PubMed

ACS Pharmacol Transl Sci. 2023 Apr 26;6(5):748-770. doi: 10.1021/acsptsci.3c00020. eCollection 2023 May 12.ABSTRACTMultitargeted agents with tumor selectivity result in reduced drug resistance and dose-limiting toxicities. We report 6-substituted thieno[2,3-d]pyrimidine compounds (3-9) with pyridine (3, 4), fluorine-substituted pyridine (5), phenyl (6, 7), and thiophene side chains (8, 9), for comparison with unsubstituted phenyl (1, 2) and thiophene side chain (10, 11) containing thieno[2,3-d]pyrimidine compounds. Compounds 3-9 inhibited proliferation of Chinese hamster ovary cells (CHO) expressing folate receptors (FRs) α or β but not the reduced folate carrier (RFC); modest inhibition of CHO cells expressing the proton-coupled folate transporter (PCFT) by 4, 5, 6, and 9 was observed. Replacement of the side-chain 1',4'-phenyl ring with 2',5'-pyridyl, or 2',5'-pyridyl with a fluorine insertion ortho to l-glutamate resulted in increased potency toward FR-expressing CHO cells. Toward KB tumor cells, 4-9 were highly active (IC50's from 2.11 to 7.19 nM). By metabolite rescue in KB cells and in vitro enzyme assays, de novo purine biosynthesis was identified as a targeted pathway (at 5-aminoimidazole-4-carboxamide ribonucleotide formyltransferase (AICARFTase) and glycinamide ribonucleotide formyltransferase (GARFTase)). Compound 9 was 17- to 882-fold more potent than previously reported compounds 2, 10, and 11 against GARFTase. By targeted metabolomics and metabolite rescue, 1, 2, and 6 also inhibited mitochondrial serine hydroxymethyl transferase 2 (SHMT2); enzyme assays confirmed inhibition of SHMT2. X-ray crystallographic structures were obtained for 4, 5, 9, and 10 with human GARFTase. This series affords an exciting new structural platform for potent multitargeted antitumor agents with FR transport selectivity.PMID:37200803 | PMC:PMC10186366 | DOI:10.1021/acsptsci.3c00020

Food Technol Biotechnol. 2023 Mar;61(1):107-117. doi: 10.17113/ftb.61.01.23.7711.ABSTRACTRESEARCH BACKGROUND: Curcuma species (Zingiberaceae) are well known medicinal herbs in India and Southeast Asia. Despite various findings reporting their beneficial biological activities, very little information has been recorded on the Curcuma caesia. Thus, this study aims to determine the phenolic content, antioxidant and α-glucosidase inhibitory activity of both rhizome and leaves of C. caesia.EXPERIMENTAL APPROACH: Rhizome and leaves of C. caesia were dried with oven (OD) and freeze (FD)-drying methods, and extracted with different Φ(ethanol,water)=100:0, 80:20, 50:50 and 0:100. The bioactivities of C. caesia extracts were evaluated using in vitro tests; total phenolic content (TPC), antioxidant (DPPH and FRAP) and α-glucosidase inhibitory activity. Proton nuclear magnetic resonance (1H NMR)-based metabolomics approach was employed to differentiate the most active extracts based on their metabolite profiles and correlation with bioactivities.RESULTS AND CONCLUSIONS: The FD rhizome extracted with Φ(ethanol,water)=100:0 was observed to have potent TPC expressed as gallic acid equivalents, FRAP expressed as Trolox equivalents and α-glucosidase inhibitory activity with values of (45.4±2.1) mg/g extract, (147.7±8.3) mg/g extract and (265.5±38.6) µg/mL (IC50), respectively. Meanwhile, for DPPH scavenging activity, the Φ(ethanol,water)=80:20 and 100:0 extracts of FD rhizome showed the highest activity with no significant difference between them. Hence, the FD rhizome extracts were selected for further metabolomics analysis. Principal component analysis (PCA) showed clear discrimination among the different extracts. Partial least square (PLS) analysis showed positive correlations of the metabolites, including xanthorrhizol derivative, 1-hydroxy-1,7-bis(4-hydroxy-3-methoxyphenyl)-(6E)-6-heptene-3,4-dione, valine, luteolin, zedoardiol, β-turmerone, selina-4(15),7(11)-dien-8-one, zedoalactone B and germacrone, with the antioxidant and α-glucosidase inhibition activities, whereas curdione and 1-(4-hydroxy-3,5-dimethoxyphenyl)-7-(4-hydroxy-3-methoxyphenyl)-(lE,6E)-1,6-heptadiene3,4-dione were correlated with α-glucosidase inhibitory activity.NOVELTY AND SCIENTIFIC CONTRIBUTION: C. caesia rhizome and leaf extracts contained phenolic compounds and had varies antioxidant and α-glucosidase inhibitory capacities. These findings strongly suggest that the rhizomes of C. caesia are an invaluable natural source of active ingredients for applications in pharmaceutical and food industries.PMID:37200789 | PMC:PMC10187568 | DOI:10.17113/ftb.61.01.23.7711

