PubMed

Front Aging Neurosci. 2022 Oct 31;14:1026688. doi: 10.3389/fnagi.2022.1026688. eCollection 2022.ABSTRACTINTRODUCTION: Neurodegenerative diseases such as Alzheimer's disease, Parkinson's disease, amyotrophic lateral sclerosis, and Huntington's disease, are heavy burdens to global health and economic development worldwide. Mounting evidence suggests that exercise, a type of non-invasive intervention, has a positive impact on the life quality of elderly with neurodegenerative diseases. X-omics are powerful tools for mapping global biochemical changes in disease and treatment.METHOD: Three major databases were searched related to current studies in exercise intervention on neurodegenerative diseases using omics tools, including metabolomics, metagenomics, genomics, transcriptomics, and proteomics.RESULT: We summarized the omics features and potential mechanisms associated with exercise and neurodegenerative diseases in the current studies. Three main mechanisms by which exercise affects neurodegenerative diseases were summed up, including adult neurogenesis, brain-derived neurotrophic factor (BDNF) signaling, and short-chain fatty acids (SCFAs) metabolism.CONCLUSION: Overall, there is compelling evidence that exercise intervention is a feasible way of preventing the onset and alleviating the severity of neurodegenerative diseases. These studies highlight the importance of exercise as a complementary approach to the treatment and intervention of neurodegenerative diseases in addition to traditional treatments. More mechanisms on exercise interventions for neurodegenerative diseases, the specification of exercise prescriptions, and differentiated exercise programs should be explored so that they can actually be applied to the clinic.PMID:36389059 | PMC:PMC9659972 | DOI:10.3389/fnagi.2022.1026688

Front Aging Neurosci. 2022 Oct 28;14:1023493. doi: 10.3389/fnagi.2022.1023493. eCollection 2022.ABSTRACTThe APOE ε2, ε3, and ε4 alleles differentially impact various complex diseases and traits. We examined whether these alleles modulated associations of 94 single-nucleotide polymorphisms (SNPs) harbored by 26 genes in 19q13.3 region with 217 plasma metabolites using Framingham Heart Study data. The analyses were performed in the E2 (ε2ε2 or ε2ε3 genotype), E3 (ε3ε3 genotype), and E4 (ε3ε4 or ε4ε4 genotype) groups separately. We identified 31, 17, and 22 polymorphism-metabolite associations in the E2, E3, and E4 groups, respectively, at a false discovery rate P FDR < 0.05. These entailed 51 and 19 associations with 20 lipid and 12 polar analytes. Contrasting the effect sizes between the analyzed groups showed 20 associations with group-specific effects at Bonferroni-adjusted P < 7.14E-04. Three associations with glutamic acid or dimethylglycine had significantly larger effects in the E2 than E3 group and 12 associations with triacylglycerol 56:5, lysophosphatidylethanolamines 16:0, 18:0, 20:4, or phosphatidylcholine 38:6 had significantly larger effects in the E2 than E4 group. Two associations with isocitrate or propionate and three associations with phosphatidylcholines 32:0, 32:1, or 34:0 had significantly larger effects in the E4 than E3 group. Nine of 70 SNP-metabolite associations identified in either E2, E3, or E4 groups attained P FDR < 0.05 in the pooled sample of these groups. However, none of them were among the 20 group-specific associations. Consistent with the evolutionary history of the APOE alleles, plasma metabolites showed higher APOE-cluster-related variations in the E4 than E2 and E3 groups. Pathway enrichment mainly highlighted lipids and amino acids metabolism and citrate cycle, which can be differentially impacted by the APOE alleles. These novel findings expand insights into the genetic heterogeneity of plasma metabolites and highlight the importance of the APOE-allele-stratified genetic analyses of the APOE-related diseases and traits.PMID:36389057 | PMC:PMC9650319 | DOI:10.3389/fnagi.2022.1023493

