PubMed

Microbiol Spectr. 2023 Mar 28:e0351022. doi: 10.1128/spectrum.03510-22. Online ahead of print.ABSTRACTTrehalose, a nonreducing disaccharide, functions as a stress protectant in many organisms, including bacteria. In symbioses involving bacteria, the bacteria have to overcome various stressors to associate with their hosts; thus, trehalose biosynthesis may be important for symbiotic bacteria. Here, we investigated the role of trehalose biosynthesis in the Burkholderia-bean bug symbiosis. Expression levels of two trehalose biosynthesis genes, otsA and treS, were elevated in symbiotic Burkholderia insecticola cells, and hence mutant ΔotsA and ΔtreS strains were generated to examine the functions of these genes in symbiosis. An in vivo competition assay with the wild-type strain revealed that fewer ΔotsA cells, but not ΔtreS cells, colonized the host symbiotic organ, the M4 midgut, than wild-type cells. The ΔotsA strain was susceptible to osmotic pressure generated by high salt or high sucrose concentrations, suggesting that the reduced symbiotic competitiveness of the ΔotsA strain was due to the loss of stress resistance. We further demonstrated that fewer ΔotsA cells infected the M4 midgut initially but that fifth-instar nymphs exhibited similar symbiont population size as the wild-type strain. Together, these results demonstrated that the stress resistance role of otsA is important for B. insecticola to overcome the stresses it encounters during passage through the midgut regions to M4 in the initial infection stage but plays no role in resistance to stresses inside the M4 midgut in the persistent stage. IMPORTANCE Symbiotic bacteria have to overcome stressful conditions present in association with the host. In the Burkholderia-bean bug symbiosis, we speculated that a stress-resistant function of Burkholderia is important and that trehalose, known as a stress protectant, plays a role in the symbiotic association. Using otsA, the trehalose biosynthesis gene, and a mutant strain, we demonstrated that otsA confers Burkholderia with competitiveness when establishing a symbiotic association with bean bugs, especially playing a role in initial infection stage. In vitro assays revealed that otsA provides the resistance against osmotic stresses. Hemipteran insects, including bean bugs, feed on plant phloem sap, which may lead to high osmotic pressures in the midguts of hemipterans. Our results indicated that the stress-resistant role of otsA is important for Burkholderia to overcome the osmotic stresses present during the passage through midgut regions to reach the symbiotic organ.PMID:36976011 | DOI:10.1128/spectrum.03510-22

Int J Neonatal Screen. 2023 Mar 17;9(1):15. doi: 10.3390/ijns9010015.ABSTRACTIn 1963, Robert Guthrie's pioneering work developing a bacterial inhibition assay to measure phenylalanine in dried blood spots, provided the means for whole-population screening to detect phenylketonuria in the USA. In the following decades, NBS became firmly established as a part of public health in developed countries. Technological advances allowed for the addition of new disorders into routine programmes and thereby resulted in a paradigm shift. Today, technological advances in immunological methods, tandem mass spectrometry, PCR techniques, DNA sequencing for mutational variant analysis, ultra-high performance liquid chromatography (UPLC), iso-electric focusing, and digital microfluidics are employed in the NBS laboratory to detect more than 60 disorders. In this review, we will provide the current state of methodological advances that have been introduced into NBS. Particularly, 'second-tier' methods have significantly improved both the specificity and sensitivity of testing. We will also present how proteomic and metabolomic techniques can potentially improve screening strategies to reduce the number of false-positive results and improve the prediction of pathogenicity. Additionally, we discuss the application of complex, multiparameter statistical procedures that use large datasets and statistical algorithms to improve the predictive outcomes of tests. Future developments, utilizing genomic techniques, are also likely to play an increasingly important role, possibly combined with artificial intelligence (AI)-driven software. We will consider the balance required to harness the potential of these new advances whilst maintaining the benefits and reducing the risks for harm associated with all screening.PMID:36975853 | DOI:10.3390/ijns9010015