Am J Bot. 2023 May 18. doi: 10.1002/ajb2.16191. Online ahead of print.ABSTRACTPREMISE OF THE STUDY: The specialized metabolites of plants are recognized as key chemical traits in mediating the ecology and evolution of sundry plant-biotic interactions, from pollination to seed predation. Intra- and interspecific patterns of specialized metabolite diversity have been studied extensively in leaves, but the diverse biotic interactions which contribute to specialized metabolite diversity encompass all plant organs. Focusing on two species of Psychotria shrubs, we investigate and compare patterns of specialized metabolite diversity in leaves and fruit with respect to each organ's diversity of biotic interactions.METHODS: To evaluate associations between biotic interaction diversity and specialized metabolite diversity, we combine UPLC-MS metabolomic analysis of foliar and fruit specialized metabolites with existing surveys of leaf- and fruit-centered biotic interactions. We compare patterns of specialized metabolite richness and variance among vegetative and reproductive tissues, among plants, and between species.KEY RESULTS: In our study system, leaves interact with a far larger number of consumer species than do fruit, while fruit-centric interactions are more ecologically diverse in that they involve antagonistic and mutualistic consumers. This was reflected in specialized metabolite richness - leaves contained more than fruit, while each organ contained over 200 organ-specific specialized metabolites. Within each species, leaf- and fruit specialized metabolite composition varied independently of one another across individual plants. Specialized metabolite composition exhibited stronger contrasts between organs than between species.CONCLUSIONS: As ecologically disparate plant organs with organ-specific specialized metabolite traits, leaves and fruit can each contribute to the tremendous overall diversity of plant specialized metabolites. This article is protected by copyright. All rights reserved.PMID:37200534 | DOI:10.1002/ajb2.16191

PLoS One. 2023 May 18;18(5):e0285505. doi: 10.1371/journal.pone.0285505. eCollection 2023.ABSTRACTRhizobia are Gram-negative bacteria known for their ability to fix atmospheric N2 in symbiosis with leguminous plants. Current evidence shows that rhizobia carry in most cases a variable number of plasmids, containing genes necessary for symbiosis or free-living, a common feature being the presence of several plasmid replicons within the same strain. For many years, we have been studying the mobilization properties of pSmeLPU88b from the strain Sinorhizobium meliloti LPU88, an isolate from Argentina. To advance in the characterization of pSmeLPU88b plasmid, the full sequence was obtained. pSmeLPU88b is 35.9 kb in size, had an average GC % of 58.6 and 31 CDS. Two replication modules were identified in silico: one belonging to the repABC type, and the other to the repC. The replication modules presented high DNA identity to the replication modules from plasmid pMBA9a present in an S. meliloti isolate from Canada. In addition, three CDS presenting identity with recombinases and with toxin-antitoxin systems were found downstream of the repABC system. It is noteworthy that these CDS present the same genetic structure in pSmeLPU88b and in other rhizobial plasmids. Moreover, in all cases they are found downstream of the repABC operon. By cloning each replication system in suicide plasmids, we demonstrated that each of them can support plasmid replication in the S. meliloti genetic background, but with different stability behavior. Interestingly, while incompatibility analysis of the cloned rep systems results in the loss of the parental module, both obtained plasmids can coexist together.PMID:37200389 | DOI:10.1371/journal.pone.0285505

Insect Sci. 2023 May 18. doi: 10.1111/1744-7917.13201. Online ahead of print.ABSTRACTEnergy metabolism is essential for insect metamorphosis. The accumulation and utilization of energy is still not completely clear during larval-pupal metamorphosis of holometabolous insects. We used metabolome and transcriptome analysis to reveal key metabolic changes in the fat body and plasma and the underlying metabolic regulation mechanism of Helicoverpa armigera, an important global agricultural insect pest, during larval-pupal metamorphosis. During the feeding stage, activation of aerobic glycolysis provided intermediate metabolites and energy for cell proliferation and lipid synthesis. During the non-feeding stages (the initiation of the wandering stage and the prepupal stage), aerobic glycolysis was suppressed, while, triglyceride degradation was activated in the fat body. The blocking of metabolic pathways in the fat body was probably caused by 20-hydroxyecdysone-induced cell apoptosis. 20-hydroxyecdysone cooperated with carnitine to promote the degradation of triglycerides and the accumulation of acylcarnitines in the hemolymph, allowing rapid transportation and supply of lipids from the fat body to other organs, which provided a valuable reference for revealing the metabolic regulation mechanism of lepidopteran larvae during the last instar. Carnitine and acylcarnitines are first reported to be key factors that mediate the degradation and utilization of lipids during larval-pupal metamorphosis of lepidopteran insects.PMID:37200210 | DOI:10.1111/1744-7917.13201