iScience. 2022 Oct 25;25(11):105437. doi: 10.1016/j.isci.2022.105437. eCollection 2022 Nov 18.ABSTRACTIschemic stroke critically impacts neurovascular homeostasis, potentially resulting in neurological disorders. However, the mechanisms through which stroke-induced inflammation modifies the molecular and metabolic circuits, particularly in ileal epithelial cells (iECs), currently remain elusive. Using multiomic approaches, we illustrated that stroke impaired the ileal microbiome and associated metabolites, leading to increased inflammatory signals and altered metabolites, potentially deteriorating the iEC homeostasis. Bulk transcriptomic and metabolomic profiling demonstrated that stroke enhanced fatty acid oxidation while reducing the tricarboxylic acid (TCA) cycle in iECs within the first day after stroke. Intriguingly, single-cell RNA sequencing analysis revealed that stroke dysregulated cell-type-specific gene responses within iECs and reduced frequencies of goblet and tuft cells. Additionally, stroke augmented interleukin-17A+ γδ T cells but decreased CD4+ T cells in the ileum. Collectively, our findings provide a comprehensive overview of stroke-induced intestinal dysbiosis and unveil responsive gene programming within iECs with implications for disease development.PMID:36388972 | PMC:PMC9650036 | DOI:10.1016/j.isci.2022.105437

Ann Transl Med. 2022 Oct;10(20):1115. doi: 10.21037/atm-22-4767.ABSTRACTBACKGROUND: Globally, the incidence and mortality of colorectal cancer (CRC) rank amongst the highest of all malignancies. Thus, research aimed at developing new screening strategies and biomarkers for the early detection of CRC is needed. At present, conventional screening methods have limitations; therefore, new testing strategies have been considered. Using metabolomics to explore the molecular changes in CRC tissue is a mainstream method for identifying potential biomarkers and key cancer factors.METHODS: In the present study, 27 samples from nine CRC patients were used to analyze the metabolite differences between the tumor, paracancerous, and normal tissues. The metabolite differences in the various stages of CRC (stages IIA, IIB, and IIIC) were analyzed as well. Subsequently, principal component analysis (PCA), permutation, and trend analyses were performed. Weighted gene co-expression and metabolite-metabolite interaction networks were also constructed.RESULTS: A total of 5,834 metabolites were identified among the included samples. Permutation analysis showed a clear separation between the different tissues and different stages. Compared with normal tissues, tumor tissues exhibited 11, 233, and 25 up-regulated metabolites as well as one, 77, and zero down-regulated metabolites in stages IIA, IIB, and IIIC, respectively. Moreover, tumor tissues in stage IIB exhibited more differential metabolites (233 up-regulated and 77 down-regulated). Weighted Gene Correlation Network Analysis (WGCNA) clustered the 5,834 metabolites into 15 different modules, of which four modules were significantly correlated with tissue specificity. Notably, glycerophospholipid metabolism, fatty acid metabolism, and other pathways were enriched in these modules.CONCLUSIONS: Fatty acids and glycerophospholipids were significantly related to the development of CRC. This result is of great significance for future targeted screening of CRC biomarkers and further clarifying the nutrient metabolism of cancer cells.PMID:36388835 | PMC:PMC9652529 | DOI:10.21037/atm-22-4767

Front Plant Sci. 2022 Oct 26;13:988861. doi: 10.3389/fpls.2022.988861. eCollection 2022.ABSTRACTThe crop production of quinoa (Chenopodium quinoa Willd.), the only plant meeting basic human nutritional requirements, is affected by drought stress. To better understand the drought tolerance mechanism of quinoa, we screened the drought-tolerant quinoa genotype "Dianli 129" and studied the seedling leaves of the drought-tolerant quinoa genotype after drought and rewatering treatments using transcriptomics and targeted metabolomics. Drought-treatment, drought control, rewatering-treated, and rewatered control were named as DR, DC, RW, and RC, respectively. Among four comparison groups, DC vs. DR, RC vs. RW, RW vs. DR, and RC vs. DC, we identified 10,292, 2,307, 12,368, and 3 differentially expressed genes (DEGs), and 215, 192, 132, and 19 differentially expressed metabolites (DEMs), respectively. A total of 38,670 genes and 142 pathways were annotated. The results of transcriptome and metabolome association analysis showed that gene-LOC110713661 and gene-LOC110738152 may be the key genes for drought tolerance in quinoa. Some metabolites accumulated in quinoa leaves in response to drought stress, and the plants recovered after rewatering. DEGs and DEMs participate in starch and sucrose metabolism and flavonoid biosynthesis, which are vital for improving drought tolerance in quinoa. Drought tolerance of quinoa was correlated with gene expression differences, metabolite accumulation and good recovery after rewatering. These findings improve our understanding of drought and rewatering responses in quinoa and have implications for the breeding of new drought-tolerance varieties while providing a theoretical basis for drought-tolerance varieties identification.PMID:36388589 | PMC:PMC9645111 | DOI:10.3389/fpls.2022.988861

