PubMed

Heart Vessels. 2024 Aug 31. doi: 10.1007/s00380-024-02452-z. Online ahead of print.ABSTRACTHeart failure (HF) is a complex, heterogeneous syndrome with several comorbidities, often life-threatening and requires urgent therapy. In HF, metabolic alterations that can be assessed using comprehensive plasma, and tissue profiling will help establish new biomarkers and therapeutic targets. Metabolomic analysis of sudden death in HF cases remains unresolved. We prospectively evaluated 19 patients who underwent implantable cardioverter defibrillator (ICD) placement for the primary prevention of sudden cardiac death (SCD). Metabolomic analysis was performed using plasma samples before ICD implantation. Ventricular arrhythmia (VA)/SCD was defined as VA with an appropriate ICD therapy or SCD. During a median follow-up of 29 months (range, 13-35 months), four patients developed VA and one patient developed SCD. Using metabolomic analysis, arginine, lysine, and valine were significantly reduced in patients with VA/SCD (n = 5) compared with those without VA/SCD (n = 14). The molecules involved in energy metabolism might be associated with VA/SCD, thus requiring further investigation as a predictive value of metabolomic analysis of VA/SCD.PMID:39215819 | DOI:10.1007/s00380-024-02452-z

Anal Bioanal Chem. 2024 Aug 31. doi: 10.1007/s00216-024-05490-8. Online ahead of print.ABSTRACTBiomarkers and their concentration levels are critical indicators of metabolomics for clinical applications. Rapid and sensitive analysis methods are essential for realizing timely and efficient quantitation of those significant biomarkers. In this work, a self-driven microfluidic immunosensor was developed for rapid all-in-one separation, enrichment, and detection of biomarkers. This immunosensor was constructed from a cyclic olefin copolymer (COC) channel layer and a polydimethylsiloxane (PDMS) sensing layer. The COC channel layer was modified through protein adsorption, immobilization, and remaining active site blocking. The obtained hydrophilic microchannels not only reduce the nonspecific adsorption, but also provide stable capillary-driven flow generation with linear velocities up to 20 mm/s for aqueous solution auto-injection. The PDMS sensing layer was modified using capture antibodies to accomplish affinity recognition of target biomarkers. Procalcitonin (PCT) and serum amyloid A (SAA) were selected as model biomarkers in the feasibility study on applying the self-driven microfluidic immunosensor to bioassay. The limits of detection of PCT and SAA were 7.9 ng/L and 7.6 μg/L, respectively. Moreover, the whole process can be accomplished within 60 min with excellent selectivity and reproducibility. In clinical serum sample analysis, satisfactory recoveries were achieved for PCT and SAA in the ranges of 85.0-103.0% and 95.5-106.0%, respectively, with relative standard deviations less than 5.3%. The method accuracy was further confirmed by the results of commercial immunoassay kits. This simple and easily operated immunosensor provides a rapid and sensitive biomarker analysis tool, and promotes the further development of automated and easy-to-use microfluidic immunoassays.PMID:39215774 | DOI:10.1007/s00216-024-05490-8