Cell Rep. 2023 May 17;42(5):112529. doi: 10.1016/j.celrep.2023.112529. Online ahead of print.ABSTRACTMale mice lacking the androgen receptor (AR) in pancreatic β cells exhibit blunted glucose-stimulated insulin secretion (GSIS), leading to hyperglycemia. Testosterone activates an extranuclear AR in β cells to amplify glucagon-like peptide-1 (GLP-1) insulinotropic action. Here, we examined the architecture of AR targets that regulate GLP-1 insulinotropic action in male β cells. Testosterone cooperates with GLP-1 to enhance cAMP production at the plasma membrane and endosomes via: (1) increased mitochondrial production of CO2, activating the HCO3--sensitive soluble adenylate cyclase; and (2) increased Gαs recruitment to GLP-1 receptor and AR complexes, activating transmembrane adenylate cyclase. Additionally, testosterone enhances GSIS in human islets via a focal adhesion kinase/SRC/phosphatidylinositol 3-kinase/mammalian target of rapamycin complex 2 actin remodeling cascade. We describe the testosterone-stimulated AR interactome, transcriptome, proteome, and metabolome that contribute to these effects. This study identifies AR genomic and non-genomic actions that enhance GLP-1-stimulated insulin exocytosis in male β cells.PMID:37200193 | DOI:10.1016/j.celrep.2023.112529

J Agric Food Chem. 2023 May 18. doi: 10.1021/acs.jafc.2c08076. Online ahead of print.ABSTRACTDeoxynivalenol (DON) is a widespread mycotoxin and causes anorexia and emesis in humans and animals; Lactobacillus rhamnosus GG (LGG), a well-characterized probiotic, can improve intestinal barrier function and modulate immune response. Currently, it is unclear whether LGG has a beneficial effect on DON-induced anorexia. In the present study, mice were treated with DON, LGG, or both by gavage for 28 days to evaluate the effects of LGG on DON-induced anorexia. Antibiotic treatment and fecal microbiota transplant (FMT) experiment were also conducted to investigate the link between DON, LGG, and gut microbiota. LGG significantly increased the villus height and reduced the crypt depth in jejunum and ileum, enhanced the tight junction proteins expression in the intestine, and regulated the TLR4/NF-κB signaling pathway, consequently attenuating the intestinal inflammation caused by DON. In addition, LGG increased the relative abundance of Lactobacillus and butyric acid production of cecal contents; remodeled phenylalanine metabolism and tryptophan metabolism; reduced plasma peptide tyrosine tyrosine (PYY), 5-hydroxytryptamine (5-HT), and glucagon-like peptide-1 (GLP-1) concentrations; and promoted hypothalamic NPY and AgPR gene expression, which will further promote food intake and reduce weight loss, ultimately alleviating DON-induced anorexia in mice. Interestingly, antibiotic treatment diminished the intestinal toxicity of DON. The FMT experiment showed that DON-originated microbiota promotes intestinal inflammation and anorexia, while LGG + DON-originated microbiota has no adverse effects on mice. Both antibiotic treatment and FMT experiment have proved that gut microbiota was the primary vector for DON to exert its toxic effects and an essential mediator of LGG protection. In summary, our findings demonstrate that gut microbiota plays essential roles in DON-induced anorexia, and LGG can reduce the adverse effects caused by DON through its structure and regulate the gut microbiota, which may lay the important scientific foundation for future applications of LGG in food and feed products.PMID:37199714 | DOI:10.1021/acs.jafc.2c08076

Microbiol Spectr. 2023 May 18:e0007623. doi: 10.1128/spectrum.00076-23. Online ahead of print.ABSTRACTFetuses diagnosed with fetal growth restriction (FGR) are at an elevated risk of stillbirth and adulthood morbidity. Gut dysbiosis has emerged as one of the impacts of placental insufficiency, which is the main cause of FGR. This study aimed to characterize the relationships among the intestinal microbiome, metabolites, and FGR. Characterization was conducted on the gut microbiome, fecal metabolome, and human phenotypes in a cohort of 35 patients with FGR and 35 normal pregnancies (NP). The serum metabolome was analyzed in 19 patients with FGR and 31 normal pregnant women. Multidimensional data was integrated to reveal the links between data sets. A fecal microbiota transplantation mouse model was used to determine the effects of the intestinal microbiome on fetal growth and placental phenotypes. The diversity and composition of the gut microbiota were altered in patients with FGR. A group of microbial species altered in FGR closely correlated with fetal measurements and maternal clinical variables. Fecal and serum metabolism profiles were distinct in FGR patients compared to those in the NP group. Altered metabolites were identified and associated with clinical phenotypes. Integrated multi-omics analysis revealed the interactions among gut microbiota, metabolites, and clinical measurements. Microbiota from FGR gravida transplanted to mice progestationally induced FGR and placental dysfunction, including impaired spiral artery remodeling and insufficient trophoblast cell invasion. Taken together, the integration of microbiome and metabolite profiles from the human cohort indicates that patients with FGR endure gut dysbiosis and metabolic disorders, which contribute to disease pathogenesis. IMPORTANCE Downstream of the primary cause of fetal growth restriction are placental insufficiency and fetal malnutrition. Gut microbiota and metabolites appear to play an important role in the progression of gestation, while dysbiosis induces maternal and fetal complications. Our study elaborates the significant differences in microbiota profiles and metabolome characteristics between women with FGR and normal pregnancies. This is the first attempt so far that reveals the mechanistic links in multi-omics in FGR, providing a novel insight into host-microbe interaction in placenta-derived diseases.PMID:37199635 | DOI:10.1128/spectrum.00076-23