Front Plant Sci. 2022 Oct 31;13:1025969. doi: 10.3389/fpls.2022.1025969. eCollection 2022.ABSTRACTThe synthesis of indole-3-acetonitrile (IAN) from the indolic glucosinolate (iGSL) glucobrassicin (GB) is a unique trait of members of the Brassicales. To assess the contribution of this pathway to indole-3-acetic acid (IAA) synthesis under stress conditions, drought stress (DS) experiments with Arabidopsis thaliana were performed in vitro. Analysis of GSLs in DS plants revealed higher contents of GB in shoots and roots compared to control plants. Deuterium incorporation experiments showed the highest turnover of GB compared to all other GSLs during drought conditions. Evidence suggests the involvement of the thioglucosidase BGLU18 in the degradation of GB. The nitrile specifier proteins NSP1 and NSP5 are known to direct the GSL hydrolysis towards formation of IAN. Nitrilases like NIT2 are able to subsequently synthesize IAA from IAN. Expression of BGLU18, NSP1, NSP5 and NIT2 and contents of GB, IAN and IAA were significantly elevated in DS plants compared to control plants suggesting the increased use of GB as IAA source. Significantly higher contents of reactive oxygen species in DS bglu18 and epithionitrile specifier protein (esp) mutants compared to Col-0 indicate higher stress levels in these mutants highlighting the need for both proteins in DS plants. Furthermore, GB accumulation in leaves was higher in both mutants during DS when compared to Col-0 indicating enhanced synthesis of GB due to a lack of breakdown products. This work provides the first evidence for the breakdown of iGSLs to IAN which seems to be used for synthesis of IAA in DS A. thaliana plants.PMID:36388588 | PMC:PMC9659865 | DOI:10.3389/fpls.2022.1025969

Front Plant Sci. 2022 Oct 27;13:1025317. doi: 10.3389/fpls.2022.1025317. eCollection 2022.ABSTRACTFlavonoids from Actinidia arguta Sieb. Zucc. can reduce uric acid in mice. However, the molecular basis of its biosynthesis is still unclear. In this paper, we used a combination of extensively targeted metabolomics and transcriptomics analysis to determine the types and differences of flavonoids in the fruit ripening period (August to September) of two main cultivated varieties in northern China. The ethanol extract was prepared, and the potential flavonoids of Chrysin (Flavone1), Rutin (Flavone2), and Daidzein (Flavone3) in Actinidia arguta Sieb. Zucc. were separated and purified by HPD600 macroporous adsorption resin and preparative liquid chromatography. The structure was identified by MS-HPLC, and the serum uric acid index of male Kunming mice was determined by an animal model test.125 flavonoids and 50 differentially regulated genes were identified. The contents of UA (uric acid), BUN (urea nitrogen), Cr (creatinine), and GAPDH in mouse serum and mouse liver glycogen decreased or increased in varying degrees. This paper reveals the biosynthetic pathway of uric acid-reducing flavonoids in the fruit of Actinidia arguta Sieb. Zucc., a major cultivar in northern China, provides valuable information for the development of food and drug homologous functional foods.PMID:36388584 | PMC:PMC9647161 | DOI:10.3389/fpls.2022.1025317

