PubMed

Food Chem Toxicol. 2023 Jan 18:113612. doi: 10.1016/j.fct.2023.113612. Online ahead of print.ABSTRACTThe toxicity effects of chiral pesticides on living organisms have attracted an increasing public attention. This study aims to investigate the toxicity effect and mechanism of hexaconazole (HEX) to human breast cancer cell (MCF-7) at enantiomer levels. HEX exposure obviously inhibited cells activities in a dose-dependent manner. Under the conditions of VIP >1 and p < 0.05, a total of 255 and 177 differential metabolites (DMs), 17 and 15 amino acid- and lipid-related metabolic pathways were disturbed after (+)-HEX and (-)-HEX exposure, respectively. HEX exposure may affect cell membrane function, signal transduction, and cell differentiation. We further investigated the mechanism of enantioselective differences by using molecular docking which showed that CYP17A1 was the main enzyme that leading to endocrine disrupting effects with the binding energy of -6.30 and -6.08 kcal/mol compared to CYP19A1 enzyme which were -5.81 and -5.93 kcal/mol for (+)-HEX and (-)-HEX, respectively. The docking results explained the reasons why (+)-HEX achieved higher cytotoxicity and induced more seriously metabolic profiles than its antipode. These findings could provide a new insight to understand the enantioselective cytotoxicity effect and mechanism of HEX and will be conducive to assessing its risk to human health at enantiomer levels.PMID:36681264 | DOI:10.1016/j.fct.2023.113612

Plant Physiol Biochem. 2023 Jan 17;195:351-361. doi: 10.1016/j.plaphy.2023.01.028. Online ahead of print.ABSTRACTRadish is an important taproot crop with medicinal and edible uses that is cultivated worldwide. However, the differences in metabolites and the underlying molecular bases among different radish types remain largely unknown. In the present study, a combined analysis of liquid chromatography-electrospray ionization-tandem mass spectrometry (LC-ESI-MS/MS) and RNA-Seq data was conducted to uncover important differentially accumulated metabolites (DAMs) among radish accessions with green, white and red taproot flesh colours. A total of 657 metabolites were identified and 138 DAMs were commonly present in red vs. green and red vs. white accessions. Red accessions were rich in phenolic compounds, while green and white accessions had more amino acids. Additionally, 41 metabolites and 98 genes encoding 37 enzymes were enriched in the shikimate and phenolic biosynthesis pathways. CHS is the rate-limiting enzyme determining flavonoid differences among accessions. A total of 119 candidate genes might contribute to red accession-specific accumulated metabolites. Specifically, one gene cluster consisting of 16 genes, including one RsMYB1, RsMYBL2, RsTT8, RsDFR, RsANS, Rs4CL3, RsSCPL10, Rs3AT1 and RsSAP2 gene, two RsTT19 and RsWRKY44 genes and three RsUGT genes, might be involved in anthocyanin accumulation in red radish fleshy taproots. More importantly, an InDel marker was developed based on an RsMYB1 promoter mutation, and the accuracy reached 95.9% when it was used to select red-fleshed radishes. This study provides comprehensive insights into the metabolite differences and underlying molecular mechanisms in fleshy taproots among different radish genotypes and will be beneficial for the genetic improvement of radish nutritional quality.PMID:36681065 | DOI:10.1016/j.plaphy.2023.01.028

J Chromatogr A. 2023 Jan 11;1690:463779. doi: 10.1016/j.chroma.2023.463779. Online ahead of print.ABSTRACTUntargeted metabolomic studies require an extensive set of analyte (metabolic) information to be obtained from each analyzed sample. Thus, highly selective, and efficient analytical methodologies together with reversed-phase (RP) or hydrophilic interaction liquid chromatography (HILIC) are usually applied in these approaches. Here, we present a performance comparison of five different chromatographic columns (C18, C8, RP Amide, zicHILIC, OH5 HILIC phases) to evaluate their sufficiency of analysis for a large analyte library, consisting of 817 authentic standards. By taking into account experimental chromatographic parameters (i.e. retention time, peak tailing and asymmetry, FWHM, signal-to-noise ratio and peak area and intensity), the proposed column scoring approach provides a simple criterion that may assist analysis in the select of a stationary phase for those metabolites of interest. RPLC methods offered better results regarding metabolic library coverage, while the zicHILIC stationary phase delivered a bigger number of properly eluted compounds. This study demonstrates the importance of choosing the most suitable configuration for the analysis of different metabolic classes.PMID:36681007 | DOI:10.1016/j.chroma.2023.463779