Microbiol Spectr. 2023 May 18:e0010423. doi: 10.1128/spectrum.00104-23. Online ahead of print.ABSTRACTHere, we report that the inhibition of the PP2A subfamily by okadaic acid results in an accumulation of polysaccharides in the acute infection stage (tachyzoites) of Toxoplasma gondii, which is a protozoan of global zoonotic importance and a model for the apicomplexan parasites. The loss of the catalytic subunit α of PP2A (ΔPP2Acα) in RHΔku80 leads to the polysaccharide accumulation phenotype in the base of tachyzoites as well as residual bodies and significantly compromises the intracellular growth in vitro and the virulence in vivo. A metabolomic analysis revealed that the accumulated polysaccharides in ΔPP2Acα are derived from interrupted glucose metabolism, which affects the production of ATP and energy homeostasis in the T. gondii knockout. The assembly of the PP2Acα holoenzyme complex involved in the amylopectin metabolism in tachyzoites is possibly not regulated by LCMT1 or PME1, and this finding contributes to the identification of the regulatory B subunit (B'/PR61). The loss of B'/PR61 results in the accumulation of polysaccharide granules in the tachyzoites as well as reduced plaque formation ability, exactly the same as ΔPP2Acα. Taken together, we have identified a PP2Acα-B'/PR61 holoenzyme complex that plays a crucial role in the carbohydrate metabolism and viability in T. gondii, and its deficiency in function remarkably suppresses the growth and virulence of this important zoonotic parasite both in vitro and in vivo. Hence, rendering the PP2Acα-B'/PR61 holoenzyme functionless should be a promising strategy for the intervention of Toxoplasma acute infection and toxoplasmosis. IMPORTANCE Toxoplasma gondii switches back and forth between acute and chronic infections, mainly in response to host immunologic status, which is characterized by flexible but specific energy metabolism. Polysaccharide granules are accumulated in the acute infection stage of T. gondii that have been exposed to a chemical inhibitor of the PP2A subfamily. The genetic depletion of the catalytic subunit α of PP2A leads to this phenotype and significantly affects the cell metabolism, energy production, and viability. Further, a regulatory B subunit PR61 is necessary for the PP2A holoenzyme to function in glucose metabolism and in the intracellular growth of T. gondii tachyzoites. A deficiency of this PP2A holoenzyme complex (PP2Acα-B'/PR61) in T. gondii knockouts results in the abnormal accumulation of polysaccharides and the disruption of energy metabolism, suppressing their growth and virulence. These findings provide novel insights into cell metabolism and identify a potential target for an intervention against a T. gondii acute infection.PMID:37199633 | DOI:10.1128/spectrum.00104-23

Mult Scler. 2023 May 18:13524585231171517. doi: 10.1177/13524585231171517. Online ahead of print.ABSTRACTBACKGROUND: The circulating metabolome is altered in multiple sclerosis (MS), but its prognostic capabilities have not been extensively explored. Lipid metabolites might be of particular interest due to their multiple roles in the brain, as they can serve as structural components, energy sources, and bioactive molecules. Gaining a deeper understanding of the disease may be possible by examining the lipid metabolism in the periphery, which serves as the primary source of lipids for the brain.OBJECTIVE: To determine if altered serum lipid metabolites are associated with the risk of relapse and disability in children with MS.METHODS: We collected serum samples from 61 participants with pediatric-onset MS within 4 years of disease onset. Prospective longitudinal relapse data and cross-sectional disability measures (Expanded Disability Status Scale (EDSS)) were collected. Serum metabolomics was performed using untargeted liquid chromatography and mass spectrometry. Individual lipid metabolites were clustered into pre-defined pathways. The associations between clusters of metabolites and relapse rate and EDSS score were estimated utilizing negative binomial and linear regression models, respectively.RESULTS: We found that serum acylcarnitines (relapse rate: normalized enrichment score (NES) = 2.1, q = 1.03E-04; EDSS: NES = 1.7, q = 0.02) and poly-unsaturated fatty acids (relapse rate: NES = 1.6, q = 0.047; EDSS: NES = 1.9, q = 0.005) were associated with higher relapse rates and EDSS, while serum phosphatidylethanolamines (relapse rate: NES = -2.3, q = 0.002; EDSS: NES = -2.1, q = 0.004), plasmalogens (relapse rate: NES = -2.5, q = 5.81E-04; EDSS: NES = -2.1, q = 0.004), and primary bile acid metabolites (relapse rate: NES = -2.0, q = 0.02; EDSS: NES = -1.9, q = 0.02) were associated with lower relapse rates and lower EDSS.CONCLUSION: This study supports the role of some lipid metabolites in pediatric MS relapses and disability.PMID:37199529 | DOI:10.1177/13524585231171517

