PubMed

Front Mol Biosci. 2023 Apr 4;10:1146069. doi: 10.3389/fmolb.2023.1146069. eCollection 2023.ABSTRACTThe opportunity to select for feed efficient cows has been limited by inability to cost-effectively record individual feed efficiency on an appropriate scale. This study investigated the differences in milk metabolite profiles between high- and low residual feed intake (RFI) categories and identified biomarkers of residual feed intake and models that can be used to predict residual feed intake in lactating Holsteins. Milk metabolomics analyses were undertaken at early, mid and late lactation stages and residual feed intake was calculated in 72 lactating dairy cows. Cows were ranked and grouped into high residual feed intake (RFI >0.5 SD above the mean, n = 20) and low residual feed intake (RFI <0.5 SD below the mean, n = 20). Milk metabolite profiles were compared between high residual feed intake (least efficient) and low residual feed intake (most efficient) groups. Results indicated that early lactation was predominantly characterized by significantly elevated levels of medium chain acyl carnitines and glycerophospholipids in high residual feed intake cows. Citrate cycle and glycerophospholipid metabolism were the associated pathways enriched with the significantly different metabolites in early lactation. At mid lactation short and medium chain acyl carnitines, glycerophospholipids and amino acids were the main metabolite groups differing according to residual feed intake category. Late lactation was mainly characterized by increased levels of amino acids in high residual feed intake cows. Amino acid metabolism and biosynthesis pathways were enriched for metabolites that differed between residual feed intake groups at the mid and late lactation stages. Receiver operating characteristic curve analysis identified candidate biomarkers: decanoylcarnitine (area under the curve: AUC = 0.81), dodecenoylcarnitine (AUC = 0.81) and phenylalanine (AUC = 0.85) at early, mid and late stages of lactation, respectively. Furthermore, panels of metabolites predicted residual feed intake with validation coefficient of determination (R 2) of 0.65, 0.37 and 0.60 at early, mid and late lactation stages, respectively. The study sheds light on lactation stage specific metabolic differences between high-residual feed intake and low-residual feed intake lactating dairy cows. Candidate biomarkers that distinguished divergent residual feed intake groups and panels of metabolites that predict individual residual feed intake phenotypes were identified. This result supports the potential of milk metabolites to select for more efficient cows given that traditional residual feed intake phenotyping is costly and difficult to conduct in commercial farms.PMID:37091872 | PMC:PMC10113888 | DOI:10.3389/fmolb.2023.1146069

Front Plant Sci. 2023 Apr 4;14:1120584. doi: 10.3389/fpls.2023.1120584. eCollection 2023.ABSTRACTThe normal methods of agricultural production worldwide have been strongly affected by the frequent occurrence of drought. Rice rhizosphere microorganisms have been significantly affected by drought stress. To provide a hypothetical basis for improving the drought resistance and N utilization efficiency of rice, the study adopted a barrel planting method at the heading stage, treating rice with no drought or drought stress and three different nitrogen (N) levels. Untargeted metabolomics and 16S rRNA gene sequencing technology were used to study the changes in microorganisms in roots and the differential metabolites (DMs) in rhizosphere soil. The results showed that under the same N application rate, the dry matter mass, N content and N accumulation in rice plants increased to different degrees under drought stress. The root soluble protein, nitrate reductase and soil urease activities were improved over those of the no-drought treatment. Proteobacteria, Bacteroidota, Nitrospirota and Zixibacteria were the dominant flora related to N absorption. A total of 184 DMs (98 upregulated and 86 downregulated) were identified between low N with no drought (LN) and normal N with no drought (NN); 139 DMs (83 upregulated and 56 downregulated) were identified between high N with no drought (HN) and NN; 166 DMs (103 upregulated and 63 downregulated) were identified between low N with drought stress (LND) and normal N with drought stress (NND); and 124 DMs (71 upregulated and 53 downregulated) were identified between high N with drought stress (HND) and NND. Fatty acyl was the metabolite with the highest proportion. KEGG analysis showed that energy metabolism pathways, such as D-alanine metabolism and the phosphotransferase system (PTS), were enriched. We conclude that N-metabolism enzymes with higher activity and higher bacterial diversity have a significant effect on drought tolerance and nitrogen uptake in rice.PMID:37089655 | PMC:PMC10114610 | DOI:10.3389/fpls.2023.1120584