Microbiol Spectr. 2023 Mar 28:e0451922. doi: 10.1128/spectrum.04519-22. Online ahead of print.ABSTRACTInfections caused by multidrug-resistant bacteria are becoming increasingly serious. The aminoglycoside antibiotics have been widely used to treat severe Gram-negative bacterial infections. Here, we reported that a class of small molecules, namely, halogenated indoles, can resensitize Pseudomonas aeruginosa PAO1 to aminoglycoside antibiotics such as gentamicin, kanamycin, tobramycin, amikacin, neomycin, ribosomalin sulfate, and cisomicin. We selected 4F-indole as a representative of halogenated indoles to investigate its mechanism and found that the two-component system (TCS) PmrA/PmrB inhibited the expression of multidrug efflux pump MexXY-OprM, allowing kanamycin to act intracellularly. Moreover, 4F-indole inhibited the biosynthesis of several virulence factors, such as pyocyanin, type III secretion system (T3SS), and type VI secretion system (T6SS) exported effectors, and reduced the swimming and twitching motility by suppressing the expression of flagella and type IV pili. This study suggests that the combination of 4F-indole and kanamycin can be more effective against P. aeruginosa PAO1 and affect its multiple physiological activities, providing a novel insight into the reactivation of aminoglycoside antibiotics. IMPORTANCE Infections caused by Pseudomonas aeruginosa have become a major public health crisis. Its resistance to existing antibiotics causes clinical infections that are hard to cure. In this study, we found that halogenated indoles in combination with aminoglycoside antibiotics could be more effective than antibiotics alone against P. aeruginosa PAO1 and preliminarily revealed the mechanism of the 4F-indole-induced regulatory effect. Moreover, the regulatory effect of 4F-indole on different physiological behaviors of P. aeruginosa PAO1 was analyzed by combined transcriptomics and metabolomics. We explain that 4F-indole has potential as a novel antibiotic adjuvant, thus slowing down the further development of bacterial resistance.PMID:36975825 | DOI:10.1128/spectrum.04519-22

J Proteome Res. 2023 Mar 28. doi: 10.1021/acs.jproteome.2c00816. Online ahead of print.ABSTRACTEarly embryonic development arrest (EEDA) is a unique form of early spontaneous abortion in pregnant women, which is previously suggested to be associated with metabolic abnormalities. Noninvasive biomarkers would significantly improve its diagnosis and clinical outcome. Here, we performed a targeted metabolomics study in plasma from EEDA patients (n = 27) and normal pregnant women (NPW, n = 27) using liquid chromatography coupled with mass spectrometry (LC-MS) to identify potential diagnostic marker metabolites. Our results showed significantly different plasma metabolic profiles between EEDA patients and NPW. Particularly, EEDA patients showed significant alterations in amino acid, carbohydrate, and vitamin metabolism, which were characterized by 21 significantly increased metabolites and five decreased metabolites in plasma. Further receiver operating characteristic analysis showed that an optimal combination of S-methyl-5'-thioadenosine, kynurenine, leucine, and malate could be used as a panel of metabolites for EEDA diagnosis. The area under the curve of the metabolite panel was 0.941, suggesting a better performance than any single metabolite for the diagnosis of EEDA. In summary, our study identifies a panel of differential metabolites in plasma that could act as potential biomarkers for the diagnosis of EEDA in clinical settings.PMID:36975128 | DOI:10.1021/acs.jproteome.2c00816