Proteomics. 2023 May 18:e2300150. doi: 10.1002/pmic.202300150. Online ahead of print.ABSTRACTBlood serum is arguably the most analyzed biofluid for disease prediction and diagnosis. Herein, we benchmarked five different serum abundant protein depletion (SAPD) kits with regard to the identification of disease-specific biomarkers in human serum using bottom-up proteomics. As expected, the IgG removal efficiency among the SAPD kits is highly variable, ranging from 70% to 93%. A pairwise comparison of database search results showed a 10%-19% variation in protein identification among the kits. Immunocapturing-based SAPD kits against IgG and albumin outperformed the others in the removal of these two abundant proteins. Conversely, non-antibody-based methods (i.e., kits using ion exchange resins) and kits leveraging a multi-antibody approach were proven to be less efficient in depleting IgG/albumin from samples but led to the highest number of identified peptides. Notably, our results indicate that different cancer biomarkers could be enriched up to 10% depending on the utilized SAPD kit compared with the undepleted sample. Additionally, functional analysis of the bottom-up proteomic results revealed that different SAPD kits enrich distinct disease- and pathway-specific protein sets. Overall, our study emphasizes that a careful selection of the appropriate commercial SAPD kit is crucial for the analysis of disease biomarkers in serum by shotgun proteomics.PMID:37199141 | DOI:10.1002/pmic.202300150

J Sci Food Agric. 2023 May 17. doi: 10.1002/jsfa.12712. Online ahead of print.ABSTRACTBACKGROUND: The aptitude of commercial peaches for minimal processing (MP) is still limited, mainly due to shorten the shelf-life. Gamma irradiation has emerged in MP fruits as a promising technology. This study aimed to investigate the effects of gamma irradiation on the sensory and metabolic profiles of MP peaches from two cultivars, 'Forastero' (FT) and 'Ruby Prince' (RP), and evaluate the relationship between both profiles. MP peaches were packaged, and divided into two groups: one without additional treatment (K), and the other was subjected to gamma irradiation (1.0 kGy - I), making up a total of four samples (FTK, FTI, RPK, and RPI). The sensory profile was carried out by an assessor panel. Metabolite analysis was accomplished by gas chromatography-mass spectrometry (GC-MS).RESULTS: Irradiation significantly affected color, homogeneity, peach aroma, total flavor intensity, peach flavor, sweetness, and juiciness in FT, increasing their intensities. In the RP cultivar, irradiation increased brightness, total aroma intensity, peach aroma, and flavor and texture descriptors. Regarding the metabolites, only malic acid and sucrose increased their concentrations in the irradiated samples. Partial least squares showed that sucrose was mainly correlated with sweet, total aroma intensity and peach flavors; and linked with FTI sample. Bitter along with to peach aroma and total intensity flavor were associated with RPI sample.CONCLUSION: The applied dose accelerated the ripening process of the peach. The study highlights the importance of complementing the sensory analysis with metabolomics tools to optimize fruit quality in minimally processed peaches. This article is protected by copyright. All rights reserved.PMID:37199063 | DOI:10.1002/jsfa.12712