Cell Metab. 2023 Apr 4:S1550-4131(23)00093-1. doi: 10.1016/j.cmet.2023.03.015. Online ahead of print.ABSTRACTAging is classically conceptualized as an ever-increasing trajectory of damage accumulation and loss of function, leading to increases in morbidity and mortality. However, recent in vitro studies have raised the possibility of age reversal. Here, we report that biological age is fluid and exhibits rapid changes in both directions. At epigenetic, transcriptomic, and metabolomic levels, we find that the biological age of young mice is increased by heterochronic parabiosis and restored following surgical detachment. We also identify transient changes in biological age during major surgery, pregnancy, and severe COVID-19 in humans and/or mice. Together, these data show that biological age undergoes a rapid increase in response to diverse forms of stress, which is reversed following recovery from stress. Our study uncovers a new layer of aging dynamics that should be considered in future studies. The elevation of biological age by stress may be a quantifiable and actionable target for future interventions.PMID:37086720 | DOI:10.1016/j.cmet.2023.03.015

Front Cell Infect Microbiol. 2023 Apr 4;13:1119616. doi: 10.3389/fcimb.2023.1119616. eCollection 2023.ABSTRACTWhite spot lesions (WSLs) have long been a noteworthy complication during orthodontic treatment. Recently, an increasing number of orthodontists have found that adolescents undergoing orthodontic treatment with clear aligners are at a higher risk of developing WSLs. The oral microbiota and metabolites are considered the etiologic and regulatory factors of WSLs, but the specific impact of clear aligners on the oral microbiota and metabolites is unknown. This study investigated the differences in the salivary microbiome and metabolome between adolescents with and without WSLs treated with clear aligners. Fifty-five adolescents (aged 11-18) with Invisalign appliances, 27 with and 28 without WSLs, were included. Saliva samples were analyzed using 16S rRNA gene sequencing and ultra-performance liquid chromatography-tandem mass spectrometry (UPLC-MS/MS); the data were further integrated for Spearman correlation analysis. The relative abundances of 14 taxa, including Actinobacteria, Actinomycetales, Rothia, Micrococcaceae, Subdoligranulum, Capnocytophaga, Azospira, Olsenella, Lachnoanaerobaculum, and Abiotrophia, were significantly higher in the WSL group than in the control group. Metabolomic analysis identified 27 potential biomarkers, and most were amino acids, including proline and glycine. The metabolites were implicated in 6 metabolic pathways, including alanine, aspartate and glutamate metabolism; glycine, serine and threonine metabolism; and aminoacyl-tRNA biosynthesis. There was a correlation between the salivary microbial and metabolomic datasets, reflecting the impact of clear aligners on the metabolic activity of the oral flora. A concordant increase in the levels of Lachnoanaerobaculum, Rothia, Subdoligranulum and some amino acids had predictive value for WSL development. In summary, when adolescents undergo long-term clear aligner therapy with poor oral hygiene habits, clear aligners can disrupt the balance of the oral microecosystem and lead to oral microbiota dysbiosis, thereby increasing the risk of developing WSLs. Our findings might contribute to the understanding of the pathogenesis of WSLs and provide candidate biomarkers for the diagnosis and treatment of WSLs associated with clear aligners.PMID:37082715 | PMC:PMC10111054 | DOI:10.3389/fcimb.2023.1119616

Front Cell Infect Microbiol. 2023 Apr 4;13:1104295. doi: 10.3389/fcimb.2023.1104295. eCollection 2023.ABSTRACTOBJECTIVE: To compare the differences in salivary metabolites between caries-active and caries-free children in the mixed dentition, and explore their correlation with caries status.METHODS: The study involved 20 children (aged 8-9 years) in the mixed dentition, including 10 caries-active (aged 8.6 ± 0.49years) and 10 caries-free children(aged 8.5 ± 0.5years), with a male/female ratio of 1:1. The saliva samples were collected from all children. Metabolite extraction, LC-MS/MS-based untargeted metabolomics, qualitative and semi-quantitative analysis and bioinformatics analysis were performed to identify differential metabolites between the two sample groups. The differential metabolites identified were further analyzed in an attempt to find their correlations with caries status.RESULTS: In the positive ion mode, a total of 1606 molecular features were detected in the samples of the two groups, 189 of which were differential metabolites when comparing the caries-active group with the caries-free group, including 104 up-regulated and 85 down-regulated metabolites. In the negative ion mode, a total of 532 molecular features were detected in the samples of two groups, 70 of which were differential metabolites when comparing the caries-active group with the caries-free group, including 37 up-regulated and 33 down-regulated metabolites. In the positive ion mode, two of the top 5 up-regulated differential metabolites were found in and annotated to specific metabolic pathways, whereas in the negative ion mode, only one of the top 5 up-regulated differential metabolites was found in and annotated to specific metabolic pathways. In both the positive and negative ion modes, the top 5 down-regulated differential metabolites were both annotated to the metabolic pathways. KEGG pathway enrichment analysis of differential metabolites showed that histamine and arachidonic acid identified in the positive ion mode, as well as succinate and L-histidine identified in the negative ion mode were enriched in the top 3 significantly altered pathways.CONCLUSION: The enriched differential metabolites including histamine, L-histidine and succinate were correlated with the presence of dental caries, but their role in the caries process needs to be further investigated.PMID:37082714 | PMC:PMC10110944 | DOI:10.3389/fcimb.2023.1104295

