PubMed

Liver Int. 2023 Apr 5. doi: 10.1111/liv.15575. Online ahead of print.ABSTRACTBACKGROUND AND AIMS: Non-alcoholic fatty liver disease (NAFLD) is characterized by the pathological accumulation of triglycerides in hepatocytes and is associated with insulin resistance, atherogenic dyslipidaemia and cardiometabolic diseases. Thus far, the extent of metabolic dysregulation associated with hepatic triglyceride accumulation has not been fully addressed. In this study, we aimed to identify metabolites associated with hepatic triglyceride content (HTGC) and map these associations using network analysis.METHODS: To gain insight in the spectrum of metabolites associated with hepatic triglyceride accumulation, we performed a comprehensive plasma metabolomics screening of 1363 metabolites in apparently healthy middle aged (age 45-65) individuals (N = 496) in whom HTGC was measured by proton magnetic resonance spectroscopy. An atlas of metabolite-HTGC associations, based on univariate results, was created using correlation-based Gaussian graphical model (GGM) and genome scale metabolic model network analyses. Pathways associated with the clinical prognosis marker fibrosis 4 (FIB-4) index were tested using a closed global test.RESULTS: Our analyses revealed that 118 metabolites were univariately associated with HTGC (p-value <6.59 × 10-5 ), including 106 endogenous, 1 xenobiotic and 11 partially characterized/uncharacterized metabolites. These associations were mapped to several biological pathways including branched amino acids (BCAA), diglycerols, sphingomyelin, glucosyl-ceramide and lactosyl-ceramide. We also identified a novel possible HTGC-related pathway connecting glutamate, metabolonic lactone sulphate and X-15245 using the GGM network. These pathways were confirmed to be associated with the FIB-4 index as well. The full interactive metabolite-HTGC atlas is provided online: https://tofaquih.github.io/AtlasLiver/.CONCLUSIONS: The combined network and pathway analyses indicated extensive associations between BCAA and the lipids pathways with HTGC and the FIB-4 index. Moreover, we report a novel pathway glutamate-metabolonic lactone sulphate-X-15245 with a potential strong association with HTGC. These findings can aid elucidating HTGC metabolomic profiles and provide insight into novel drug targets for fibrosis-related outcomes.PMID:37017544 | DOI:10.1111/liv.15575

mSphere. 2023 Apr 5:e0062522. doi: 10.1128/msphere.00625-22. Online ahead of print.ABSTRACTBacteria are known to cope with amino acid starvation by the stringent response signaling system, which is mediated by the accumulation of the (p)ppGpp alarmones when uncharged tRNAs stall at the ribosomal A site. While a number of metabolic processes have been shown to be regulatory targets of the stringent response in many bacteria, the global impact of amino acid starvation on bacterial metabolism remains obscure. This work reports the metabolomic profiling of the human pathogen Streptococcus pneumoniae under methionine starvation. Methionine limitation led to the massive overhaul of the pneumococcal metabolome. In particular, methionine-starved pneumococci showed a massive accumulation of many metabolites such as glutamine, glutamic acid, lactate, and cyclic AMP (cAMP). In the meantime, methionine-starved pneumococci showed a lower intracellular pH and prolonged survival. Isotope tracing revealed that pneumococci depend predominantly on amino acid uptake to replenish intracellular glutamine but cannot convert glutamine to methionine. Further genetic and biochemical analyses strongly suggested that glutamine is involved in the formation of a "prosurvival" metabolic state by maintaining an appropriate intracellular pH, which is accomplished by the enzymatic release of ammonia from glutamine. Methionine starvation-induced intracellular pH reduction and glutamine accumulation also occurred to various extents under the limitation of other amino acids. These findings have uncovered a new metabolic mechanism of bacterial adaptation to amino acid limitation and perhaps other stresses, which may be used as a potential therapeutic target for infection control. IMPORTANCE Bacteria are known to cope with amino acid starvation by halting growth and prolonging survival via the stringent response signaling system. Previous investigations have allowed us to understand how the stringent response regulates many aspects of macromolecule synthesis and catabolism, but how amino acid starvation promotes bacterial survival at the metabolic level remains largely unclear. This paper reports our systematic profiling of the methionine starvation-induced metabolome in S. pneumoniae. To the best of our knowledge, this represents the first reported bacterial metabolome under amino acid starvation. These data have revealed that the significant accumulation of glutamine and lactate enables S. pneumoniae to form a "prosurvival" metabolic state with a lower intracellular pH, which inhibits bacterial growth for prolonged survival. Our findings have provided insightful information on the metabolic mechanisms of pneumococcal adaptation to nutrient limitation during the colonization of the human upper airway.PMID:37017541 | DOI:10.1128/msphere.00625-22

Adv Biol (Weinh). 2023 Apr 5:e2200318. doi: 10.1002/adbi.202200318. Online ahead of print.ABSTRACTEven in this post genomic era, no national level newborn screening (NBS) programs for inborn errors of metabolism (IEMs) are yet available in several developing countries including Pakistan. Through NBS, various IEMs can be screened using minute quantities of biofluids. Targeted metabolomics and genomic techniques are the main approaches used for NBS. However, lack of technical expertise and such high-end "omics" based analytical facilities, and meager funding for healthcare in developing countries are the major reasons for unavailability of NBS programs. As it is reflected by only a handful reports about IEMs from Pakistan with population of ≈220 million and consanguinity rate of about 70%, which suggests an unmet need for an NBS program owing to reasonably high prevalence of inherited diseases. Around 200 IEMs are potentially treatable if diagnosed at an earlier stage through biochemical marker and genetic screening, so such patients can get benefit from the NBS program. This overview will help to persuade the stakeholders to setup NBS programs in developing countries including Pakistan, due to multitude of benefits for IEMs; timely diagnosis and early treatment can help the patients to live a nearly healthy life, reduced suffering of the family and minimal burden on society or national healthcare system.PMID:37017505 | DOI:10.1002/adbi.202200318