Mol Oncol. 2023 May 18. doi: 10.1002/1878-0261.13454. Online ahead of print.ABSTRACTSnail1 is a transcriptional factor required for cancer-associated fibroblast (CAF) activation, and mainly detected in CAFs in human tumors. In the mouse mammary tumor virus-polyoma middle tumor-antigen (MMTV-PyMT) model of murine mammary gland tumors, Snai1 gene deletion, besides increasing tumor-free lifespan, altered macrophage differentiation, with fewer expressing low levels of MHC class II. Snail1 was not expressed in macrophages, and in vitro polarization with interleukin-4 (IL4) or interferon-γ (IFNγ) was not altered by Snai1 gene depletion. We verified that CAF activation modified polarization of naïve bone-marrow-derived macrophages (BMDMΦs). When BMDMΦs were incubated with Snail1-expressing (active) CAFs or with conditioned medium derived from these cells, they exhibited a lower cytotoxic capability than when incubated with Snail1-deleted (inactive) CAFs. Gene expression analysis of BMDMΦs polarized by conditioned medium from wild-type or Snai1-deleted CAFs revealed that active CAFs differentially stimulated a complex combination of genes comprising genes that are normally induced by IL4, downregulated by IFNγ or not altered during the two canonical differentiations. Levels of RNAs relating to this CAF-induced alternative polarization were sensitive to inhibitors of factors specifically released by active CAFs, such as prostaglandin E2 and TGFβ. Finally, CAF-polarized macrophages promoted the activation of the immunosuppressive regulatory T cells (T-regs). Our results imply that an active CAF-rich tumor microenvironment induces the polarization of macrophages to an immunosuppressive phenotype, preventing the macrophage cytotoxic activity on tumor cells and enhancing the activation of T-reg cells.PMID:37199012 | DOI:10.1002/1878-0261.13454

PeerJ. 2023 May 12;11:e15319. doi: 10.7717/peerj.15319. eCollection 2023.ABSTRACTFraxinus angustifolia is a type of street tree and shade tree with ornamental value. It has a beautiful shape and yellow or reddish purple autumn leaves, but its leaf color formation mechanism and molecular regulation network need to be studied. In this study, we integrated the metabolomes and transcriptomes of stage 1 (green leaf) and stage 2 (red-purple leaf) leaves at two different developmental stages to screen differential candidate genes and metabolites related to leaf color variation. The results of stage 1 and stage 2 transcriptome analysis showed that a total of 5,827 genes were differentially expressed, including 2,249 upregulated genes and 3,578 downregulated genes. Through functional enrichment analysis of differentially expressed genes, we found that they were involved in flavonoid biosynthesis, phenylpropanoid biosynthesis, pigment metabolism, carotene metabolism, terpenoid biosynthesis, secondary metabolite biosynthesis, pigment accumulation, and other biological processes. By measuring the metabolites of Fraxinus angustifolia leaves, we found the metabolites closely related to the differentially expressed genes in two different periods of Fraxinus angustifolia, among which flavonoid compounds were the main differential metabolites. Through transcriptome and metabolomics data association analysis, we screened nine differentially expressed genes related to anthocyanins. Transcriptome and qRT-PCR results showed that these nine genes showed significant expression differences in different stages of the sample, and we speculate that they are likely to be the main regulatory factors in the molecular mechanism of leaf coloration. This is the first time that we have analyzed the transcriptome combination metabolome in the process of leaf coloration of Fraxinus angustifolia, which has important guiding significance for directional breeding of colored-leaf Fraxinus species and will also give new insights for enriching the landscape.PMID:37197583 | PMC:PMC10184661 | DOI:10.7717/peerj.15319

J Inflamm Res. 2023 May 11;16:2023-2039. doi: 10.2147/JIR.S402592. eCollection 2023.ABSTRACTPURPOSE: Mesenchymal stem cells (MSCs) have become novel therapeutic agents for the treatment of inflammatory bowel diseases (IBDs). However, the precise cellular and molecular mechanisms by which MSCs restore intestinal tissue homeostasis and repair the epithelial barrier have not been well elucidated. This study aimed to investigate the therapeutic effects and possible mechanisms of human MSCs in the treatment of experimental colitis.METHODS: We performed an integrative transcriptomic, proteomic, untargeted metabolomics, and gut microbiota analyses in a dextran sulfate sodium (DSS)-induced IBD mouse model. The cell viability of IEC-6 cells was determined by Cell Counting Kit-8 (CCK-8) assay. The expression of MUC-1 and ferroptosis-related genes were determined by immunohistochemical staining, Western blot, and real-time quantitative polymerase chain reaction (RT-qPCR).RESULTS: Mice treated with MSCs showed notable amelioration in the severity of DSS-induced colitis, which was associated with reduced levels of proinflammatory cytokines and restoration of the lymphocyte subpopulation balance. Treatment with MSC restored the gut microbiota and altered their metabolites in DSS-induced IBD mice. The 16s rDNA sequencing showed that treatment with MSC modulated the composition of probiotics, including the upregulation of the contents of Firmicutes, Lactobacillus, Blautia, Clostridia, and Helicobacter bacteria in mouse colons. Protein proteomics and transcriptome analyses revealed that pathways related to cell immune responses, including inflammatory cytokines, were suppressed in the MSC group. The ferroptosis-related gene, MUC-1, was significantly upregulated in the MSC-treated group. MUC-1-inhibition experiments indicated that MUC-1 was essential for epithelial cell growth. Through overexpression of MUC-1, it showed that upregulation of SLC7A11 and GPX4, and downregulation of ACSL4 in erastin and RSL3-treated IEC-6 cells, respectively.CONCLUSION: This study described a mechanism by which treatment with MSCs ameliorated the severity of DSS-induced colitis by modulating the gut microbiota, immune response, and the MUC-1 pathway.PMID:37197438 | PMC:PMC10184855 | DOI:10.2147/JIR.S402592