Planta. 2023 Jan 21;257(2):41. doi: 10.1007/s00425-022-04065-0.ABSTRACTSevere N stress allows an accumulation of C-based compounds but impedes that of N-based compounds required to lower the susceptibility of tomato stem to Botrytis cinerea. Botrytis cinerea, a necrotrophic filamentous fungus, forms potentially lethal lesions on the stems of infected plants. Contrasted levels of susceptibility to B. cinerea were obtained in a tomato cultivar grown on a range of nitrate concentration: low N supply resulted in high susceptibility while high N supply conferred a strong resistance. Metabolic deviations and physiological traits resulting from both infection and nitrogen limitation were investigated in the symptomless stem tissue surrounding the necrotic lesion. Prior to infection, nitrogen-deficient plants showed reduced levels of nitrogen-based compounds such as amino acids, proteins, and glutathione and elevated levels of carbon-based and defence compounds such as α-tomatine and chlorogenic acid. After B. cinerea inoculation, all plants displayed a few common responses, mainly alanine accumulation and galactinol depletion. The metabolome of resistant plants grown under high N supply showed no significant change after inoculation. On the contrary, the metabolome of susceptible plants grown under low N supply showed massive metabolic adjustments, including changes in central metabolism around glutamate and respiratory pathways, suggesting active resource mobilization and production of energy and reducing power. Redox and defence metabolisms were also stimulated by the infection in plants grown under low N supply; glutathione and chlorogenic acid accumulated, as well as metabolites with more controversial defensive roles, such as polyamines, GABA, branched-chain amino acids and phytosterols. Taken together, the results showed that nitrogen deficiency, although leading to an increase in secondary metabolites even before the pathogen attack, must have compromised the constitutive levels of defence proteins and delayed or attenuated the induced responses. The involvement of galactinol, alanine, cycloartenol and citramalate in the tomato stem response to B. cinerea is reported here for the first time.PMID:36680621 | DOI:10.1007/s00425-022-04065-0

J Inherit Metab Dis. 2023 Jan 21. doi: 10.1002/jimd.12591. Online ahead of print.ABSTRACTImproved second-tier assays are needed to reduce the number of false positives in newborn screening (NBS) for inherited metabolic disorders including those on the Recommended Uniform Screening Panel (RUSP). We developed an expanded metabolite panel for second-tier testing of dried blood spot (DBS) samples from screen-positive cases reported by the California NBS program, consisting of true- and false-positives from four disorders: glutaric acidemia type 1 (GA1), methylmalonic acidemia (MMA), ornithine transcarbamylase deficiency (OTCD), and very long-chain acyl-CoA dehydrogenase deficiency (VLCADD). This panel was assembled from known disease markers and new features discovered by untargeted metabolomics and applied to second-tier analysis of single DBS punches using liquid chromatography-tandem mass spectrometry (LC-MS/MS) in a 3-min run. Additionally, we trained a Random Forest (RF) machine learning classifier to improve separation of true- and false positive cases. Targeted metabolomic analysis of 121 analytes from DBS extracts in combination with RF classification at a sensitivity of 100% reduced false positives for GA1 by 83%, MMA by 84%, OTCD by 100%, and VLCADD by 51%. This performance was driven by a combination of known disease markers (3-hydroxyglutaric acid, methylmalonic acid, citrulline, C14:1), other amino acids and acylcarnitines, and novel metabolites identified to be isobaric to several long-chain acylcarnitine and hydroxy-acylcarnitine species. These findings establish the effectiveness of this second-tier test to improve screening for these four conditions and demonstrate the utility of supervised machine learning in reducing false-positives for conditions lacking clearly discriminating markers, with future studies aimed at optimizing and expanding the panel to additional disease targets. This article is protected by copyright. All rights reserved.PMID:36680545 | DOI:10.1002/jimd.12591