ACS Nano. 2024 Aug 31. doi: 10.1021/acsnano.4c03451. Online ahead of print.ABSTRACTMetal-organic framework nanoparticles (MOF NPs) have received much attention for their potential use in nanopesticides. However, little is known about the potential health and environmental risks associated with these materials. In this study, the toxicological responses of zebrafish exposed to five MOF NPs for short and long periods of time were evaluated. The acute toxicity results showed that the toxicity of the five MOF NPs to zebrafish embryos and adult zebrafish was in the order of Cu-MOF > ZIF-90 > ZIF-8 > Fe-MOF > Zr-MOF. Histopathological analysis revealed that ZIF-8, ZIF-90, and Cu-MOF NPs caused liver swelling and vacuolization in zebrafish. The cellular ultrastructure showed that ZIF-8, ZIF-90, and Cu-MOF NPs severely damaged the mitochondrial structure in intestinal epithelial cells and liver cells. The 16S rDNA sequencing data showed that all five MOF NPs significantly altered the dominant microorganisms in the zebrafish intestine. The microbial markers of intestinal inflammation, Proteobacteria (Aeromonas, Plesiomonas, and Legionella), were significantly increased in the Fe-MOF, ZIF-8, Zr-MOF, and Cu-MOF treatment groups. Metabolomics results indicated that the levels of inflammatory promoting factors (Leukotriene E4, 20-hydroxyeicosatetraenoic acid) in arachidonic acid metabolism were decreased, and the levels of inflammatory suppressing factors (8,9-epoxyeicosatrienoic acid) were increased. Metabolites related to oxidative stress, such as glutamine, pyridoxamine, and l-glutamic acid in vitamin B6 metabolism and other signaling pathways, were significantly reduced. Overall, these results suggest that the different MOF NPs had widely varying toxicity to zebrafish, and further attention should be paid to the toxicity of MOF NPs in the real environment.PMID:39215720 | DOI:10.1021/acsnano.4c03451

J Sep Sci. 2024 Sep;47(17):e2400421. doi: 10.1002/jssc.202400421.ABSTRACTShaoyao Gancao Decoction (SGD), a traditional Chinese medicine, has been proven to have a good liver protection effect, but the mechanism and pharmacodynamic substances of SGD in the treatment of acute liver injury are still unclear. In this study, an ultra-high-performance liquid chromatography-quadrupole-time-of-flight mass spectrometry (UHPLC-Q-TOF-MS) method was established to characterize 107 chemical components of SGD and 12 compounds absorbed in rat plasma samples after oral administration of SGD. Network pharmacology was applied to construct a component-target-pathway network to screen the possible effective components of SGD in acute liver injury. Using lipidomics based on UHPLC-Q-TOF-MS coupled with a variety of statistical analyses, 20 lipid biomarkers were screened and identified, suggesting that the improvement of acute liver injury by SGD was involved in cholesterol metabolism, glycerol-phospholipid metabolism, sphingolipid signaling pathways and fatty acid biosynthesis. In addition, the UHPLC-tandem MS method was established for pharmacokinetics analysis, and 10 potential active components were determined simultaneously within 12 min through the optimization of 0.1% formic acid water and acetonitrile as a mobile phase system. A Pharmacokinetics study showed that paeoniflorin, albiflorin, oxypaeoniflorin, liquiritigenin, isoliquiritigenin, liquiritin, ononin, formononetin, glycyrrhizic acid, and glycyrrhetinic acid as the potential active compounds of SGD curing acute liver injury.PMID:39215583 | DOI:10.1002/jssc.202400421

Commun Biol. 2024 Aug 30;7(1):1065. doi: 10.1038/s42003-024-06760-y.ABSTRACTCytidine deaminase (CDA) converts cytidine and deoxycytidine into uridine and deoxyuridine as part of the pyrimidine salvage pathway. Elevated levels of CDA are found in pancreatic tumors and associated with chemoresistance. Recent evidence suggests that CDA has additional functions in cancer cell biology. In this work, we uncover a novel role of CDA in pancreatic cancer cell metabolism. CDA silencing impairs mitochondrial metabolite production, respiration, and ATP production in pancreatic cancer cells, leading to a so-called Pasteur effect metabolic shift towards glycolysis. Conversely, we find that CDA expression promotes mitochondrial biogenesis and oxidative phosphorylation, independently of CDA deaminase activity. Furthermore, we observe that patient primary cells overexpressing CDA are more sensitive to mitochondria-targeting drugs. Collectively, this work shows that CDA plays a non-canonical role in pancreatic cancer biology by promoting mitochondrial function, which could be translated into novel therapeutic vulnerabilities.PMID:39215188 | DOI:10.1038/s42003-024-06760-y