Food Funct. 2023 Mar 28. doi: 10.1039/d3fo00009e. Online ahead of print.ABSTRACTFerroptosis, a form of regulated cell death caused by iron-mediated lipid peroxidation, has become a potential strategy to overcome drug resistance and improve the efficacy of traditional cancer treatments. In this study, we investigated whether treatment with the combination of Gracilariopsis lemaneiformis polysaccharides and cisplatin (CP) potentiated the antitumor activity in a Colon-26 carcinoma tumor-bearing mouse model by ferroptosis activation. The G. lemaneiformis polysaccharide GP90 was mainly composed of (1→3) linked 4-O-sulfate-β-D-galactose and (1→4) linked 3,6-anhydro-α-L-galactose with a molecular weight of 12.45 kDa. Compared with the CP group, the combination of GP90 and CP significantly suppressed tumor growth. Based on the transcriptomic and metabolomic analyses of tumor tissue, GP90 enhanced the antitumor effect of CP by promoting ferroptosis and regulating ferroptosis-related metabolic pathways. Moreover, the accumulation of 4-hydroxy-2-nonenal (4-HNE) and down-regulation of the expression of solute carrier family 7 member 11 (SLC7A11) and glutathione peroxidase 4 (Gpx4) were verified by immunohistochemistry staining. Finally, gene set enrichment analysis showed that positive immunoregulatory pathways were significantly enriched in the GP90 and CP combination group. Our results indicate that GP90 potentiates chemotherapy sensitivity by targeting the transferrin receptor and SLC7A11/Gpx4 pathway to induce ferroptosis, which might be a useful therapeutic target in colorectal cancer patients.PMID:36974905 | DOI:10.1039/d3fo00009e

Plant Physiol. 2023 Mar 28:kiad186. doi: 10.1093/plphys/kiad186. Online ahead of print.ABSTRACTMikania micrantha Kunth is a fast-growing global invasive weed species that causes severe damage to natural ecosystems and very large economic losses of forest and crop production. Although Puccinia spegazzinii can effectively inhibit the growth of M. micrantha and is used as a biological control strain in many countries, the mechanism of inhibiting the growth in Mikania micrantha is not clear. Here, we used a combination of phenotypic, enzyme activity, transcriptomic and metabolomic approaches to study the response of M. micrantha after infection by P. spegazzinii. In the early stages of rust infection, JA, JA-Ile and SA levels in infected leaves were significantly lower than that in uninfected leaves. In teliospore initial and developed stages of P. spegazzinii, JA and JA-Ile levels substantially increased by more than 6 times, which resulted in a significant decrease in accumulation of defense hormone SA in infected leaves of M. micrantha. The contents of plant growth-promoting hormones were significantly reduced in the infected plants as a result of substantial downregulation of expression of key genes related to hormone biosynthesis. Furthermore, rust infection led to high levels of ROS in chloroplasts and the destruction of chlorophyll structure, which also led to decreased photosynthetic gene expression, net photosynthetic rate, activity of Rubisco and levels of important organic acids in the Calvin cycle. We hypothesised that after P. spegazzinii infection, JA or JA-Ile accumulation not only inhibited SA levels to promote rust infection and development, but also impeded the rapid growth of M. micrantha by affecting plant growth hormones, carbon, and nitrogen metabolic pathways.PMID:36974897 | DOI:10.1093/plphys/kiad186

J Am Heart Assoc. 2023 Mar 28:e027934. doi: 10.1161/JAHA.122.027934. Online ahead of print.ABSTRACTBackground The evidence is equivocal on the association between meat consumption and ischemic heart disease (IHD) risk. To what extent the variation of individuals' metabolic responses to the same diet may account for this association is not fully understood. We aim to identify metabolomic signatures characterizing consumption of unprocessed red meat and processed meat and whether such signatures are associated with IHD risk. Methods and Results We conducted a cohort study of 92 246 individuals (mean age, 56.1 years; 55.1% women) using the UK Biobank. During the median follow-up of 8.74 years, 3059 incident IHD events were documented. Unprocessed red meat and processed meat consumption was assessed using a touchscreen dietary questionnaire. Plasma metabolome was profiled by high-throughput nuclear magnetic resonance spectroscopy. Cox proportional hazards regression model was used to test the association of meat consumption with IHD. Genome-wide association analysis and 1-sample Mendelian randomization were performed for metabolomic signatures and causal association of signatures with IHD. Using elastic net regularized regressions, we constructed metabolomic signatures consisting of 157 and 142 metabolites for unprocessed red meat (Spearman correlation coefficient [r]=0.223) and processed meat (r=0.329), respectively. These signatures showed positive associations with incident IHD (red meat related signature: hazard ratio [HR] per SD increment=1.11 [95% CI, 1.06-1.16], P<0.001; processed meat related signature: HR, 1.16 [95% CI, 1.11-1.21], P<0.001). Genome-wide association studies identified 45 and 4 loci, involved in lipid and lipoprotein metabolism, for red and processed meat related signatures. Mendelian randomization showed that there were casual associations of signatures with risk of incident IHD. Conclusions We identify metabolomic signatures that reflect consumption of unprocessed red meat and processed meat, and these signatures are associated with an increased risk of IHD.PMID:36974753 | DOI:10.1161/JAHA.122.027934