Front Plant Sci. 2022 Oct 27;13:1050840. doi: 10.3389/fpls.2022.1050840. eCollection 2022.ABSTRACTSoil salinity is a very serious abiotic stressor that affects plant growth and threatens crop yield. Thus, it is important to explore the mechanisms of salt tolerance of plant and then to stabilize and improve crop yield. Asparagus is an important cash crop, but its salt tolerance mechanisms are largely unknown. Full-length transcriptomic and metabolomic analyses were performed on two asparagus genotypes: 'jx1502' (a salt-tolerant genotype) and 'gold crown' (a salt-sensitive genotype). Compared with the distilled water treatment (control), 877 and 1610 differentially expressed genes (DEGs) were identified in 'jx1502' and 'gold crown' under salt stress treatment, respectively, and 135 and 73 differentially accumulated metabolites (DAMs) were identified in 'jx1502' and 'gold crown' under salt stress treatment, respectively. DEGs related to ion transport, plant hormone response, and cell division and growth presented differential expression profiles between 'jx1502' and 'gold crown.' In 'jx1502,' 11 ion transport-related DEGs, 8 plant hormone response-related DEGs, and 12 cell division and growth-related DEGs were upregulated, while 7 ion transport-related DEGs, 4 plant hormone response-related DEGs, and 2 cell division and growth-related DEGs were downregulated. Interestingly, in 'gold crown,' 14 ion transport-related DEGs, 2 plant hormone response-related DEGs, and 6 cell division and growth-related DEGs were upregulated, while 45 ion transport-related DEGs, 13 plant hormone response-related DEGs, and 16 cell division and growth-related DEGs were downregulated. Genotype 'jx1502' can modulate K+/Na+ and water homeostasis and maintain a more constant transport system for nutrient uptake and distribution than 'gold crown' under salt stress. Genotype 'jx1502' strengthened the response to auxin (IAA), as well as cell division and growth for root remodeling and thus salt tolerance. Therefore, the integration analysis of transcriptomic and metabolomic indicated that 'jx1502' enhanced sugar and amino acid metabolism for energy supply and osmotic regulatory substance accumulation to meet the demands of protective mechanisms against salt stress. This work contributed to reveal the underlying salt tolerance mechanism of asparagus at transcription and metabolism level and proposed new directions for asparagus variety improvement.PMID:36388563 | PMC:PMC9648818 | DOI:10.3389/fpls.2022.1050840

Front Plant Sci. 2022 Oct 27;13:1016475. doi: 10.3389/fpls.2022.1016475. eCollection 2022.ABSTRACTCamellia fruit is a woody edible oil source with a recalcitrant pericarp, which increases processing costs. However, the relevance of pericarp thickness variations in Camellia species remains unclear. Therefore, this study aimed to identify pericarp differences at the metabolic and transcription levels between thick-pericarp Camellia drupifera BG and thin-pericarp Camellia oleifera SG. Forty differentially accumulated metabolites were screened through non-targeted UHPLC-Q-TOF MS-based metabolite profiling. S-lignin was prominently upregulated in BG compared with SG, contributing to the thick pericarp of BG. KEGG enrichment and coexpression network analysis showed 29 differentially expressed genes associated with the lignin biosynthetic pathway, including 21 genes encoding catalysts and 8 encoding transcription factors. Nine upregulated genes encoding catalysts potentially led to S-lignin accumulation in BG pericarp, and transcription factors NAC and MYB were possibly involved in major transcriptional regulatory mechanisms. Conventional growth-related factors WRKYs and AP2/ERFs were positively associated while pathogenesis-related proteins MLP328 and NCS2 were negatively associated with S-lignin content. Thus, Camellia balances growth and defense possibly by altering lignin biosynthesis. The results of this study may guide the genetic modifications of C. drupifera to optimize its growth-defense balance and improve seed accessibility.PMID:36388553 | PMC:PMC9647060 | DOI:10.3389/fpls.2022.1016475

Front Plant Sci. 2022 Oct 25;13:1038625. doi: 10.3389/fpls.2022.1038625. eCollection 2022.ABSTRACTCereal grains accumulate anthocyanin during developmental process. The anthocyanin content increases at grain filling stages to develop grain coloration in cereals. However, anthocyanin biosynthesis responsible for grain coloring and its regulatory mechanisms controlled by structural and functional genes remain unclear. Therefore, this study aimed to explore the global map of metabolic changes linked to grain coloration of Tibetan hulless barley (qingke) using an integrative metabolome and transcriptome approach. Grains from three colored qingke cultivars at different developmental stages were considered for molecular and metabolic investigations. A total of 120 differentially accumulated metabolites (DAMs) and 8,327 differentially expressed genes (DEGs) were filtered. DEGs were mainly enriched in the phenylpropanoid and flavonoid pathways. The transcript levels of anthocyanin biosynthesis genes (PAL, C4H, 4CL, CHS, FLS, F3H, F3'H, DFR, ANS, GT, OMT, and MAT) significantly upregulate in colored qingke compared to the non-colored variety. During grain development and maturation, the strong correlation of HvMYC2 expression with anthocyanin contents and anthocyanin biosynthesis genes suggested it as a critical gene in anthocyanin accumulation. Further results confirmed that HvMYC2 could be activated by HvMYB and be a positive regulator of UV-B and cold tolerance in qingke. In addition, verification based on enzymatic assays indicated that six key modifier enzymes could catalyze glycosylation, malonylation, and methylation of anthocyanins, thereby dissecting the major anthocyanin modification pathway in colored qingke. Overall, our study provides global insight into anthocyanin accumulation and the mechanism underlying grain coloration in qingke.PMID:36388537 | PMC:PMC9641248 | DOI:10.3389/fpls.2022.1038625