Alzheimers Dement. 2023 Apr 5. doi: 10.1002/alz.13007. Online ahead of print.ABSTRACTINTRODUCTION: The ketogenic diet (KD) is an intriguing therapeutic candidate for Alzheimer's disease (AD) given its protective effects against metabolic dysregulation and seizures. Gut microbiota are essential for KD-mediated neuroprotection against seizures as well as modulation of bile acids, which play a major role in cholesterol metabolism. These relationships motivated our analysis of gut microbiota and metabolites related to cognitive status following a controlled KD intervention compared with a low-fat-diet intervention.METHODS: Prediabetic adults, either with mild cognitive impairment (MCI) or cognitively normal (CN), were placed on either a low-fat American Heart Association diet or high-fat modified Mediterranean KD (MMKD) for 6 weeks; then, after a 6-week washout period, they crossed over to the alternate diet. We collected stool samples for shotgun metagenomics and untargeted metabolomics at five time points to investigate individuals' microbiome and metabolome throughout the dietary interventions.RESULTS: Participants with MCI on the MMKD had lower levels of GABA-producing microbes Alistipes sp. CAG:514 and GABA, and higher levels of GABA-regulating microbes Akkermansia muciniphila. MCI individuals with curcumin in their diet had lower levels of bile salt hydrolase-containing microbes and an altered bile acid pool, suggesting reduced gut motility.DISCUSSION: Our results suggest that the MMKD may benefit adults with MCI through modulation of GABA levels and gut-transit time.PMID:37017243 | DOI:10.1002/alz.13007

Chronobiol Int. 2023 Apr 5:1-8. doi: 10.1080/07420528.2023.2197063. Online ahead of print.ABSTRACTBipolar disorder (BD) is a common mental condition with a seasonal pattern (SP) of onset. In the spring, there is a higher incidence rate of mania or mixed onset and suicide. However, the underlying mechanism of this SP remains unclear. In this study, targeted metabolomics was used to understand metabolic changes in patients with BD before and after the spring equinox. Nine patients with BD and matched healthy controls were tested for serum metabolomics at the spring equinox and 15 days before and after the spring equinox. The results showed that 27 metabolite levels changed significantly, three of which interacted between three time points and groups involving triglyceride (TG, 20:4_34:2), TG (20:4_34:3) and TG (16:0_36:6). The identified metabolic pathways mainly involved arginine biosynthesis, D-glutamine and D-glutamate metabolism, and nitrogen metabolism. Changes in solar radiation and lunar cycle during spring may be the external causes of metabolic changes. These findings help to further explore seasonal metabolic changes in patients with BD and provide insights into the mechanisms of patients' emotional changes in spring.PMID:37017129 | DOI:10.1080/07420528.2023.2197063

Biosci Microbiota Food Health. 2023;42(2):124-130. doi: 10.12938/bmfh.2022-057. Epub 2023 Jan 13.ABSTRACTClostridium butyricum TO-A, Enterococcus faecium T-110, and Bacillus subtilis TO-A are sold as oral probiotic preparations and reportedly exhibit many beneficial effects on the health of hosts, including humans and livestock. In this study, we compared the ability of these clinically applied probiotic bacteria with Escherichia coli OP50 in extending the lifespan of Caenorhabditis elegans. To compare the C. elegans lifespan-extending effects of the three bacteria, experiments were performed using a nematode growth medium containing a small amount of trypticase soy agar. The maximum lifespans of worms fed C. butyricum TO-A, E. faecium T-110, or B. subtilis TO-A increased by 11, 12, and 26%, respectively, compared with worms fed E. coli OP50. In addition, we conducted a metabolomic analysis of methanol extracts of B. subtilis TO-A cells, which exhibited the strongest lifespan-extending effect on C. elegans among the probiotic bacteria tested in this study. As a result, 59 candidate substances involved in extending the lifespan of C. elegans were identified in B. subtilis TO-A cells.PMID:37016687 | PMC:PMC10067327 | DOI:10.12938/bmfh.2022-057

Curr Med Chem. 2023 Apr 3. doi: 10.2174/0929867330666230403100008. Online ahead of print.ABSTRACTCancer is a complex and debilitating disease that is one of the leading causes of death in the modern world. Computational methods have contributed to the successful design and development of several drugs. The recent advances in computational methodology, coupled with the avalanche of data being acquired through high throughput genomics, proteomics, and metabolomics, are likely to increase the contribution of computational methods toward the development of more effective treatments for cancer. Recent advances in the application of neural networks for the prediction of the native conformation of proteins have provided structural information regarding the complete human proteome. In addition, advances in machine learning and network pharmacology have provided novel methods for target identification and for the utilization of biological, pharmacological, and clinical databases for the design and development of drugs. This is a review of the key advances in computational methods that have the potential for application in the design and development of drugs for cancer.PMID:37016530 | DOI:10.2174/0929867330666230403100008

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