J Sci Food Agric. 2023 Mar 28. doi: 10.1002/jsfa.12579. Online ahead of print.ABSTRACTBACKGROUND: Lignification causes detrimental impact on quality of edible sprouts, while the mechanism of inhibition of lignification of edible sprouts by nano selenium and lentinans remains unclear.RESULTS: To reveal the mechanism of lignification regulation of sprouts by nano selenium and lentinans, this study investigated the changes in antioxidant indicators, phytohormones, polyphenols, and metabolites in the lignin biosynthesis in pea sprouts following sprays of nano selenium or/and lentinans twice. There was an overall increase in the above indices following treatment. In particular, the combined application of 5 mg/L nano selenium and 20 mg/L lentinans was more effective than the individual applications in enhancing peroxidase, catalase, DPPH free radical scavenging rate, luteolin, sinapic acid, as well as inhibiting malondialdehyde generation and lignin accumulation. Combined with the results from correlation analysis, nano selenium and lentinans may inhibit lignification by enhancing antioxidant systems, inducing phytohormonal mediated signaling, and enriching precursor metabolites (caffeyl alcohol, sinapyl alcohol, 4-coumaryl alcohol). In terms of the results of non-targeted metabolomics, the combined application of 5 mg/L nano selenium and 20 mg/L lentinans mainly affected biosynthesis of plant secondary metabolites, biosynthesis of phenylpropanoids, phenylpropanoid biosynthesis, arginine and proline metabolism, and linoleic acid metabolism pathways, which supported and complemented results from targeted screenings.CONCLUSION: Overall, the combined sprays of nano selenium and lentinans showed synergistic effects in delaying lignification and optimizing quality of pea sprouts. This study provides a novel and practicable technology for delaying lignification in the cultivation of edible sprouts. This article is protected by copyright. All rights reserved.PMID:36974656 | DOI:10.1002/jsfa.12579

Food Chem X. 2023 Feb 16;17:100601. doi: 10.1016/j.fochx.2023.100601. eCollection 2023 Mar 30.ABSTRACTThis study investigated the differences in proteins and metabolites from goat and bovine milk, and their mixtures, using data-independent-acquisition-based proteomics and metabolomics methods. In the skim milk, relative abundances of secretoglobin family 1D member (SCGB1D), polymeric immunoglobulin receptor, and glycosylation-dependent cell adhesion molecule 1 were increased, with an increase in the amount of 1-100 % bovine milk and served as markers at the 1 % adulteration level. In whey samples, β-lactoglobulin and α-2-HS-glycoprotein could be used to detect adulteration at the 0.1 % adulteration level, and SCGB1D and zinc-alpha-2-glycoprotein at the 1 % level. The metabolites of uric acid and N-formylkynurenine could be used to detect bovine milk at adulteration levels as low as 1 % based on variable importance at a projection value of > 1.0 and P-value of < 0.05. Our findings suggest novel markers of SCGB1D, uric acid, and N-formylkynurenine that can help to facilitate assessments of goat milk authenticity.PMID:36974185 | PMC:PMC10039227 | DOI:10.1016/j.fochx.2023.100601

