nov 16. doi: 10.1007/s13353-023-00799-z. Online ahead of print.ABSTRACTLambdoid bacteriophages are excellent models in studies on molecular aspects of virus-host interactions. However, some of them carry genes encoding toxins which are responsible for virulence of pathogenic strains of bacteria. Shiga toxin-converting bacteriophages (Stx phages) encode Shiga toxins that cause virulence of enterohemorrhagic Escherichia coli (EHEC), and their effective production depends on Stx prophage induction. The exo-xis region of the lambdoid phage genome consists of genes which are dispensable for the phage multiplication under laboratory conditions; however, they might modulate the virus development. Nevertheless, their exact effects on the phage and host physiology remained unclear. Here, we present results of complex studies on the role of the exo-xis region of bacteriophage Φ24B, one of Stx2b phages. Transcriptomic analyses, together with proteomic and metabolomic studies, provided the basis for understanding the functions of the exo-xis region. Genes from this region promoted lytic development of the phage over lysogenization. Moreover, expression of the host genes coding for DnaK, DnaJ, GrpE, and GroELS chaperones was impaired in the cells infected with the Δexo-xis phage mutant, relative to the wild-type virus, corroborating the conclusion about lytic development promotion by the exo-xis region. Proteomic and metabolomic analyses indicated also modulation of gad and nrf operons, and levels of amino acids and acylcarnitines, respectively. In conclusion, the exo-xis region controls phage propagation and host metabolism by influencing expression of different phage and bacterial genes, directing the virus to the lytic rather than lysogenic developmental mode.PMID:37968427 | DOI:10.1007/s13353-023-00799-z

Geroscience. 2023 Nov 16. doi: 10.1007/s11357-023-01005-y. Online ahead of print.ABSTRACTOlder women and Black individuals are more likely to experience frailty. A metabolomic characterization of frailty may help inform more effective interventions aimed at improving health, reducing disparities, and preventing frailty with aging. We sought to identify metabolites and pathways associated with vigor to frailty and determine whether associations differed by sex and/or race among n = 2189 older Black and White men and women from the Health, Aging, and Body Composition (Health ABC) study. Fasting plasma metabolites were measured using liquid chromatography-mass spectrometry. Vigor to frailty was based on weight change, physical activity, gait speed, grip strength, and usual energy. We used linear regression of a single metabolite on vigor to frailty, adjusting for age, sex, race, study site, and multiple comparisons using a Bonferroni correction. Among 500 metabolites, 113 were associated with vigor to frailty (p < 0.0001). Associations between metabolites and vigor to frailty did not differ significantly by race and/or sex. Lower amino acids, glycerophospholipids, sphingolipids, and dehydroepiandrosterone sulfate and higher acylcarnitines, fatty acids, amino acid derivatives, organic acids, carbohydrates, citric acid cycle metabolites, and trimethylamine oxide were associated with frailer scores. Pathway analyses identified the citric acid cycle as containing more frailty-associated metabolites than expected by chance (p = 0.00005). Calories and protein intake did not differ by vigor to frailty. Frailer Health ABC participants may have lower utilization of energy pathways, potentially as a result of less demand and less efficient utilization of similar amounts of nutrients when compared to more vigorous participants.PMID:37968423 | DOI:10.1007/s11357-023-01005-y

Nat Commun. 2023 Nov 15;14(1):7385. doi: 10.1038/s41467-023-43315-x.ABSTRACTInfections and vaccines can induce enhanced long-term responses in innate immune cells, establishing an innate immunological memory termed trained immunity. Here, we show that monocytes with a trained immunity phenotype, due to exposure to the Bacillus Calmette-Guérin (BCG) vaccine, are characterized by an increased biosynthesis of different lipid mediators (LM) derived from long-chain polyunsaturated fatty acids (PUFA). Pharmacological and genetic approaches show that long-chain PUFA synthesis and lipoxygenase-derived LM are essential for the BCG-induced trained immunity responses of human monocytes. Furthermore, products of 12-lipoxygenase activity increase in monocytes of healthy individuals after BCG vaccination. Grasping the underscoring lipid metabolic pathways contributes to our understanding of trained immunity and may help to identify therapeutic tools and targets for the modulation of innate immune responses.PMID:37968313 | DOI:10.1038/s41467-023-43315-x