Sci Rep. 2024 Aug 30;14(1):20155. doi: 10.1038/s41598-024-71211-x.ABSTRACTThe limited understanding of the molecular mechanism underlying MYCN-amplified (MNA) neuroblastoma (NB) has hindered the identification of effective therapeutic targets for MNA NB, contributing to its higher mortality rate compared to MYCN non-amplified (non-MNA) NB. Therefore, a comprehensive analysis integrating metabolomics and transcriptomics was conducted to systematically investigate the MNA NB. Metabolomics analysis utilized plasma samples from 28 MNA NB patients and 68 non-MNA NB patients, while transcriptomics analysis employed tissue samples from 15 MNA NB patients and 37 non-MNA NB patients. Notably, joint metabolomics and transcriptomics analysis was performed. A total of 46 metabolites exhibited alterations, with 21 displaying elevated levels and 25 demonstrating reduced levels in MNA NB. In addition, 884 mRNAs in MNA NB showed significant changes, among which 766 mRNAs were higher and 118 mRNAs were lower. Joint-pathway analysis revealed three aberrant pathways involving glycerolipid metabolism, purine metabolism, and lysine degradation. This study highlights the substantial differences in metabolomics and transcriptomics between MNA NB and non-MNA NB, identifying three abnormal metabolic pathways that may serve as potential targets for understanding the molecular mechanisms underlying MNA NB.PMID:39215128 | DOI:10.1038/s41598-024-71211-x

Sci Rep. 2024 Aug 30;14(1):20240. doi: 10.1038/s41598-024-71073-3.ABSTRACTAs environmental and health concerns of beef production and consumption mount, there is growing interest in agroecological production methods, including finishing beef cattle on pastures with phytochemically diverse grasses, forbs, and/or shrubs. The goal of this metabolomics, lipidomics, and fatty acid methyl ester profiling study was to compare meat (pectoralis profundus) of Black Angus cattle from two commercial US beef finishing systems (pasture-finished on Western U.S. rangeland; n = 18 and grain-finished in a Midwest U.S. feedlot; n = 18). A total of 907 out of 1575 compounds differed in abundance between pasture-finished and grain-finished beef samples (all, false discovery rate adjusted P < 0.05). Pasture-finished beef contained higher levels of phenolic antioxidants (2.6-fold), alpha-tocopherol (3.1-fold), nicotinate/vitamin B3 (9.4-fold), choline (1.2-fold), myo-inositol (1.8-fold), and omega-3 fatty acids (4.1-fold). Grain-finished beef contained higher levels of gamma-tocopherol (14.6-fold), nicotinamide/vitamin B3 (1.5-fold), pantothenate/vitamin B5 (1.3-fold), and pyridoxine/vitamin B6 (1.3-fold); indicating that feeding some grain (by-products) could be beneficial to increase levels of certain B-vitamins. Pasture-finished beef samples also displayed lower levels of oxidative stress (homocysteine, 0.6-fold; and 4-hydroxy-nonenal-glutathione, 0.4-fold) and improved mitochondrial function (1.3-fold) compared to grain-finished animals. Two potential metabolites of fluoroquinolone antibiotics, 2,8-quinolinediol and 2,8-quinolinediol sulfate, were only observed in grain-finished beef, though the source remains unknown. While pasture-finished cattle displayed improved markers of metabolic health and concentrated additional, potentially health-promoting compounds in their meat, our findings should not be interpreted as that grain-finished beef is unhealthy to consume. Randomized controlled trials in humans are required to further assess whether observed differences between pasture-finished and feedlot-finished beef have an appreciable effect on human health.PMID:39215122 | DOI:10.1038/s41598-024-71073-3

Nat Rev Immunol. 2024 Aug 30. doi: 10.1038/s41577-024-01084-8. Online ahead of print.NO ABSTRACTPMID:39215056 | DOI:10.1038/s41577-024-01084-8