Front Plant Sci. 2022 Oct 26;13:1043378. doi: 10.3389/fpls.2022.1043378. eCollection 2022.ABSTRACTWasabi (Eutrema japonicum), also known as Japanese horseradish, is a perennial herb widely used in Japanese cuisine for its special flavour. The health-promoting phytochemicals and antioxidant capacity of four organs (leaf, petiole, rhizome, and root) of two cultivars (Chuankui-1 and Chuankui-2) of wasabi from two producing areas, Leibo and Guangyuan in Sichuan Province, China, were investigated in this study. The results showed that leaves were rich in pigments, soluble protein, ascorbic acid, and total phenolics and had the highest antioxidant capacity. Soluble sugars were highest in the petioles and were 1.1- to 5-fold higher than those in the other three organs. Glucosinolates and glucosinolate breakdown products (GBPs) were the most abundant in rhizomes, and their maximum values were 271.61 mmol kg-1 DW and 249.78 mmol kg-1 DW, respectively. The rhizomes of Chuankui-1 in Leibo and the leaves of Chuankui-1 in Guangyuan were superior in terms of glucosinolates and GBPs. These findings provide new insights that will aid the use of wasabi cultivars; they also have implications for the environmental characteristics needed to obtain better quality wasabi products. In the future, metabolome and transcriptome can be used to analyze the potential mechanism of differences among typical varieties, origins and parts.PMID:36388524 | PMC:PMC9643873 | DOI:10.3389/fpls.2022.1043378

Front Plant Sci. 2022 Oct 25;13:1052464. doi: 10.3389/fpls.2022.1052464. eCollection 2022.ABSTRACTArbuscular mycorrhizal fungi (AMF) and plants form a symbiotic relationship that promotes plant growth and development. However, the regulatory mechanisms through which AMF promote plant growth and development are largely unexplored. In this study, the apple rootstock M26 was assessed physiologically, transcriptionally and metabolically when grown with and without AMF inoculation. AMF significantly promoted the number of lateral root (LR) increase and shoot elongation. Root transcriptomic and metabolic data showed that AMF promoted lateral root development mainly by affecting glucose metabolism, fatty acid metabolism, and hormone metabolism. Shoot transcriptomic and metabolic data showed that AMF promoted shoot elongation mainly by affecting hormone metabolism and the expression of genes associated with cell morphogenesis. To investigate whether shoot elongation is caused by root development, we analyzed the root/shoot dry weight ratio. There was a correlation between shoot growth and root development, but analysis of root and shoot metabolites showed that the regulation of AMF on plant shoot metabolites is independent of root growth. Our study bridged the gap in the field of growth and development related to AMF.PMID:36388499 | PMC:PMC9641280 | DOI:10.3389/fpls.2022.1052464

Front Plant Sci. 2022 Oct 26;13:1027567. doi: 10.3389/fpls.2022.1027567. eCollection 2022.ABSTRACTDuring natural evolution and artificial selection, the fruit color of many species has been repeatedly gained or lost and is generally associated with mutations in genes encoding R2R3-MYB transcription factors, especially MYB10. In this study, we show that a heterozygous frameshift mutation (FaMYB10AG-insert/FaMYB10wild ) is responsible for the loss of anthocyanins in the flesh of cultivated strawberry. Comparative transcriptomic and metabolomic analyses of red- and white-fleshed strawberry indicated that the low expression level of FaUFGT (flavonol-O-glucosyltransferases) was responsible for the loss of anthocyanins and accumulation of proanthocyanidin in the white-fleshed strawberry and was the crucial gene that encodes enzymes of the anthocyanin biosynthesis pathway. Accordingly, overexpression and silencing of FaUFGT altered anthocyanin content and changed the flesh color of strawberry fruits. Furthermore, whole-genome resequencing analyses identified an AG insertion in the FaMYB10 coding region (FaMYB10AG-insert ) of white-fleshed strawberry. Y1H and EMSA assays showed that FaMYB10wild was able to bind to the promoter of the FaUFGT gene, while the FaMYB10AG-insert could not. The skin and flesh color were tightly linked to the number of fully functional FaMYB10 copies in the selfing progeny of white-fleshed strawberry. Our results suggested that heterozygous frameshift mutation of FaMYB10 resulted in the loss of the ability to activate the expression of the FaUFGT gene, was responsible for the natural formation of red and white-fleshed strawberry.PMID:36388497 | PMC:PMC9644031 | DOI:10.3389/fpls.2022.1027567