Front Cell Infect Microbiol. 2023 May 1;13:1190602. doi: 10.3389/fcimb.2023.1190602. eCollection 2023.ABSTRACTINTRODUCTION: Previous studies reported that fucose plays a protective role in inhibiting pathogens. Fusobacterium nucleatum (Fn) was recently found to promote the progression of colitis. However, the effects of fucose on Fn are poorly understood. This study aimed to explore whether fucose could ameliorate the proinflammatory property of Fn in colitis and the underlying mechanisms.METHODS: To validate our hypothesis, mice were administrated with Fn and fucose-treated Fn (Fnf) before dextran sulfate sodium (DSS) treatment to establish Fn related colitis model. The metabolism variation of Fn was detected by metabolomic analysis. To verify the effects of bacterial metabolites on intestinal epithelial cells (IECs), Caco-2 cells were treated with bacterial supernatant.RESULTS: More severe inflammation, intestinal barrier damage, autophagy block, and apoptosis in the colon were noted in DSS mice that were administrated with Fn or Fnf. However, the severity degree in Fnf+DSS group was less compared to Fn+DSS group. Metabolic pathways of Fn were altered after fucose treatment and proinflammatory metabolites were decreased. The supernatant of Fnf induced a lower level of inflammation than Fn in Caco-2 cells. One of the decreased metabolites, homocysteine thiolactone (HT), was proven to induce inflammatory effects in Caco-2 cells.DISCUSSION: In conclusion, fucose ameliorates the proinflammatory property of Fn via altering its metabolism and these findings provide evidence for the application of fucose as functional food or prebiotic in the treatment of Fn related colitis.PMID:37197204 | PMC:PMC10183584 | DOI:10.3389/fcimb.2023.1190602

Diabetes Metab Syndr Obes. 2023 May 11;16:1367-1381. doi: 10.2147/DMSO.S404352. eCollection 2023.ABSTRACTBACKGROUND: Fecal microbiota transplantation (FMT) has emerged as a new therapy targeting gastrointestinal microbiota for the treatment of a growing number of diseases in recent years. Previous studies have suggested that FMT may be a potential therapy for type 2 diabetes (T2D), but the underlying mechanism remains unclear. Therefore, in the present study, we aimed to investigate the role of FMT in T2D and its underlying mechanisms.METHODS: To induce T2D, mice were fed a high-fat diet and injected with low-dose streptozotocin (STZ) for four weeks. The mice were then randomly divided into four groups: control group (n = 7), T2D group (n = 7), metformin (MET)-treated group (n = 7), and FMT group (n = 7). The MET group was orally administered 0.2 g/kg MET, the FMT group was orally administered 0.3 mL of bacterial solution, and the other two groups were orally administered the same volume of saline for four weeks. Serum and fecal samples were collected for non-targeted metabolomics, biochemical indicators, and 16S rRNA sequencing, respectively.RESULTS: Our results demonstrated that FMT had a curative effect on T2D by ameliorating hyperlipidemia and hyperglycemia. Using 16S rRNA sequencing and serum untargeted metabolomic analysis, we found that FMT could restore the disorders of gastrointestinal microbiota in T2D mice. Moreover, corticosterone, progesterone, L-urobilin, and other molecules were identified as biomarkers after FMT treatment. Our bioinformatics analysis suggested that steroid hormone biosynthesis, arginine, proline metabolism, and unsaturated fatty acid biosynthesis could be potential regulatory mechanisms of FMT.CONCLUSION: In summary, our study provides comprehensive evidence for the role of FMT in the treatment of T2D. FMT has the potential to become a promising strategy for the treatment of metabolic disorders, T2D, and diabetes-related complications.PMID:37197060 | PMC:PMC10184852 | DOI:10.2147/DMSO.S404352