Nat Commun. 2024 Aug 30;15(1):7533. doi: 10.1038/s41467-024-51989-0.ABSTRACTPolymers can facilitate detergent-free extraction of membrane proteins into nanodiscs (e.g., SMALPs, DIBMALPs), incorporating both integral membrane proteins as well as co-extracted native membrane lipids. Lipid-only SMALPs and DIBMALPs have been shown to possess a unique property; the ability to exchange lipids through 'collisional lipid mixing'. Here we expand upon this mixing to include protein-containing DIBMALPs, using the rhomboid protease GlpG. Through lipidomic analysis before and after incubation with DMPC or POPC DIBMALPs, we show that lipids are rapidly exchanged between protein and lipid-only DIBMALPs, and can be used to identify bound or associated lipids through 'washing-in' exogenous lipids. Additionally, through the requirement of rhomboid proteases to cleave intramembrane substrates, we show that this mixing can be performed for two protein-containing DIBMALP populations, assessing the native function of intramembrane proteolysis and demonstrating that this mixing has no deleterious effects on protein stability or structure.PMID:39215029 | DOI:10.1038/s41467-024-51989-0

J Allergy Clin Immunol. 2024 Aug 28:S0091-6749(24)00869-8. doi: 10.1016/j.jaci.2024.08.017. Online ahead of print.ABSTRACTBACKGROUND: Wheezing in childhood is prevalent, with over half of all children experiencing at least one episode by age six. The pathophysiology of wheeze, especially why some children develop asthma while others do not, remains unclear.OBJECTIVE: This study addresses the knowledge gap by investigating the transition from preschool wheeze to asthma using multi-omic profiling.METHODS: Unsupervised, group-agnostic integrative multi-omic factor analysis was performed using host/bacterial (meta-)transcriptomic and bacterial shotgun metagenomic datasets from bronchial brush samples paired with metabolomic/lipidomic data from bronchoalveolar lavage samples acquired from children 1-17 years old.RESULTS: Two multi-omic factors were identified: one characterising preschool-aged recurrent wheeze and another capturing an inferred trajectory from health to wheeze and school-aged asthma. Recurrent wheeze was driven by Type 1-immune signatures, coupled with upregulation of immune-related and neutrophil-associated lipids and metabolites. Comparatively, progression towards asthma from ages 1-18 was dominated by changes related to airway epithelial cell gene expression, Type 2-immune responses, and constituents of the airway microbiome, such as increased Haemophilus influenzae.CONCLUSION: These factors highlighted distinctions between an inflammation-related phenotype in preschool wheeze, and the predominance of airway epithelial-related changes linked with the inferred trajectory toward asthma. These findings provide insights into the differential mechanisms driving the progression from wheeze to asthma and may inform targeted therapeutic strategies.PMID:39214237 | DOI:10.1016/j.jaci.2024.08.017

J Ethnopharmacol. 2024 Aug 28:118751. doi: 10.1016/j.jep.2024.118751. Online ahead of print.ABSTRACTETHNOPHARMACOLOGICAL RELEVANCE: Huachansu Capsule (HCSc) is a simple enteric-coated capsule refined from the skin of the dried toad, a traditional medicinal herb. It has been used clinically for many years to treat a variety of malignant tumors with remarkable efficacy. To date, a number of main components of HCSc have been reported to be cardiotoxic, but the specific mechanism of cardiotoxicity is still unknown.AIM OF THE STUDY: The aim of this study is to elucidate the adverse effects of HCSc in clinical application, clarify the main toxic components of HCSc and the mechanism of cardiotoxicity caused by HCSc.MATERIALS AND METHODS: UPLC-Q-Exactive Orbitrap MS and network toxicology were used to identify and predict the potential toxic components, related signaling pathways. Then, we used acute and subacute toxicity experiments to reveal the apparent phenomenon of HCSc-induced cardiotoxicity. Finally, we combined transcriptomics and metabolomics to elucidate the potential mechanism of action, and verified the putative mechanism by molecular docking, RT-qPCR, and Western blot.RESULTS: We found 8 toad bufadienolides components may be induced cardiac toxicity HCSc main toxic components. Through toxicity experiments, we found that high dose of HCSc could increase a variety of blood routine indexes, five cardiac enzymes, heart failure indexes (BNP), troponin (cTnI and cTnT), heart rate and the degree of heart tissue damage. In addition, by molecular docking, found that 8 kinds of main toxic components and cAMP, AMPK, IL1β, mTOR all can be a very good combination, especially in the cAMP. Meanwhile, RT-qPCR and Western blot results showed that HCSc could induce cardiotoxicity by regulating a variety of heart-related differential genes and activating the cAMP signaling pathway.CONCLUSIONS: In this study, network toxicology, transcriptomics and metabolomics were used to elucidate the complex mechanism of high-dose HCSc-induced cardiotoxicity. Animal experiments, molecular docking, Western blot and RT-qPCR experiments were also used to verify the above mechanism. These findings will inform further mechanistic studies and provide theoretical support for its safe clinical application.PMID:39214192 | DOI:10.1016/j.jep.2024.118751