Front Plant Sci. 2022 Oct 28;13:1002772. doi: 10.3389/fpls.2022.1002772. eCollection 2022.ABSTRACTDrought poses a serious threat to plant growth. Plant growth-promoting bacteria (PGPB) have great potential to improve plant nutrition, yield, and drought tolerance. Sphingomonas is an important microbiota genus that is extensively distributed in the plant or rhizosphere. However, the knowledge of its plant growth-promoting function in dry regions is extremely limited. In this study, we investigated the effects of PGPB Sphingomonas sp. Hbc-6 on maize under normal conditions and drought stress. We found that Hbc-6 increased the biomass of maize under normal conditions and drought stress. For instance, the root fresh weight and shoot dry weight of inoculated maize increased by 39.1% and 34.8% respectively compared with non-inoculated plant, while they increased by 61.3% and 96.3% respectively under drought conditions. Hbc-6 also promoted seed germination, maintained stomatal morphology and increased chlorophyll content so as to enhance photosynthesis of plants. Hbc-6 increased antioxidant enzyme (catalase, superoxide, peroxidase) activities and osmoregulation substances (proline, soluble sugar) and up-regulated the level of beneficial metabolites (resveratrol, etc.). Moreover, Hbc-6 reshaped the maize rhizosphere bacterial community, increased its richness and diversity, and made the rhizosphere bacterial community more complex to resist stress; Hbc-6 could also recruit more potentially rhizosphere beneficial bacteria which might promote plant growth together with Hbc-6 both under normal and drought stress. In short, Hbc-6 increased maize biomass and drought tolerance through the above ways. Our findings lay a foundation for exploring the complex mechanisms of interactions between Sphingomonas and plants, and it is important that Sphingomonas sp. Hbc-6 can be used as a potential biofertilizer in agricultural production, which will assist finding new solutions for improving the growth and yield of crops in arid areas.PMID:36388485 | PMC:PMC9650444 | DOI:10.3389/fpls.2022.1002772

Front Plant Sci. 2022 Oct 31;13:1005764. doi: 10.3389/fpls.2022.1005764. eCollection 2022.ABSTRACTXanthomonas campestris pv. campestris (Xcc) is a vascular bacteria pathogen causing black rot in cabbage. Here, the resistance mechanisms of cabbage against Xcc infection were explored by integrated metabolome and transcriptome analysis. Pathogen perception, hormone metabolisms, sugar metabolisms, and phenylpropanoid metabolisms in cabbage were systemically re-programmed at both transcriptional and metabolic levels after Xcc infection. Notably, the salicylic acid (SA) metabolism pathway was highly enriched in resistant lines following Xcc infection, indicating that the SA metabolism pathway may positively regulate the resistance of Xcc. Moreover, we also validated our hypothesis by showing that the flavonoid pathway metabolites chlorogenic acid and caffeic acid could effectively inhibit the growth of Xcc. These findings provide valuable insights and resource datasets for further exploring Xcc-cabbage interactions and help uncover molecular breeding targets for black rot-resistant varieties in cabbage.PMID:36388482 | PMC:PMC9659849 | DOI:10.3389/fpls.2022.1005764