Sci Total Environ. 2023 May 15:164204. doi: 10.1016/j.scitotenv.2023.164204. Online ahead of print.ABSTRACTDBDPE and Cd are representative contaminants commonly found in electronic waste (e-waste), which tend to be gradually discharged and accumulated in the environment during e-waste dismantling, resulting in frequent outbreaks and detection of these pollutants. The toxicity of both chemicals to vegetables after combined exposure has not been determined. The accumulation and mechanisms of phytotoxicity of the two compounds, alone and in combination, were studied using lettuce. The results showed that the enrichment ability of Cd and DBDPE in root was significantly higher than that in aerial part. Exposure to 1 mg/L Cd + DBDPE reduced the toxicity of Cd to lettuce, while exposure to 5 mg/L Cd + DBDPE increased the toxicity of Cd to lettuce. The absorption of Cd in the underground part of lettuce of 5 mg/L Cd + DBDPE was significantly increased by 108.75 % compared to 5 mg/L Cd. The significant enhancement of antioxidant system activity in lettuce under 5 mg/L Cd + DBDPE exposure, and the root activity and total chlorophyll content were decreased by 19.62 % and 33.13 %, respectively, compared to the control. At the same time, the organelles and cell membranes of lettuce root and leaf were significantly damaged, which was significantly worse than that of single Cd and DBDPE treatment. Combined exposure significantly affected the pathways related to amino acid metabolism, carbon metabolism and ABC transport in lettuce. This study filled the safety gap of DBDPE and Cd combined exposure on vegetables and would provide a theoretical basis for the environmental behavior and toxicological study of DBDPE and Cd.PMID:37196961 | DOI:10.1016/j.scitotenv.2023.164204

Plant Sci. 2023 May 15:111731. doi: 10.1016/j.plantsci.2023.111731. Online ahead of print.ABSTRACTIn the current climate change scenario, water stress is a serious threat to limit crop growth and yields. It is necessary to develop tolerant plants that cope with water stress and, for this purpose, tolerance mechanisms should be studied. NIBER® is a proven water stress- and salt-tolerant pepper hybrid rootstock (Gisbert-Mullor et al., 2020; López-Serrano et al., 2020), but tolerance mechanisms remain unclear. In this experiment, NIBER® and A10 (a sensitive pepper accession (Penella et al., 2014)) response to short-term water stress at 5 h and 24 h was studied in terms of gene expression and metabolites content in roots. GO terms and gene expression analyses evidenced constitutive differences in the transcriptomic profile of NIBER® and A10, associated with detoxification systems of reactive oxygen species (ROS). Upon water stress, transcription factors like DREBs and MYC are upregulated and the levels of auxins, abscisic acid and jasmonic acid are increased in NIBER®. NIBER® tolerance mechanisms involve an increase in osmoprotectant sugars (i.e., trehalose, raffinose) and in antioxidants (spermidine), but lower contents of oxidized glutathione compared to A10, which indicates less oxidative damage. Moreover, the gene expression for aquaporins and chaperones is enhanced. These results show the main NIBER® strategies to overcome water stress.PMID:37196901 | DOI:10.1016/j.plantsci.2023.111731

J Ethnopharmacol. 2023 May 15:116545. doi: 10.1016/j.jep.2023.116545. Online ahead of print.ABSTRACTETHNOPHARMACOLOGICAL RELEVANCE: Ruda-6 (RD-6), a typical traditional Mongolian medicine formulae consisting of 6 herbs, has been traditionally used in treating gastric disorders. Even though it has been shown to protect against gastric ulcers (GU) in animal models, the gut microbiome and serum metabololite-related mechanisms that prevent GU are not well understood.AIM OF THE STUDY: This study was conducted to evaluate the gastroprotective mechanism of RD-6 associated with the alteration of the gut microbiome and serum metabolic profiles in GU rats.MATERIALS AND METHODS: RD-6 (0.27, 1.35 and 2.7 g/kg) or ranitidine (40 mg/kg) were orally administered in rats for three weeks before the induction of gastric ulcer using indomethacin (30 mg/kg, single oral dose). The gastric ulcer index, ulcer area, H&E staining, and the levels of TNF-α, iNOS, MPO and MDA were quantified to evaluate the ulcer inhibitory effects of RD-6. Then, 16S rRNA gene sequencing combined with LC-MS metabolic profiling was performed to investigate the effect of RD-6 on the gut microbiota and serum metabolites in rats. Moreover, a spearman analysis was used to calculate the correlation coefficient between the different microbiota and the metabolites.RESULTS: RD-6 inhibited the gastric lesion damage caused by indomethacin in rats, decreased the ulcer index by 50.29% (p < 0.05), reduced the levels of TNF-α, iNOS, MDA and MPO in gastric tissue. Additionally, RD-6 reshaped the diversity and microbial composition, and reversed the reduced bacteria including [Eubacterium]_xylanophilum group, Sellimonas, Desulfovibrio, and UCG-009, and the increased bacteria Aquamicrobium caused by indomethacin induction. Furthermore, RD-6 regulated the levels of metabolites including amino acids and organic acids, and these affected metabolites were involved in taurine and hypotaurine metabolism and tryptophan metabolism. Spearman analysis revealed that the perturbed gut microbiota were closely related to the changes in differential serum metabolites.CONCLUSION: In view of the 16S rRNA gene sequencing and LC-MS metabolic results, the present study suggests the mechanism of RD-6 ameliorating GU via modulating intestinal microbiota and their metabolites.PMID:37196816 | DOI:10.1016/j.jep.2023.116545