Cell Host Microbe. 2024 Aug 22:S1931-3128(24)00291-9. doi: 10.1016/j.chom.2024.08.004. Online ahead of print.ABSTRACTAcute lower gastrointestinal GVHD (aLGI-GVHD) is a serious complication of allogeneic hematopoietic stem cell transplantation. Although the intestinal microbiota is associated with the incidence of aLGI-GVHD, how the intestinal microbiota impacts treatment responses in aLGI-GVHD has not been thoroughly studied. In a cohort of patients with aLGI-GVHD (n = 37), we found that non-response to standard therapy with corticosteroids was associated with prior treatment with carbapenem antibiotics and a disrupted fecal microbiome characterized by reduced abundances of Bacteroides ovatus. In a murine GVHD model aggravated by carbapenem antibiotics, introducing B. ovatus reduced GVHD severity and improved survival. These beneficial effects of Bacteroides ovatus were linked to its ability to metabolize dietary polysaccharides into monosaccharides, which suppressed the mucus-degrading capabilities of colonic mucus degraders such as Bacteroides thetaiotaomicron and Akkermansia muciniphila, thus reducing GVHD-related mortality. Collectively, these findings reveal the importance of microbiota in aLGI-GVHD and therapeutic potential of B. ovatus.PMID:39214085 | DOI:10.1016/j.chom.2024.08.004

Poult Sci. 2024 Aug 14;103(11):104184. doi: 10.1016/j.psj.2024.104184. Online ahead of print.ABSTRACTThis study investigated the diet-additive interactions of a Lactobacilli-based probiotic (Pro) and postbiotic (Post) on immune parameters and cecal microbiota composition, with subsequent effects on the metabolome in broilers. A completely randomized block design was employed with 2 diets [standard (SD), and challenge (CD)] and 3 additive conditions (Control, Pro, Post) involving 1,368 one-day-old male Ross 308 broilers equally distributed among 36 pens in a 42 d study. Diets were formulated to contain identical nutrient levels, with CD higher than SD in non-starch polysaccharide content by including rye and barley. Total non-specific serum Ig A, M and G concentrations were determined weekly from d14 to 35. Following vaccination, titres of specific antibodies binding Newcastle disease virus (NDV) and infectious bursal disease virus (IBDV) were measured. Microbiota composition was analyzed by 16S rRNA gene sequencing at d14 and 35, and α- and β-diversity indexes (Observed, Chao1, Bray, Jaccard) were calculated. Cecal short-chain fatty acids and the semi-polar metabolome were determined in the Control SD and all CD groups at d35. At d35, a diet-additive interaction was observed on cecal microbiota composition. Within SD, Pro and Post did not affect operational taxonomic units (OTU) abundance (adjusted-P > 0.05) and diversity indexes (P > 0.05). Within CD, Pro and Post affected the relative abundances of 37 and 44 OTUs, respectively (adjusted-P < 0.05), with Post but not Pro affecting β-diversity indexes (P = 0.041 and 0.064 for Bray and Jaccard, respectively). Within CD, Post increased cecal acetate (21%; P = 0.007) and butyrate (41%; P = 0.002) concentration and affected the concentration of 2 metabolites (adjusted-P < 0.05), while Pro affected 240 metabolites (adjusted-P < 0.05). No diet-additive interactions were observed on serum Ig (P > 0.05), except for IgM at d14 (P = 0.004). Diet composition, but not the additives, affected immune status parameters. The Pro and Post affected cecal microbiota composition only under dietary challenging conditions as previously reported for growth.PMID:39214057 | DOI:10.1016/j.psj.2024.104184