Brain Commun. 2023 Apr 4;5(2):fcad110. doi: 10.1093/braincomms/fcad110. eCollection 2023.ABSTRACTMolecular subtyping of brain tissue provides insights into the heterogeneity of common neurodegenerative conditions, such as Alzheimer's disease. However, existing subtyping studies have mostly focused on single data modalities and only those individuals with severe cognitive impairment. To address these gaps, we applied similarity network fusion, a method capable of integrating multiple high-dimensional multi-omic data modalities simultaneously, to an elderly sample spanning the full spectrum of cognitive ageing trajectories. We analyzed human frontal cortex brain samples characterized by five omic modalities: bulk RNA sequencing (18 629 genes), DNA methylation (53 932 CpG sites), histone acetylation (26 384 peaks), proteomics (7737 proteins) and metabolomics (654 metabolites). Similarity network fusion followed by spectral clustering was used for subtype detection, and subtype numbers were determined by Eigen-gap and rotation cost statistics. Normalized mutual information determined the relative contribution of each modality to the fused network. Subtypes were characterized by associations with 13 age-related neuropathologies and cognitive decline. Fusion of all five data modalities (n = 111) yielded two subtypes (n S1 = 53, n S2 = 58), which were nominally associated with diffuse amyloid plaques; however, this effect was not significant after correction for multiple testing. Histone acetylation (normalized mutual information = 0.38), DNA methylation (normalized mutual information = 0.18) and RNA abundance (normalized mutual information = 0.15) contributed most strongly to this network. Secondary analysis integrating only these three modalities in a larger subsample (n = 513) indicated support for both three- and five-subtype solutions, which had significant overlap, but showed varying degrees of internal stability and external validity. One subtype showed marked cognitive decline, which remained significant even after correcting for tests across both three- and five-subtype solutions (p Bonf = 5.9 × 10-3). Comparison to single-modality subtypes demonstrated that the three-modal subtypes were able to uniquely capture cognitive variability. Comprehensive sensitivity analyses explored influences of sample size and cluster number parameters. We identified highly integrative molecular subtypes of ageing derived from multiple high dimensional, multi-omic data modalities simultaneously. Fusing RNA abundance, DNA methylation, and histone acetylation measures generated subtypes that were associated with cognitive decline. This work highlights the potential value and challenges of multi-omic integration in unsupervised subtyping of post-mortem brain.PMID:37082508 | PMC:PMC10110975 | DOI:10.1093/braincomms/fcad110

Front Plant Sci. 2023 Apr 4;14:1138865. doi: 10.3389/fpls.2023.1138865. eCollection 2023.ABSTRACTCitric acid is the primary organic acid that affects the taste of strawberry fruit. Glycolysis supplies key substrates for the tricarboxylic acid cycle (TCA cycle). However, little is known about the regulatory mechanisms of glycolytic genes on citric acid metabolism in strawberry fruits. In this study, the citric acid content of strawberry fruit displayed a trend of rising and decreasing from the initial red stage to the full red stage and then dark red stage. Thus, a difference in citric acid metabolic regulation was suspected during strawberry fruit development. In addition, overexpression of either cytoplasm glyceraldehyde-3-phosphate dehydrogenase (FxaC_14g13400, namely FaGAPC2) or pyruvate kinase (FxaC_15g00080, namely FaPKc2.2) inhibited strawberry fruit ripening and the accumulation of citric acid, leading to a range of maturity stages from partial red to full red stage. The combined transcriptome and metabolome analysis revealed that overexpression of FaGAPC2 and FaPKc2.2 significantly suppressed the expression of phosphoenolpyruvate carboxykinase (FxaC_1g21491, namely FaPEPCK) but enhanced the content of glutamine and aspartic acid. Meanwhile, the activities of PEPCK and glutamate decarboxylase (GAD) were inhibited, but the activities of glutamine synthase (GS) were increased in FaGAPC2/FaPKc2.2-overexpressed fruit. Further, functional verification demonstrated that overexpression of FaPEPCK can promote strawberry fruit ripening, resulting in a range of maturity stage from full red to dark red stage, while the citric acid synthase (CS) activities and citric acid content were significantly decreased. Overall, this study revealed that FaGAPC2/FaPKc2.2 and FaPEPCK perform an important role in reducing citric acid content in strawberry fruit, and FaGAPC2/FaPKc2.2 mainly by promoting the GS degradation pathway and FaPEPCK mainly by inhibiting the CS synthesis pathway.PMID:37082348 | PMC:PMC10110876 | DOI:10.3389/fpls.2023.1138865