Food Chem X. 2023 Feb 26;17:100612. doi: 10.1016/j.fochx.2023.100612. eCollection 2023 Mar 30.ABSTRACTTo meet the consumer demand for high-quality flesh sources, this study investigated the impacts of exercise training (ET) combined with a high-fat diet (HFD) on flesh quality. The results showed that HFD increased muscular fat content but reduced hardness, flexibility and adhesiveness. ET decreased fat content but increased flesh water holding capacity, hardness and stickiness. In terms of flavour, ET decreased the umami and sweet amino acid contents, which were restored when concomitantly feeding the HFD. Metabolomics further revealed that ET and HFD mainly affect the alanine, aspartate and glutamate metabolism, the citrate cycle and purine metabolism. The E-nose and volatile metabolomics analysis demonstrated that the combination of ET and HFD improved the aroma of flesh by enhancing the content of key flavour compounds within flesh such as hexadecenoic acid, ethyl ester and methyl stearate. This research provides a new strategy for improving the flesh quality of cultured fish.PMID:36974184 | PMC:PMC10039234 | DOI:10.1016/j.fochx.2023.100612

Mol Genet Metab Rep. 2023 Mar 20;35:100968. doi: 10.1016/j.ymgmr.2023.100968. eCollection 2023 Jun.ABSTRACTThe pyruvate dehydrogenase complex serves as the main connection between cytosolic glycolysis and the tricarboxylic acid cycle within mitochondria. An infant with pyruvate dehydrogenase complex deficiency was treated with vitamin B1 supplementation and a ketogenic diet. These dietary modifications resolved the renal tubular reabsorption, central apnea, and transfusion-dependent anemia. A concurrent metabolome analysis demonstrated the resolution of the amino aciduria and an increased total amount of substrates in the tricarboxylic acid cycle, reflecting the improved mitochondrial energetics. Glutamate was first detected in the cerebrospinal fluid, accompanied by a clinical improvement, after the ketogenic ratio was increased to 3:1; thus, glutamate levels in cerebrospinal fluid may represent a biomarker for neuronal recovery. Metabolomic analyses of body fluids are useful for monitoring therapeutic effects in infants with inborn errors of carbohydrate metabolism.PMID:36974075 | PMC:PMC10038782 | DOI:10.1016/j.ymgmr.2023.100968

BMC Genomics. 2023 Mar 27;24(1):152. doi: 10.1186/s12864-023-09246-z.ABSTRACTBACKGROUND: The mechanisms underlying rice root responses to drought during the early developmental stages are yet unknown.RESULTS: This study aimed to determine metabolic differences in IR64, a shallow-rooting, drought-susceptible genotype, and Azucena, a drought-tolerant and deep-rooting genotype under drought stress. The morphological evaluation revealed that Azucena might evade water stress by increasing the lateral root system growth, the root surface area, and length to access water. At the same time, IR64 may rely mainly on cell wall thickening to tolerate stress. Furthermore, significant differences were observed in 49 metabolites in IR64 and 80 metabolites in Azucena, for which most metabolites were implicated in secondary metabolism, amino acid metabolism, nucleotide acid metabolism and sugar and sugar alcohol metabolism. Among these metabolites, a significant positive correlation was found between allantoin, galactaric acid, gluconic acid, glucose, and drought tolerance. These metabolites may serve as markers of drought tolerance in genotype screening programs. Based on corresponding biological pathways analysis of the differentially abundant metabolites (DAMs), biosynthesis of alkaloid-derivatives of the shikimate pathway, fatty acid biosynthesis, purine metabolism, TCA cycle and amino acid biosynthesis were the most statistically enriched biological pathway in Azucena in drought response. However, in IR64, the differentially abundant metabolites of starch and sucrose metabolism were the most statistically enriched biological pathways.CONCLUSION: Metabolic marker candidates for drought tolerance were identified in both genotypes. Thus, these markers that were experimentally determined in distinct metabolic pathways can be used for the development or selection of drought-tolerant rice genotypes.PMID:36973662 | DOI:10.1186/s12864-023-09246-z