Mol Immunol. 2024 Aug 29;174:57-68. doi: 10.1016/j.molimm.2024.08.004. Online ahead of print.ABSTRACTThe microenvironment within solid tumors often becomes acidic due to various factors associated with abnormal metabolism and cellular activities, including increased lactate production as a result of dysregulated tumor glycolysis. Recently, we have identified multiple tumor microenvironment (TME) factors that potentiate regulatory T (Treg) cell function in evading anti-tumor immunosurveillance. Despite the strong correlation between lactate and acidity, the potential roles of acidity in intratumoral Treg cell adaptation and underlying molecular mechanisms have gone largely unstudied. In this study, we demonstrate that acidity significantly enhances immunosuppressive functions of nTreg cells, but not iTreg cells, without altering the expression of either FoxP3 or the cell surface receptors CD25, CTLA4, or GITR in these cells. Surprisingly, the addition of lactate, often considered a major contributor to increased acidity of the TME, completely abolished the acidity-induced enhancement of nTreg suppressive functions. Consistently, metabolic flux analyses showed elevated basal mitochondrial respiratory capacity and ATP-coupled respiration in acidity-treated nTreg cells without altering glycolytic capacity. Genome-wide transcriptome and metabolomics analyses revealed alterations in multiple metabolic pathways, particularly the one-carbon folate metabolism pathway, with reduced SAM, folate, and glutathione, in nTreg cells exposed to low pH conditions. Addition of a one-carbon metabolic contributor, formate, diminished the acidity-induced enhancement in nTreg cell suppressive functions, but neither SAM nor glutathione could reverse the phenotype. Remarkably, in vitro transient treatment of nTreg cells resulted in sustained enhancement of their functions, as evidenced by more vigorous tumor growth observed in mice adoptively receiving acidity-treated nTreg cells. Further analysis of intratumoral infiltrated T cells confirmed a significant reduction in CD8+ T cell frequency and their granzyme B production. In summary, our study elucidates how acidity-mediated metabolic reprogramming leads to sustained Treg-mediated tumor immune evasion.PMID:39213947 | DOI:10.1016/j.molimm.2024.08.004

Plant Physiol Biochem. 2024 Aug 27;215:109074. doi: 10.1016/j.plaphy.2024.109074. Online ahead of print.ABSTRACTMangroves, due to their unique habitats, endure dual stressors from land to ocean and ocean to land directions. While extensive researches have been conducted on land-ocean stressors, studies on ocean-land stressors like upwelling are considerably scarce. In this study, ecophysiological, transcriptome, and metabolome analyses were conducted to determine the responses of mangrove plant (Bruguiera gymnorhiza, B. gymnorhiza) to upwelling stress. The results suggested that upwelling stress in B. gymnorhiza induces oxidative stress and membrane damage, which are mitigated by the synergistic actions of antioxidant enzymes and osmoprotectants. Transcriptomic and metabolomic analyses revealed that upregulated genes related to oxidation-reduction and carbohydrate metabolism, along with accumulated metabolites such as amino acids, lipids, phenols, and organic acids, contribute to enhancing antioxidant capacity and maintaining osmotic balance. Further analysis identified key KEGG pathways involved in the response to upwelling stress, including amino acid metabolism, carbohydrate and energy metabolism, flavonoid biosynthesis, and plant hormone signal transduction. These findings provide vital information into the multi-level response mechanisms of mangrove plants to upwelling stress.PMID:39213943 | DOI:10.1016/j.plaphy.2024.109074