Front Plant Sci. 2023 Apr 4;14:1105162. doi: 10.3389/fpls.2023.1105162. eCollection 2023.ABSTRACTGiven its limited land and water use and the changing climate conditions, indoor farming of halophytes has a high potential to contribute significantly to global agriculture in the future. Notably, indoor farming and classical greenhouse cultivation differ in their light regime between artificial and solar lighting, which can influence plant metabolism, but how this affects the cultivation of halophytes has not yet been investigated. To address this question, we studied the yield and content of abscisic acid, carotenoids, and chlorophylls as well as chloride of three halophyte species (Cochlearia officinalis, Atriplex hortensis, and Salicornia europaea) differing in their salt tolerance mechanisms and following four salt treatments (no salt to 600 mM of NaCl) in two light regimes (greenhouse/indoor farming). In particular, salt treatment had a strong influence on chloride accumulation which is only slightly modified by the light regime. Moreover, fresh and dry mass was influenced by the light regime and salinity. Pigments exhibited different responses to salt treatment and light regime, reflecting their differing functions in the photosynthetic apparatus. We conclude that the interaction of light regime and salt treatment modulates the content of photosynthetic pigments. Our study highlights the potential applications of the cultivation of halophytes for indoor farming and underlines that it is a promising production system, which provides food alternatives for future diets.PMID:37082347 | PMC:PMC10110887 | DOI:10.3389/fpls.2023.1105162

Front Physiol. 2023 Apr 4;14:1123391. doi: 10.3389/fphys.2023.1123391. eCollection 2023.ABSTRACTBackground: The prominent mitochondrial metabolic changes of the atrium reportedly have significant impact on electrical signals and structural remodeling which play important roles in the occurrence and development of atrial fibrillation (AF). However, the mechanism is not completely known. Objective: This study was aimed to explore the mitochondrial metabolism reprogrammed in AF patients by integrating metabolomics as well as proteomics of human atrium tissues. Methods and Results: Left atrial tissue samples were harvested from 10 non-valvular AF patients and 10 matched samples from healthy donors for transplantation. In metabolomics analysis, 113 metabolites were upregulated and 10 metabolites were downregulated in AF, where multiple pathways related to mitochondrial energy metabolism were enriched. Correlation analysis between the differentially expressed proteins and metabolites identified several hub proteins related to mitochondrial function including Glycerol-3-phosphate dehydrogenase 2 (GPD2), Synemin (SYNM), Plectin (PLEC), with MCC score of 27, 17, 16, respectively, which have the most interactions with the dysregulated metabolites and ranked at the top in network string interactions scored by MCC method. All 330 differentially expressed proteins including 225 upregulated and 105 downregulated molecules were revealed and analyzed, which identified the downregulation of GPD2 (p = 0.02 and FC = 0.77), PLEC (p < 0.001 and FC = 0.71) and SYNM (p = 0.04 and FC = 0.76) in AF patients. Gene Set Variation Analysis (GSEA) showed mitochondrial metabolism-associated pathways including oxidative phosphorylation (NES: -1.73) and ATP biosynthetic process (NES: -2.29), were dramatically diversified in human AF. In GSVA, the expression levels of GPD2, PLEC, and SYNM were demonstrated to be associated with multiple metabolic pathways related to mitochondrial function (e.g., lipid metabolism and AMP activated protein kinase signaling) and cardiac structural and electrical remodeling (e.g., contractile fiber, ion homeostasis), which were proven vital in the development and maintenance of AF. Conclusion: In all, this study provides new insights into understanding the mechanisms of AF progression, especially the reprogramming mitochondrial metabolism, and identifies several genes related to mitochondrial function as novel targets for AF, which may be involved in the occurrence and development of AF.PMID:37082238 | PMC:PMC10110950 | DOI:10.3389/fphys.2023.1123391