Viruses. 2023 Jan 14;15(1):242. doi: 10.3390/v15010242.ABSTRACTInfluenza represents a major and ongoing public health hazard. Current collaborative efforts are aimed toward creating a universal flu vaccine with the goals of both improving responses to vaccination and increasing the breadth of protection against multiple strains and clades from a single vaccine. As an intermediate step toward these goals, the current work is focused on evaluating the systemic host response to vaccination in both normal and high-risk populations, such as the obese and geriatric populations, which have been linked to poor responses to vaccination. We therefore employed a metabolomics approach using a time-course (n = 5 time points) of the response to human vaccination against influenza from the time before vaccination (pre) to 90 days following vaccination. We analyzed the urinary profiles of a cohort of subjects (n = 179) designed to evenly sample across age, sex, BMI, and other demographic factors, stratifying their responses to vaccination as "High", "Low", or "None" based on the seroconversion measured by hemagglutination inhibition assay (HAI) from plasma samples at day 28 post-vaccination. Overall, we putatively identified 15,903 distinct, named, small-molecule structures (4473 at 10% FDR) among the 895 samples analyzed, with the aim of identifying metabolite correlates of the vaccine response, as well as prognostic and diagnostic markers from the periods before and after vaccination, respectively. Notably, we found that the metabolic profiles could unbiasedly separate the high-risk High-responders from the high-risk None-responders (obese/geriatric) within 3 days post-vaccination. The purine metabolites Guanine and Hypoxanthine were negatively associated with high seroconversion (p = 0.0032, p &lt; 0.0001, respectively), while Acetyl-Leucine and 5-Aminovaleric acid were positively associated. Further changes in Cystine, Glutamic acid, Kynurenine and other metabolites implicated early oxidative stress (3 days) after vaccination as a hallmark of the High-responders. Ongoing efforts are aimed toward validating these putative markers using a ferret model of influenza infection, as well as an independent cohort of human seasonal vaccination and human challenge studies with live virus.PMID:36680282 | DOI:10.3390/v15010242

Viruses. 2022 Dec 30;15(1):121. doi: 10.3390/v15010121.ABSTRACTMixed virus infections threaten crop production because interactions between the host and the pathogen mix may lead to viral synergism. While individual infections by potato virus A (PVA), a potyvirus, and potato virus X (PVX), a potexvirus, can be mild, co-infection leads to synergistic enhancement of PVX and severe symptoms. We combined image-based phenotyping with metabolite analysis of single and mixed PVA and PVX infections and compared their effects on growth, photosynthesis, and metabolites in Nicotiana benthamiana. Viral synergism was evident in symptom severity and impaired growth in the plants. Indicative of stress, the co-infection increased leaf temperature and decreased photosynthetic parameters. In contrast, singly infected plants sustained photosynthetic activity. The host's metabolic response differed significantly between single and mixed infections. Over 200 metabolites were differentially regulated in the mixed infection: especially defense-related metabolites and aromatic and branched-chain amino acids increased compared to the control. Changes in the levels of methionine cycle intermediates and a low S-adenosylmethionine/S-adenosylhomocysteine ratio suggested a decline in the methylation potential in co-infected plants. The decreased ratio between reduced glutathione, an important scavenger of reactive oxygen species, and its oxidized form, indicated that severe oxidative stress developed during co-infection. Based on the results, infection-associated oxidative stress is successfully controlled in the single infections but not in the synergistic infection, where activated defense pathways are not sufficient to counter the impact of the infections on plant growth.PMID:36680161 | DOI:10.3390/v15010121

Plants (Basel). 2023 Jan 15;12(2):408. doi: 10.3390/plants12020408.ABSTRACTSystems biology has been increasingly applied with multiple omics for a holistic comprehension of complex biological systems beyond the reductionist approach that focuses on individual molecules. Different high-throughput omics approaches, including genomics, transcriptomics, metagenomics, proteomics, and metabolomics have been implemented to study the molecular mechanisms of botanical carnivory. This covers almost all orders of carnivorous plants, namely Caryophyllales, Ericales, Lamiales, and Oxalidales, except Poales. Studies using single-omics or integrated multi-omics elucidate the compositional changes in nucleic acids, proteins, and metabolites. The omics studies on carnivorous plants have led to insights into the carnivory origin and evolution, such as prey capture and digestion as well as the physiological adaptations of trap organ formation. Our understandings of botanical carnivory are further enhanced by the discoveries of digestive enzymes and transporter proteins that aid in efficient nutrient sequestration alongside dynamic molecular responses to prey. Metagenomics studies revealed the mutualistic relationships between microbes and carnivorous plants. Lastly, in silico analysis accelerated the functional characterization of new molecules from carnivorous plants. These studies have provided invaluable molecular data for systems understanding of carnivorous plants. More studies are needed to cover the diverse species with convergent evolution of botanical carnivory.PMID:36679121 | DOI:10.3390/plants12020408