Talanta. 2024 Aug 16;280:126710. doi: 10.1016/j.talanta.2024.126710. Online ahead of print.ABSTRACTCell-derived extracellular vesicles (EVs) have emerged as a promising non-invasive liquid biopsy technique due to their accessibility and their ability to encapsulate and transport diverse biomolecules. EVs have garnered substantial research interest, notably in cardiovascular diseases (CVDs), where their roles in pathophysiology and as diagnostic and prognostic biomarkers are increasingly recognized. This review provides a comprehensive overview of EVs, starting with their origins, followed by the techniques used for their isolation and characterization. We explore the diverse cargo of EVs, including nucleic acids, proteins, lipids, and metabolites, highlighting their roles in intercellular communication and as potential biomarkers. We then delve into the application of genomics, transcriptomics, proteomics, and metabolomics in the analysis of EVs, particularly within the context of CVDs. Finally, we discuss how integrated multi-omics approaches are unveiling novel biomarkers, offering fresh insights into the diagnosis and prognosis of CVDs. This review underscores the growing importance of EVs in clinical diagnostics and the potential of multi-omics to propel future advancements in CVD biomarker discovery.PMID:39213888 | DOI:10.1016/j.talanta.2024.126710

Biochim Biophys Acta Mol Basis Dis. 2024 Aug 29;1870(8):167482. doi: 10.1016/j.bbadis.2024.167482. Online ahead of print.ABSTRACTTwo distinct defense strategies, disease resistance (DR) and disease tolerance (DT), enable a host to survive infectious diseases. Newborns, constrained by limited energy reserves, predominantly rely on DT to cope with infection. However, this approach may fail when pathogen levels surpass a critical threshold, prompting a shift to DR that can lead to dysregulated immune responses and sepsis. The mechanisms governing the interplay between DR and DT in newborns remain poorly understood. Here, we compare metabolic traits and defense strategies between survivors and non-survivors in Staphylococcus epidermidis (S. epidermidis)-infected preterm piglets, mimicking infection in preterm infants. Compared to non-survivors, survivors displayed elevated DR during the initial phase of infection, followed by stronger DT in later stages. In contrast, non-survivors showed clear signs of respiratory and metabolic acidosis and hyperglycemia, together with exaggerated inflammation and organ dysfunctions. Hepatic transcriptomics revealed a strong association between the DT phenotype and heightened oxidative phosphorylation in survivors, coupled with suppressed glycolysis and immune signaling. Plasma metabolomics confirmed the findings of metabolic regulations associated with DT phenotype in survivors. Our study suggests a significant association between the initial DR and subsequent DT, which collectively contributes to improved infection survival. The regulation of metabolic processes that optimize the timing and balance between DR and DT holds significant potential for developing novel therapeutic strategies for neonatal infection.PMID:39213794 | DOI:10.1016/j.bbadis.2024.167482

Biochem Biophys Res Commun. 2024 Aug 23;739:150598. doi: 10.1016/j.bbrc.2024.150598. Online ahead of print.ABSTRACTColorectal cancer is globally ranked as the third most common malignant tumor. Its development involves a complex biological process driven by various genetic and epigenetic alterations. To elucidate the biological significance of the extensive omics data, we conducted comparative multi-omics studies on colorectal cancer patients at different clinical stages. Bioinformatics methods were applied to analyze multi-omics datasets and explore the molecular landscape. Drug prediction and molecular docking also were conducted to assess potential therapeutic interventions. In vitro experiments were used to validate the inhibitory effect on the migration and proliferation of cell lines. The results indicate up-regulated proteins involved in immune-inflammatory related pathways, while biomarkers related to muscular contraction and cell adhesion are significantly down-regulated. Drug prediction, coupled with in vitro experiments, suggests that AZ-628 may act as a potential drug to inhibit the proliferation and migration of CRC cell lines HCT-116 and HT-29 by regulating the aforementioned key biological pathways or proteins. Complementing these findings, metabolomics analysis unveiled a down-regulation of key carbon metabolism pathways, alongside an up-regulation in amino acid metabolism, particularly proline metabolism. This metabolic shift may reflect an adaptive response in cancer cells, favoring specific amino acids to support their growth. Together, these integrated results provide valuable insights into the intricate landscape of tumor development, highlighting the crossroads of immune regulation, cellular structure, and metabolic reprogramming in the tumorigenic process and providing valuable insights into cancer pathology.PMID:39213754 | DOI:10.1016/j.bbrc.2024.150598