Front Pharmacol. 2023 Apr 4;14:1164827. doi: 10.3389/fphar.2023.1164827. eCollection 2023.ABSTRACTBackground: Xihuang Wan (XHW), a purgative and detoxifying agent, is commonly utilized in modern medicine as a treatment and adjuvant therapy for various malignancies, including breast cancer, liver cancer, and lung cancer. A clinical study demonstrated the potential usefulness of the combination of XHW and gemcitabine as a therapy for pancreatic cancer (PC), indicating that XHW's broad-spectrum antitumor herbal combination could be beneficial in the treatment of PC. However, the precise therapeutic efficacy of XHW in treating pancreatic cancer remains uncertain. Aim: This study assessed the biological activity of XHW by optimizing the therapeutic concentration of XHW (Xihuang pills, XHP). We performed cell culture and developed an animal test model to determine whether XHP can inhibit pancreatic cancer (PC). We also applied the well-known widely targeted metabolomics analysis and conducted specific experiments to assess the feasibility of our method in PC therapy. Materials and Methods: We used UPLC/Q-TOF-MS to test XHP values to set up therapeutic concentrations for the in vivo test model. SW1990 pancreatic cancer cells were cultured to check the effect the anti-cancer effects of XHP by general in vitro cell analyses including CCK-8, Hoechst 33258, and flow cytometry. To develop the animal model, a solid tumor was subcutaneously formed on a mouse model of PC and assessed by immunohistochemistry and TUNEL apoptosis assay. We also applied the widely targeted metabolomics method following Western blot and RT-PCR to evaluate multiple metabolites to check the therapeutic effect of XHP in our cancer test model. Results: Quantified analysis from UPLC/Q-TOF-MS showed the presence of the following components of XHP: 11-carbonyl-β-acetyl-boswellic acid (AKBA), 11-carbonyl-β-boswellic acid (KBA), 4-methylene-2,8,8-trimethyl-2-vinyl-bicyclo [5.2.0]nonane, and (1S-endo)-2-methyl-3-methylene-2-(4-methyl-3-3-pentenyl)-bicyclo [2.2.1heptane]. The results of the cell culture experiments demonstrated that XHP suppressed the growth of SW1990 PC cells by enhancing apoptosis. The results of the animal model tests also indicated the suppression effect of XHP on tumor growth. Furthermore, the result of the widely targeted metabolomics analysis showed that the steroid hormone biosynthesis metabolic pathway was a critical factor in the anti-PC effect of XHP in the animal model. Moreover, Western blot and RT-PCR analyses revealed XHP downregulated CYP3A4 expression as an applicable targeted therapeutic approach. Conclusion: The results of this study demonstrated the potential of XHP in therapeutic applications in PC. Moreover, the widely targeted metabolomics method revealed CYP3A4 is a potential therapeutic target of XHP in PC control. These findings provide a high level of confidence that XHP significantly acts as a CYP3A4 inhibitor in anti-cancer therapeutic applications.PMID:37081969 | PMC:PMC10110895 | DOI:10.3389/fphar.2023.1164827

Front Immunol. 2023 Apr 4;14:1157373. doi: 10.3389/fimmu.2023.1157373. eCollection 2023.ABSTRACTAllergic inflammation of the airways such as allergic asthma is a major health problem with growing incidence world-wide. One cardinal feature in severe type 2-dominated airway inflammation is the release of lipid mediators of the eicosanoid family that can either promote or dampen allergic inflammation. Macrophages are key producers of prostaglandins and leukotrienes which play diverse roles in allergic airway inflammation and thus require tight control. Using RNA- and ATAC-sequencing, liquid chromatography coupled to mass spectrometry (LC-MS/MS), enzyme immunoassays (EIA), gene expression analysis and in vivo models, we show that the aryl hydrocarbon receptor (AhR) contributes to this control via transcriptional regulation of lipid mediator synthesis enzymes in bone marrow-derived as well as in primary alveolar macrophages. In the absence or inhibition of AhR activity, multiple genes of both the prostaglandin and the leukotriene pathway were downregulated, resulting in lower synthesis of prostanoids, such as prostaglandin E2 (PGE2), and cysteinyl leukotrienes, e.g., Leukotriene C4 (LTC4). These AhR-dependent genes include PTGS1 encoding for the enzyme cyclooxygenase 1 (COX1) and ALOX5 encoding for the arachidonate 5-lipoxygenase (5-LO) both of which major upstream regulators of the prostanoid and leukotriene pathway, respectively. This regulation is independent of the activation stimulus and partially also detectable in unstimulated macrophages suggesting an important role of basal AhR activity for eicosanoid production in steady state macrophages. Lastly, we demonstrate that AhR deficiency in hematopoietic but not epithelial cells aggravates house dust mite induced allergic airway inflammation. These results suggest an essential role for AhR-dependent eicosanoid regulation in macrophages during homeostasis and inflammation.PMID:37081886 | PMC:PMC10110899 | DOI:10.3389/fimmu.2023.1157373