Drug Des Devel Ther. 2022 Nov 9;16:3893-3913. doi: 10.2147/DDDT.S383537. eCollection 2022.ABSTRACTPURPOSE: Semaglutide, a new long-acting glucagon-like peptide-1 analogue, has shown benefits for renal diseases, but its direct role on kidney metabolism under obesity remains unclear. The study aims to elucidate the protective effect and metabolic modulation mechanism of semaglutide on obesity-related kidney injury.METHODS: Male C57BL/6J mice were divided into control and obesity groups. Mice in the obesity group had a high-fat diet and were treated with or without semaglutide (30nmol/kg/day). The study assayed blood biochemistry and then evaluated renal pathological injury through Periodic Acid-Schiff staining and electron microscopy. Metabolomics was utilized to analyze obesity-related metabolites in kidney samples.RESULTS: Semaglutide significantly improved glucose homeostasis, insulin resistance, and kidney injury in obese mice. We successfully identified 377 altered metabolites (P<0.05). It was suggested that semaglutide directly improved oxidative stress and inflammation-related metabolites such as nicotinamide adenine dinucleotide (NAD+) and adenosine in the kidney of obese mice, which have not been documented in obesity-related kidney injury. Relevant enriched pathways were included phospholipids and lysophospholipids metabolism, purine metabolism, NAD+ metabolism, and insulin resistance-related metabolism. They could serve as potential targets for intervention of obesity-related kidney injury.CONCLUSION: Our study revealed the metabolomics-based renoprotective mechanism of semaglutide in obese mice for the first time. The innovation lied in the identified metabolites such as NAD+ and adenosine targeted by semaglutide, which have not been documented in obesity-related kidney injury. Semaglutide may be a promising therapy for obesity-related kidney diseases.PMID:36388084 | PMC:PMC9656502 | DOI:10.2147/DDDT.S383537

Drug Des Devel Ther. 2022 Nov 8;16:3877-3891. doi: 10.2147/DDDT.S381667. eCollection 2022.ABSTRACTPURPOSE: We designed this study to investigate the potential correlations between gut microbiota compositions and hepatic metabolomic disorders in mice with methotrexate (MTX)-induced hepatoxicity.METHODS: We used MTX to induce hepatoxicity in healthy Kunming mice, and we determined plasma ALT and AST levels and assessed the liver tissue histopathology. We applied an integrated gas chromatography-mass spectrometry (GC-MS) and 16S ribosomal RNA (rRNA) gene sequencing approach to evaluate the effects of MTX on the gut microbiota and hepatic metabolic profiles of mice. We uncovered correlations between the gut microbiota and hepatic metabolomic profiles by calculating the Spearman correlation coefficient.RESULTS: MTX caused ALT and AST level elevations and hepatoxicity in our mouse model. MTX disrupted amino acid metabolic pathways (including biosyntheses of valine, leucine, and isoleucine; and arginine; and, metabolism of alanine, aspartate, and glutamate; histidine; beta-alanine; and glycine, serine, and threonine); biosyntheses of aminoacyl-tRNA; and pantothenate, and CoA; and, metabolic pathways of energy, glutathione, and porphyrin; and chlorophyll. In addition, MTX increased the abundances of Staphylococcus, Enterococcus, Collinsella, Streptococcus, and Aerococcus, but decreased the amounts of Lactobacillus, Ruminococcus, norank_f_Muribaculaceae, unclassified_f_Lachnospiraceae, norank_f_Lachnospiraceae, A2, Eubacterium_xylanophilum_group, Phascolarctobacterium, Bifidobacterium, and Faecalibaculum. Our correlation analyses showed that different flora abundance changes including those of Phascolarctobacterium, Faecalibaculum, norank_f_Muribaculaceae, Streptococcus, Enterococcus, Staphylococcus, and Collinsella were associated with liver injury.CONCLUSION: We present evidence supporting the notion that MTX causes hepatoxicity by altering the gut microbiota and hepatic metabolite profiles, our findings provide new venues for the management of MTX-induced hepatoxicity.PMID:36388083 | PMC:PMC9653027 | DOI:10.2147/DDDT.S381667

Contemp Clin Trials Commun. 2022 Nov 8;30:101034. doi: 10.1016/j.conctc.2022.101034. eCollection 2022 Dec.ABSTRACTBACKGROUND: Morbid obesity (body mass index ≥40 kg/m2) represents a severe health risk and implies the need of urgent therapeutic action. (Poly)phenols may play a relevant role in the management of this disease modulating physiological and molecular pathways involved in energy metabolism and adiposity. The purpose of this double-blinded, placebo-controlled, randomised trial is to determine if (poly)phenol supplementation, in combination with a dietary intervention, can improve anthropometric and cardiometabolic parameters in participants with morbid obesity.METHODS: Adults (n = 40) with morbid obesity, bariatric surgery candidates, will be recruited from the Bellvitge University Hospital, Spain, and randomly assigned (stratified by sex) to intervention (poly)phenol-rich supplement 1,200 mg/day + hypocaloric diet) or control group (placebo + hypocaloric diet) for 12 weeks. The primary outcome is body weight. Secondary outcomes are: other anthropometric markers and body composition measured through standardized methods and a bioimpedance analysis, cardiometabolic and inflammatory biomarkers, metabolic pathways, and gut microbiota diversity. Anthropometric parameters, dietary, physical activity and lifestyle questionnaires, blood pressure, and blood and urine samples will be collected at baseline, 6 weeks, and 12 weeks. Faecal samples will be collected at baseline and at 12 weeks. Informed consent of participants will be obtained before the start of the study.DISCUSSION: The present study is expected to provide evidence on the effects of a combination of (poly)phenols on several well-established obesity and cardiometabolic markers, and to unravel possible underlying mechanisms by metabolomic analyses. Gut microbiota diversity will be considered as a potential future endpoint. The study will contribute to future strategies for prevention or treatment of obesity and related conditions.PMID:36387986 | PMC:PMC9661663 | DOI:10.1016/j.conctc.2022.101034