J Med Microbiol. 2024 Aug;73(8). doi: 10.1099/jmm.0.001839.ABSTRACTIntroduction. Hypertension is the most prevalent chronic disease and a major risk factor for cardiovascular and cerebrovascular diseases.Gap statement. However, there has been no substantial breakthrough in aetiology, new drug targets, and drug development of hypertension in recent 50 years.Research aim. Therefore, this study was to screen unique intestinal microbiome and serum metabolic biomarkers which can early diagnose and track the prognosis of hypertension patients in different periods, and analyse its underlying mechanisms and functions.Methods. Four groups of stool and serum samples, including healthy controls (HCs), prehypertension (PHT), hypertension (HT), and hypertension-related complications (HTC), were collected. Microbial diversity assessed using 16S rRNA sequencing. The metabolites in serum samples were detected through LC-MS/MS analysis.Results. The composition of gut microbiota in patients exhibited dissimilarities compared to that in healthy subjects, which was distinguished by Prevotella, Slackia, Enterococcus, Bifidobacterium, and Lactobacillales may be potential markers for tracking the progression of hypertension, and Bifidobacterium, Butyricimonas, Adlercreutzia, Faecalibacterium, Lactobacillus, Ruminococcus, Clostridium, and Acidaminococcus demonstrated diagnostic value. Meanwhile, tracking the dynamic changes of deoxycholic acid, 4-oxododecanedioic acid, and l-arginine can serve as biomarkers for early diagnosis, and investigation into the mechanism by which the intestinal microbiome influences the onset and progression of hypertension. In terms of pathogenesis, the findings revealed that Bifidobacterium may caused the changes of AST, indirect bilirubin, ALT, triglyceride and uric acid by affecting metabolites cis-7-hexadecenoic acid methyl ester and N1-acetylspermidine. Additionally, Coprococcus may cause changes in albumin through the influence of androsterone enanthate.Conclusions. These findings highlight that the unique intestinal microbiome and serum metabolic profile in different periods of hypertension will provide valuable insight for timely diagnosis and prognosis tracking in hypertension patients with promising clinical applications.PMID:39213028 | DOI:10.1099/jmm.0.001839

Inflammation. 2024 Aug 30. doi: 10.1007/s10753-024-02136-w. Online ahead of print.ABSTRACTSevere pneumonia is one of the most common critical diseases in clinical practice. Existing models for severe pneumonia have limitations, leading to limited clinical translation. In this study, a two-hit severe pneumonia mouse model was established by inducing primary pneumonia through intratracheal instillation of 800 μg lipopolysaccharide (LPS), followed by intraperitoneal injection of 10 mg/kg LPS. The effectiveness of various inflammatory indicators and the lung tissue damage during the time course of this model were confirmed and evaluated. At 3 h post two-hit, the IL-6, TNF-α levels in peripheral blood and bronchoalveolar lavage fluid (BALF), and the white blood cells, neutrophils, and lymphocytes in BALF notably exhibited the most pronounced elevation. At 12 h post two-hit, the white blood cells and neutrophils in peripheral blood significantly increased, accompanied by notable alterations in splenic immune cells and worsened pulmonary histopathological damage. Transcriptomics of lung tissue, microbiota analysis of lung and gut, as well as plasma metabolomics analyses further indicated changes in transcriptional profiles, microbial composition, and metabolites due to the two-hit modeling. These results validate that the two-hit model mimics the clinical presentation of severe pneumonia and serves as a robust experimental tool for studying the pathogenesis of severe pneumonia and developing and assessing treatment strategies.PMID:39212889 | DOI:10.1007/s10753-024-02136-w