Front Mol Biosci. 2023 Apr 4;10:1154149. doi: 10.3389/fmolb.2023.1154149. eCollection 2023.ABSTRACTIntroduction:Galactosemia (GAL) is a genetic disorder that results in disturbances in galactose metabolism and can lead to life-threatening complications. However, the underlying pathophysiology of long-term complications in GAL remains poorly understood. Methods: In this study, a metabolomics approach using ultra-performance liquid chromatography coupled with high-resolution mass spectrometry was used to investigate metabolomic changes in dried blood spots of 15 patients with GAL and 39 healthy individuals. Results: The study found that 2,819 metabolites underwent significant changes in patients with GAL compared to the control group. 480 human endogenous metabolites were identified, of which 209 and 271 were upregulated and downregulated, respectively. PA (8:0/LTE4) and ganglioside GT1c (d18:0/20:0) metabolites showed the most significant difference between GAL and the healthy group, with an area under the curve of 1 and 0.995, respectively. Additionally, the study identified potential biomarkers for GAL, such as 17-alpha-estradiol-3-glucuronide and 16-alpha-hydroxy DHEA 3-sulfatediphosphate. Conclusion: This metabolomics study deepened the understanding of the pathophysiology of GAL and presented potential biomarkers that might serve as prognostic biomarkers to monitor the progression or support the clinical diagnosis of GAL.PMID:37081853 | PMC:PMC10110906 | DOI:10.3389/fmolb.2023.1154149

Mol Med. 2023 Apr 4;29(1):48. doi: 10.1186/s10020-023-00646-1.ABSTRACTBACKGROUND: Despite constant advances in regenerative medicine, the closure of chronic wounds is still challenging. Therapeutic approaches using locally administered MSCs have been considered a promising option. However, the viability of these cells is seriously threatened by acute hypoxic stress linked to wound healing. In this work, we aimed to study the tolerance of Menstrual blood-derived stromal cells (MenSCs) to acute hypoxia and their therapeutic paracrine effect.METHODS: Isolated MenSCs were phenotypically characterized and evaluated in terms of proliferation, viability, and gene expression, under acute hypoxia (AH) compared with conventional cultured condition or normoxia (N). A step further, the secretome of MenSCs under acute hypoxia was analyzed with respect to their miRNAs content and by in vitro functional assays. For the analysis of differences between the two groups, Student's t-test was performed and one-way ANOVA and Tukey's multiple comparisons test for multiple groups were used.RESULTS: Our results revealed that the viability of MenSCs was not affected under acute hypoxia, although proliferation rate slowed down. Gene analysis revealed 5 up-regulated (BNIP3, ANGPTL4, IL6, IL1B, and PDK1) and 4 down-regulated genes (IDO1, HMOX1, ANGPTL2, and HGF) in AH compared to N. Global gene expression analysis revealed a decrease in the gene ontology functions of migration and wound response with respect to the normoxic condition. In contrast, functions such as angiogenesis were enriched under the AH condition. Regarding the secretome analysis, two miRNAs involved in angiogenic processes (hsa-miR-148a-3p and hsa-miR-378a-3p), were significantly up-expressed when compared to the normoxic condition, being MYC gene, the unique target of both. Functional assays on HUVECs revealed a potential pro-angiogenic capacity of MenSCs cultured in both oxygen conditions (N and AH) based on the wound closure and tube formation results of their released paracrine factors. However, when compared to normoxia, the paracrine factors of MenSCs under acute hypoxia slightly reduced the proliferation, migration, and in vitro wound closure of HUVECs.CONCLUSIONS: MenSC exhibited a good survival capacity under acute hypoxic conditions as well as beneficial properties applicable in the field of tissue regeneration through their secretome, which makes them a potential cell source for wound healing interventions.PMID:37016307 | PMC:PMC10074862 | DOI:10.1186/s10020-023-00646-1