Nat Chem Biol. 2023 Mar 27. doi: 10.1038/s41589-023-01283-9. Online ahead of print.ABSTRACTAlthough nicotinamide adenine dinucleotide phosphate (NADPH) is produced and consumed in both the cytosol and mitochondria, the relationship between NADPH fluxes in each compartment has been difficult to assess due to technological limitations. Here we introduce an approach to resolve cytosolic and mitochondrial NADPH fluxes that relies on tracing deuterium from glucose to metabolites of proline biosynthesis localized to either the cytosol or mitochondria. We introduced NADPH challenges in either the cytosol or mitochondria of cells by using isocitrate dehydrogenase mutations, administering chemotherapeutics or with genetically encoded NADPH oxidase. We found that cytosolic challenges influenced NADPH fluxes in the cytosol but not NADPH fluxes in mitochondria, and vice versa. This work highlights the value of using proline labeling as a reporter system to study compartmentalized metabolism and reveals that NADPH homeostasis in the cytosolic and mitochondrial locations of a cell are independently regulated, with no evidence for NADPH shuttle activity.PMID:36973440 | DOI:10.1038/s41589-023-01283-9

Nat Commun. 2023 Mar 27;14(1):1713. doi: 10.1038/s41467-023-37450-8.ABSTRACTThe functions of the influenza virus neuraminidase has been well documented but those of the mammalian neuraminidases remain less explored. Here, we characterize the role of neuraminidase 1 (NEU1) in unilateral ureteral obstruction (UUO) and folic acid (FA)-induced renal fibrosis mouse models. We find that NEU1 is significantly upregulated in the fibrotic kidneys of patients and mice. Functionally, tubular epithelial cell-specific NEU1 knockout inhibits epithelial-to-mesenchymal transition, inflammatory cytokines production, and collagen deposition in mice. Conversely, NEU1 overexpression exacerbates progressive renal fibrosis. Mechanistically, NEU1 interacts with TGFβ type I receptor ALK5 at the 160-200aa region and stabilizes ALK5 leading to SMAD2/3 activation. Salvianolic acid B, a component of Salvia miltiorrhiza, is found to strongly bind to NEU1 and effectively protect mice from renal fibrosis in a NEU1-dependent manner. Collectively, this study characterizes a promotor role for NEU1 in renal fibrosis and suggests a potential avenue of targeting NEU1 to treat kidney diseases.PMID:36973294 | DOI:10.1038/s41467-023-37450-8

Nat Commun. 2023 Mar 27;14(1):1705. doi: 10.1038/s41467-023-37215-3.ABSTRACTBacterial pathogens have evolved intricate mechanisms to evade the human immune system, including the production of immunomodulatory enzymes. Streptococcus pyogenes serotypes secrete two multi-modular endo-β-N-acetylglucosaminidases, EndoS and EndoS2, that specifically deglycosylate the conserved N-glycan at Asn297 on IgG Fc, disabling antibody-mediated effector functions. Amongst thousands of known carbohydrate-active enzymes, EndoS and EndoS2 represent just a handful of enzymes that are specific to the protein portion of the glycoprotein substrate, not just the glycan component. Here, we present the cryoEM structure of EndoS in complex with the IgG1 Fc fragment. In combination with small-angle X-ray scattering, alanine scanning mutagenesis, hydrolytic activity measurements, enzyme kinetics, nuclear magnetic resonance and molecular dynamics analyses, we establish the mechanisms of recognition and specific deglycosylation of IgG antibodies by EndoS and EndoS2. Our results provide a rational basis from which to engineer novel enzymes with antibody and glycan selectivity for clinical and biotechnological applications.PMID:36973249 | DOI:10.1038/s41467-023-37215-3