Plants (Basel). 2023 Jan 15;12(2):404. doi: 10.3390/plants12020404.ABSTRACTThe Plasmopara viticola pathogen causes one of the most severe grapevine diseases, namely downy mildew. The response to P. viticola involves both visible symptoms and intricate metabolomic alterations, particularly in relation to volatile organic compounds, and depends on the degree of resistance of a particular variety. There are numerous native grapevine varieties in Croatia, and they vary in susceptibility to this oomycete. As previously reported, in vitro leaf disc bioassay and polyphenolic compound analysis are complementary methods that can be used to separate native varieties into various resistance classes. This research used the Solid Phase Microextraction-Arrow Gas Chromatography-Mass Spectrometry method to identify the early alterations in the VOCs in the leaves after P. viticola inoculation. Based on the absolute peak area of sesquiterpenes, some discrepancies between the sampling terms were noticed. The presence of certain chemical compounds such as humulene, ylangene, and α-farnesene helped distinguish the non-inoculated and inoculated samples. Although specific VOC responses to P. viticola infection of native varieties from various resistance classes could not be identified, the response of less susceptible native varieties and resistant controls was associated with an increase in the absolute peak area of several compounds, including geranylacetone, ß-ocimene, and (E)-2-hexen-1-ol.PMID:36679116 | DOI:10.3390/plants12020404

Plants (Basel). 2023 Jan 10;12(2):325. doi: 10.3390/plants12020325.ABSTRACTBrassica napus L. is a vital plant oil resource worldwide. The fatty acid biosynthesis and oil accumulation in its seeds are controlled by several genetic and environmental factors, including daytime and nighttime temperatures. We analyzed changes in oleic and erucic acid content in two double haploid (DH) lines, DH0729, a weakly temperature-sensitive line, and DH0815, a strongly temperature-sensitive line, derived from B. napus plants grown at different altitudes (1600, 1800, 2000, 2200, and 2400 m a.s.l., 28.85° N, 112.35° E) and nighttime temperatures (20/18, 20/16, 20/13 and 20/10 °C, daytime/nighttime temperature). Based on medium- and long-chain fatty acid metabolites, the total oleic acid content 35 and 43 days after flowering was significantly lower in low nighttime temperature (LNT, 20/13 °C) plants than in high nighttime temperature (HNT, 20/18 °C) plants (HNT: 58-62%; LNT: 49-54%; an average decrease of 9%), and the total erucic acid content was significantly lower in HNT than in LNT plants (HNT: 1-2%; LNT: 8-13%; an average increase of 10%). An RNA-seq analysis showed that the expression levels of SAD (LOC106366808), ECR (LOC106396280), KCS (LOC106419344), KAR (LOC106367337), HB1(LOC106430193), and DOF5 (LOC111211868) in STSL seeds increased under LNT conditions. In STSL seeds, a base mutation in the cis-acting element involved in low-temperature responsiveness (LTR), the HB1 and KCS promoter caused loss of sensitivity to low temperatures, whereas that of the KCS promoter caused increased sensitivity to low temperatures.PMID:36679038 | DOI:10.3390/plants12020325

Plants (Basel). 2023 Jan 9;12(2):308. doi: 10.3390/plants12020308.ABSTRACTPrunus mume is a traditional Chinese plant with high ornamental and application values due to its very early blooming and unique fragrance. Long-term breeding and cultivation have resulted in a variety of P. mume blossoms and have made their exploitation more possible. Existing studies on the volatile metabolome and aroma of P. mume blossoms are limited. In this study, six extensively planted cultivars of P. mume blossoms, including Gulihong (GLH), Yudie (YD), LvE (LE), Dongfang Zhusha (DFZS), Jiangmei (JM), and Gongfen (GF), were investigated for their differences in terms of volatile metabolome, as well as their aroma characteristics based on the strategies and methods of metabolomics. The volatile metabolites were analyzed using HS-SPME-GC-MS technique. A total of eighty-nine compounds were detected and sixty-five of them were tentatively identified, including thirty-seven phenylpropanoids/benzenes, seventeen fatty acid derivatives, ten terpenoids, and one other compound. YD contains the most volatile metabolites in terms of number and amounts, which impart more abundant aromas to this cultivar. Fifteen differential compounds were screened through the untargeted metabolic analysis of twenty-nine samples by principal component analysis (PCA) and partial least squares-discriminant analysis (PLS-DA), while nine compounds were screened based on the odor activity value (OAV) analysis of the sixty-five identified compounds. GLH and GF, JM and LE were found to be more similar to each other based on chemometrics analysis of both volatile contents and OAVs, while YD and DFZS were markedly different from other cultivars. Six main metabolites, including benzaldehyde, methyl benzoate, benzyl acetate, eugenol, (E)-cinnamic alcohol, and 4-allylphenol, together with 2-nonenal, 3,4-dimethoxytoluene, and trans-β-Ionone were screened as differential compounds, owing to their higher contents and/or lower olfactory threshold, which endow an almond, cherry, phenolic, wintergreen, cananga odorata, floral, jasmine, hyacinth, cinnamon, clove, woody, medicinal, and violet fragrance to each variety, and greatly contribute to the aroma differences of six cultivars of P. mume blossom.PMID:36679020 | DOI:10.3390/plants12020308