Chin Med. 2023 Apr 4;18(1):36. doi: 10.1186/s13020-023-00721-z.ABSTRACTBACKGROUND: Acute lung injury (ALI), an acute inflammatory lung disease, can cause a rapid inflammatory response in clinic, which endangers the patient's life. The components of platycodon grandiflorum, such as platycodins have a wide range of pharmacological activities such as expectorant, anti-apoptotic, anti-inflammatory, anti-tumor and anti-oxidant properties, and can be used for improving human immunity. Previous studies have shown that aqueous extract of platycodon grandiflorum (PAE) has a certain protective effect on ALI, but the main pharmacodynamic components and the mechanism of action are not clear.METHODS: The anti-inflammatory properties of PAE were studied using the lipopolysaccharide (LPS)-induced ALI animal model. Hematoxylin and eosin stains were used to assess the degree of acute lung damage. Changes in RNA levels of pro-inflammatory cytokines in the lungs were measured using quantitative RT-qPCR. The potential molecular mechanism of PAE preventing ALI was predicted by lipidomics and network pharmacology. To examine the anti-apoptotic effects of PAE, TdT-mediated dUTP nick-end labelling (TUNEL) was employed to determine apoptosis-related variables. The amounts of critical pathway proteins and apoptosis-related proteins were measured using Western blotting.RESULTS: Twenty-six chemical components from the PAE were identified, and their related pathways were obtained by the network pharmacology. Combined with the analysis of network pharmacology and literature, it was found that the phosphatidylinositol 3 kinase (PI3K)/protein kinase B (AKT) signaling pathway is related to ALI. The results of lipidomics show that PAE alleviates ALI via regulating lung lipids especially phosphatidylinositol (PI). Finally, the methods of molecular biology were used to verify the mechanism of PAE. It can be found that PAE attenuates the inflammatory response to ALI by inhibiting apoptosis through PI3K/Akt signaling pathway.CONCLUSION: The study revealed that the PAE attenuates lipopolysaccharide-induced apoptosis and inflammatory cell infiltration in mouse lungs by inhibiting PI3K/Akt signaling. Furthermore, our findings provide a novel strategy for the application of PAE as a potential agent for preventing patients with ALI.PMID:37016413 | DOI:10.1186/s13020-023-00721-z

Cell Mol Biol Lett. 2023 Apr 4;28(1):28. doi: 10.1186/s11658-023-00442-z.ABSTRACTBladder cancer (BC) is a clinical challenge worldwide with late clinical presentation, poor prognosis, and low survival rates. Traditional cystoscopy and tissue biopsy are routine methods for the diagnosis, prognosis, and monitoring of BC. However, due to the heterogeneity and limitations of tumors, such as aggressiveness, high cost, and limited applicability of longitudinal surveillance, the identification of tumor markers has attracted significant attention in BC. Over the past decade, liquid biopsies (e.g., blood) have proven to be highly efficient methods for the discovery of BC biomarkers. This noninvasive sampling method is used to analyze unique tumor components released into the peripheral circulation and allows serial sampling and longitudinal monitoring of tumor progression. Several liquid biopsy biomarkers are being extensively studied and have shown promising results in clinical applications of BC, including early detection, detection of microscopic residual disease, prediction of recurrence, and response to therapy. Therefore, in this review, we aim to provide an update on various novel blood-based liquid biopsy markers and review the advantages and current limitations of liquid biopsy in BC therapy. The role of blood-based circulating tumor cells, circulating tumor DNA, cell-free RNA, exosomes, metabolomics, and proteomics in diagnosis, prognosis, and treatment monitoring, and their applicability to the personalized management of BC, are highlighted.PMID:37016296 | DOI:10.1186/s11658-023-00442-z

Eur Heart J. 2023 Apr 5:ehad167. doi: 10.1093/eurheartj/ehad167. Online ahead of print.NO ABSTRACTPMID:37016271 | DOI:10.1093/eurheartj/ehad167

Inflamm Res. 2023 Apr 4. doi: 10.1007/s00011-023-01728-w. Online ahead of print.ABSTRACTOBJECTIVE: This study investigated the impacts of SIRT1 activation on rheumatoid arthritis (RA)-related angiogenesis.METHODS: HUVECs were cultured by different human serum. Intracellular metabolites were quantified by UPLC-MS. Next, HUVECs and rat vascular epithelial cells under different inflammatory conditions were treated by a SIRT1 agonist resveratrol (RSV). Cytokines and biochemical indicators were detected by corresponding kits. Protein and mRNA expression levels were assessed by immunoblotting and PCR methods, respectively. Angiogenesis capabilities were evaluated by migration, wound-healing and tube-formation experiments. To down-regulate certain signals, gene-specific siRNA were applied.RESULTS: Metabolomics study revealed the accelerated glycolysis in RA serum-treated HUVECs. It led to ATP accumulation, but did not affect GTP levels. RSV inhibited pro-angiogenesis cytokines production and glycolysis in both the cells, and impaired the angiogenesis potentials. These effects were mimicked by an energy metabolism interrupter bikini in lipopolysaccharide (LPS)-primed HUVECs, largely independent of HIF-1α. Both RSV and bikinin can inhibit the activation of the GTP-dependent pathway Rho/ROCK and reduce VEGF production. Abrogation of RhoA signaling reinforced HIF-1α silencing-brought changes in LPS-stimulated HUVECs, and overshadowed the anti-angiogenesis potentials of RSV.CONCLUSION: Glycolysis provides additional energy to sustain Rho/ROCK activation in RA subjects, which promotes VEGF-driven angiogenesis and can be inhibited by SIRT1 activation.PMID:37016140 | DOI:10.1007/s00011-023-01728-w