J Am Soc Mass Spectrom. 2023 Mar 27. doi: 10.1021/jasms.2c00294. Online ahead of print.ABSTRACTHigh-resolution mass spectrometry (HRMS)-based untargeted metabolomics strategies have emerged as an effective tool for discovering biomarkers of Alzheimer's disease (AD). There are various HRMS-based untargeted metabolomics strategies for biomarker discovery, including the data-dependent acquisition (DDA) method, the combination of full scan and target MS/MS, and the all ion fragmentation (AIF) method. Hair has emerged as a potential biospecimen for biomarker discovery in clinical research since it might reflect the circulating metabolic profiles over several months, while the analytical performances of the different data acquisition methods for hair biomarker discovery have been rarely investigated. Here, the analytical performances of three data acquisition methods in HRMS-based untargeted metabolomics for hair biomarker discovery were evaluated. The human hair samples from AD patients (N = 23) and cognitively normal individuals (N = 23) were used as an example. The most significant number of discriminatory features was acquired using the full scan (407), which is approximately 10-fold higher than that using the DDA strategy (41) and 11% higher than that using the AIF strategy (366). Only 66% of discriminatory chemicals discovered in the DDA strategy were discriminatory features in the full scan dataset. Moreover, compared to the deconvoluted MS/MS spectra with coeluted and background ions from the AIF method, the MS/MS spectrum obtained from the targeted MS/MS approach is cleaner and purer. Therefore, an untargeted metabolomics strategy combining the full scan with the targeted MS/MS method could obtain most discriminatory features along with a high quality MS/MS spectrum for discovering the AD biomarkers.PMID:36973238 | DOI:10.1021/jasms.2c00294

Phytochemistry. 2023 Mar 25:113653. doi: 10.1016/j.phytochem.2023.113653. Online ahead of print.ABSTRACTChaetomium (Chaetomiaceae), a large fungal genus consisting of at least 400 species, has been acknowledged as a promising resource for the exploration of novel compounds with potential bioactivities. Over the past decades, emerging chemical and biological investigations have suggested the structural diversity and extensive potent bioactivity of the specialized metabolites in the Chaetomium species. To date, over 500 compounds with diverse chemical types have been isolated and identified from this genus, including azaphilones, cytochalasans, pyrones, alkaloids, diketopiperazines, anthraquinones, polyketides, and steroids. Biological research has indicated that these compounds possess a broad range of bioactivities, including antitumor, anti-inflammatory, antimicrobial, antioxidant, enzyme inhibitory, phytotoxic, and plant growth inhibitory activities. This paper summarizes current knowledge referring to the chemical structure, biological activity, and pharmacologic potency of the specialized metabolites in the Chaetomium species from 2013 to 2022, which might provide insights for the exploration and utilization of bioactive compounds in this genus both in the scientific field and pharmaceutical industry.PMID:36972807 | DOI:10.1016/j.phytochem.2023.113653

Am J Clin Nutr. 2023 Mar 25:S0002-9165(23)46300-9. doi: 10.1016/j.ajcnut.2023.03.017. Online ahead of print.ABSTRACTBACKGROUND: Evidence suggests that intake of blueberry (poly)phenols is associated with improvements in vascular function and cognitive performance. Whether these cognitive effects are linked to increases in cerebral and vascular blood flow or changes in the gut microbiota is currently unknown.METHODS: A double-blind, parallel randomized controlled trial was conducted in 61 healthy older individuals aged 65-80 y. Participants received either 26g of freeze-dried wild blueberry (WBB) powder (302 mg anthocyanins) or a matched placebo (0 mg anthocyanins). Endothelial function measured by flow-mediated dilation (FMD), cognitive function, arterial stiffness, blood pressure (BP), cerebral blood flow (CBF), gut microbiome and blood parameters were measured at baseline and 12 weeks following daily consumption. Plasma and urinary (poly)phenol metabolites were analyzed using micro-elution solid phase-extraction coupled with LC-MS.RESULTS: A significant increase in FMD and reduction in 24 h ambulatory systolic BP were found in the WBB group compared to placebo (0.86%; 95% CI 0.56, 1.17, p<0.001; -3.59 mmHg; 95% CI -6.95, -0.23, p=0.037; respectively). Enhanced immediate recall on the auditory verbal learning task, alongside better accuracy on a task-switch task were also found following WBB treatment compared to placebo (p<0.05). Total 24 h urinary (poly)phenol excretion increased significantly in the WBB group compared to placebo. No changes in CBF or gut microbiota composition were found.CONCLUSIONS: Daily intake of WBB powder, equivalent to 178 g fresh weight, improves vascular and cognitive function, and decreases 24h ambulatory systolic BP in healthy older individuals. This suggests that WBB (poly)phenols may reduce future cardiovascular disease (CVD) disease risk in an older population, and may improve episodic memory processes and executive functioning in older adults at risk of cognitive decline. CLINICAL TRIAL REGISTRATION NUMBER IN CLINICALTRIALS.GOV: NCT04084457.PMID:36972800 | DOI:10.1016/j.ajcnut.2023.03.017