Front Endocrinol (Lausanne). 2022 Oct 27;13:1037164. doi: 10.3389/fendo.2022.1037164. eCollection 2022.ABSTRACTDiabetic retinopathy (DR) is a universal microvascular complication of diabetes mellitus (DM), which is the main reason for global sight damage/loss in middle-aged and/or older people. Current clinical analyses, like hemoglobin A1c, possess some importance as prognostic indicators for DR severity, but no effective circulating biomarkers are used for DR in the clinic currently, and studies on the latent pathophysiology remain lacking. Recent developments in omics, especially metabolomics, continue to disclose novel potential biomarkers in several fields, including but not limited to DR. Therefore, based on the overview of metabolomics, we reviewed progress in analytical technology of metabolomics, the prominent roles and the current status of biomarkers in DR, and the update of potential biomarkers in various DR-related samples via metabolomics, including tear as well as vitreous humor, aqueous humor, retina, plasma, serum, cerebrospinal fluid, urine, and feces. In this review, we underscored the in-depth analysis and elucidation of the common biomarkers in different biological samples based on integrated results, namely, alanine, lactate, and glutamine. Alanine may participate in and regulate glucose metabolism through stimulating N-methyl-D-aspartate receptors and subsequently suppressing insulin secretion, which is the potential pathogenesis of DR. Abnormal lactate could cause extensive oxidative stress and neuroinflammation, eventually leading to retinal hypoxia and metabolic dysfunction; on the other hand, high-level lactate may damage the structure and function of the retinal endothelial cell barrier via the G protein-coupled receptor 81. Abnormal glutamine indicates a disturbance of glutamate recycling, which may affect the activation of Müller cells and proliferation via the PPP1CA-YAP-GS-Gln-mTORC1 pathway.PMID:36387907 | PMC:PMC9646596 | DOI:10.3389/fendo.2022.1037164

Heliyon. 2022 Nov 5;8(11):e11412. doi: 10.1016/j.heliyon.2022.e11412. eCollection 2022 Nov.ABSTRACTA genome-based systematic analysis was conducted to characterize the metabolic, probiotic, fitness, and safety properties of Limosilactobacillus fermentum LAB-1, a lactic acid bacterium demonstrating strong antimicrobial effects against clinical pathogens. Gene functional characterization revealed a large number of genes for carbohydrate metabolism and a heterofermentative system for carbon dissimilation. Genes for intact pyruvate oxidation, pentose phosphate, and PRPP biosynthetic pathways were identified. Substantial carbohydrate-active enzymes and transporters were also predicted. Metabolic reconstruction revealed complete sets of enzymes for arginine, lysine, methionine, threonine, proline, and ornithine biosynthesis. The bacterium harbors a diverse range of peptidases, and a large variety of peptide and amino acid uptake systems. It encodes restriction-modification and CRISPR-Cas systems for protection against phage infections and carries a wide spectrum of stress proteins for adaptation in the gut and industrial conditions. Genes related to the biosynthesis of B-group and K vitamins were identified allowing its application for novel bio-enriched food production. Other beneficial traits of probiotic and industrial importance such as production of flavor compounds, exopolysaccharide, acetoin, and butanediol were identified. Three antimicrobial peptides were predicted which showed >98% sequence-identity to experimentally validated bacteriocins. Negative traits such as transmissible antibiotic resistance, pathogenicity or virulence appeared to be absent suggesting the strain to be considered safe. The genome analysis will allow precisely targeted laboratory research and full exploitation of the probiotic potentials towards functional-food, biotechnology and health-related applications.PMID:36387576 | PMC:PMC9647476 | DOI:10.1016/j.heliyon.2022.e11412