Sci Rep. 2023 Apr 4;13(1):5488. doi: 10.1038/s41598-023-32713-2.ABSTRACTA growing body of preclinical and clinical literature suggests that brain-gut-microbiota interactions may contribute to obesity pathogenesis. In this study, we use a machine learning approach to leverage the enormous amount of microstructural neuroimaging and fecal metabolomic data to better understand key drivers of the obese compared to overweight phenotype. Our findings reveal that although gut-derived factors play a role in this distinction, it is primarily brain-directed changes that differentiate obese from overweight individuals. Of the key gut metabolites that emerged from our model, many are likely at least in part derived or influenced by the gut-microbiota, including some amino-acid derivatives. Remarkably, key regions outside of the central nervous system extended reward network emerged as important differentiators, suggesting a role for previously unexplored neural pathways in the pathogenesis of obesity.PMID:37016129 | DOI:10.1038/s41598-023-32713-2

Nat Commun. 2023 Apr 4;14(1):1638. doi: 10.1038/s41467-023-37269-3.ABSTRACTThe pathogenesis of multi-organ dysfunction associated with severe acute SARS-CoV-2 infection remains poorly understood. Endothelial damage and microvascular thrombosis have been identified as drivers of COVID-19 severity, yet the mechanisms underlying these processes remain elusive. Here we show alterations in fluid shear stress-responsive pathways in critically ill COVID-19 adults as compared to non-COVID critically ill adults using a multiomics approach. Mechanistic in-vitro studies, using microvasculature-on-chip devices, reveal that plasma from critically ill COVID-19 adults induces fibrinogen-dependent red blood cell aggregation that mechanically damages the microvascular glycocalyx. This mechanism appears unique to COVID-19, as plasma from non-COVID sepsis patients demonstrates greater red blood cell membrane stiffness but induces less significant alterations in overall blood rheology. Multiomics analyses in pediatric patients with acute COVID-19 or the post-infectious multi-inflammatory syndrome in children (MIS-C) demonstrate little overlap in plasma cytokine and metabolite changes compared to adult COVID-19 patients. Instead, pediatric acute COVID-19 and MIS-C patients show alterations strongly associated with cytokine upregulation. These findings link high fibrinogen and red blood cell aggregation with endotheliopathy in adult COVID-19 patients and highlight differences in the key mediators of pathogenesis between adult and pediatric populations.PMID:37015925 | DOI:10.1038/s41467-023-37269-3

Cell Death Dis. 2023 Apr 5;14(4):238. doi: 10.1038/s41419-023-05740-0.ABSTRACTMany anticancer agents induce apoptosis, mitotic catastrophe or cellular senescence. Here, we report the functional characterization of an experimental inducer of tumor necrosis factor (TNF)-independent necrosis, necrocide-1 (NC1). NC1 (but not its stereoisomer) killed a panel of human cancer cells (but not normal cells) at nanomolar concentrations and with a non-apoptotic, necrotic morphotype, both in vitro and in vivo. NC1-induced killing was not inhibited by caspase blockers, anti-apoptotic BCL2 overexpression or TNFα neutralization, suggesting that NC1 elicits a bona fide necrotic pathway. However, pharmacological or genetic inhibition of necroptosis, pyroptosis and ferroptosis failed to block NC1-mediated cell death. Instead, NC1 elicited reactive oxygen species (ROS) production by mitochondria, and elimination of mitochondrial DNA, quenching of mitochondrial ROS, as well as blockade of mitochondrial permeability transition with cyclosporine A, interfered with NC1-induced cell death. NC1 induced hallmarks of immunogenic cell death incurring calreticulin (CALR) exposure, ATP secretion and high mobility group box 1 (HMGB1) release. Taken together, these data identify a previously uncharacterized signaling cascade leading to an immunogenic variant of mitochondrion-regulated necrosis, supporting the notion that eliciting regulated necrosis may constitute a valid approach for anticancer therapy.PMID:37015922 | DOI:10.1038/s41419-023-05740-0