Chem Res Toxicol. 2023 Mar 27. doi: 10.1021/acs.chemrestox.2c00316. Online ahead of print.ABSTRACTThe diversity of microbial species in the gut has a strong influence on health and development of the host. Further, there are indications that the variation in expression of gut bacterial metabolic enzymes is less diverse than the taxonomic profile, underlying the importance of microbiome functionality, particularly from a toxicological perspective. To address these relationships, the gut bacterial composition of Wistar rats was altered by a 28 day oral treatment with the antibiotics tobramycin or colistin sulfate. On the basis of 16S marker gene sequencing data, tobramycin was found to cause a strong reduction in the diversity and relative abundance of the microbiome, whereas colistin sulfate had only a marginal impact. Associated plasma and fecal metabolomes were characterized by targeted mass spectrometry-based profiling. The fecal metabolome of tobramycin-treated animals had a high number of significant alterations in metabolite levels compared to controls, particularly in amino acids, lipids, bile acids (BAs), carbohydrates, and energy metabolites. The accumulation of primary BAs and significant reduction of secondary BAs in the feces indicated that the microbial alterations induced by tobramycin inhibit bacterial deconjugation reactions. The plasma metabolome showed less, but still many alterations in the same metabolite groups, including reductions in indole derivatives and hippuric acid, and furthermore, despite marginal effects of colistin sulfate treatment, there were nonetheless systemic alterations also in BAs. Aside from these treatment-based differences, we also uncovered interindividual differences particularly centering on the loss of Verrucomicrobiaceae in the microbiome, but with no apparent associated metabolite alterations. Finally, by comparing the data set from this study with metabolome alterations in the MetaMapTox database, key metabolite alterations were identified as plasma biomarkers indicative of altered gut microbiomes resulting from a wide activity spectrum of antibiotics.PMID:36972423 | DOI:10.1021/acs.chemrestox.2c00316

J Pharm Pharmacol. 2023 Mar 27:rgad025. doi: 10.1093/jpp/rgad025. Online ahead of print.ABSTRACTOBJECTIVES: This study aims to elucidate Oridonin' s inhibitory mechanism to cervical cancer using metabolomics methods and pharmacological assays.METHODS: Network pharmacology and KEGG pathway analysis are used to identify overlapped targets and involved metabolic pathways. UPLC-MS/MS metabolomics analysis is used to determine altered metabolites after Oridonin treatment. Other bioassays are also employed to uncover the changes in critical molecules that are highly related to altered metabolites.KEY FINDINGS: Seventy-five overlapped targets are identified between Oridonin and cervical cancer. Twenty-one metabolites involved in tricarboxylic acid cycle glutathione metabolism, branched-chain amino acid metabolism and so on changes significantly after Oridonin treatment. Oridonin treatment significantly reduces the content of cysteine and inhibit the catalytic activity of glutamine-cysteine ligase subunit, a rate-limiting enzyme for the synthesis of glutathione. As a result, the content of glutathione is also reduced. The antioxidant enzyme glutathione peroxidase 4 which uses glutathione as a cofactor, is inactivated, resulting in a burst release of reactive oxygen species. The ATP content is also significantly reduced in Hela cells after Oridonin treatment.CONCLUSIONS: This study finds that Oridonin treatment induces Hela cell apoptosis possibly via inhibition of the glutathione metabolism.PMID:36972333 | DOI:10.1093/jpp/rgad025