Plants (Basel). 2023 Jan 6;12(2):269. doi: 10.3390/plants12020269.ABSTRACTPlants undergo metabolic perturbations under various abiotic stress conditions; due to their sessile nature, the metabolic network of plants requires continuous reconfigurations in response to environmental stimuli to maintain homeostasis and combat stress. The comprehensive analysis of these metabolic features will thus give an overview of plant metabolic responses and strategies applied to mitigate the deleterious effects of stress conditions at a biochemical level. In recent years, the adoption of metabolomics studies has gained significant attention due to the growing technological advances in analytical biochemistry (plant metabolomics). The complexity of the plant biochemical landscape requires sophisticated, advanced analytical methods. As such, technological advancements in the field of metabolomics have been realized, aided much by the development and refinement of separatory techniques, including liquid and gas chromatography (LC and GC), often hyphenated to state-of-the-art detection instruments such as mass spectrometry (MS) or nuclear resonance magnetic (NMR) spectroscopy. Significant advances and developments in these techniques are briefly highlighted in this review. The enormous progress made thus far also comes with the dawn of the Internet of Things (IoT) and technology housed in machine learning (ML)-based computational tools for data acquisition, mining, and analysis in the 4IR era allowing for broader metabolic coverage and biological interpretation of the cellular status of plants under varying environmental conditions. Thus, scientists can paint a holistic and comprehensive roadmap and predictive models for metabolite-guided crop improvement. The current review outlines the application of metabolomics and related technological advances in elucidating plant responses to abiotic stress, mainly focusing on heavy metal toxicity and subsequent osmotic stress tolerance.PMID:36678982 | DOI:10.3390/plants12020269

Plants (Basel). 2023 Jan 6;12(2):262. doi: 10.3390/plants12020262.ABSTRACTChemotaxonomy presents various challenges that need to be overcome in order to obtain valid and reliable results. Individual genetic and environmental variations can give a false picture and lead to wrong conclusions. Applying a holistic approach, based on multivariate data analysis, these challenges can be overcome. Thus, a metabolomics approach has to be optimized depending on the subject of research. We used 1H NMR-based metabolomics as a potential chemotaxonomic tool on the selected Euphorbia species growing wild in Serbia. Principal components analysis (PCA), soft independent modeling by class analogy (SIMCA) and Orthogonal Projections to Latent Structures Discriminant Analysis (OPLS-DA) were used to analyze obtained NMR data in order to reveal chemotaxonomic biomarkers. The standard protocol for plant metabolomics was optimized aiming to extract more specific metabolites, which are characteristic for the Euphorbia genus. The obtained models were validated, which revealed that variables unique for each species were associated with certain classes of molecules according to literature data. In E. salicifolia, acacetin-7-O-glycoside (not found before in the species) was detected, and the structure of the aglycone part was solved based on 2D NMR data. In the presented paper, we have shown that metabolomics can be successfully used in Euphorbia chemotaxonomy.PMID:36678975 | DOI:10.3390/plants12020262

Pharmaceutics. 2022 Dec 31;15(1):152. doi: 10.3390/pharmaceutics15010152.ABSTRACTInfectious diseases continue to be a leading cause of morbidity and mortality worldwide. The majority of infectious diseases are caused by intracellular pathogenic bacteria (IPB). Historically, conventional vaccination drives have helped control the pathogenesis of intracellular bacteria and the emergence of antimicrobial resistance, saving millions of lives. However, in light of various limitations, many diseases that involve IPB still do not have adequate vaccines. In response to increasing demand for novel vaccine development strategies, a new area of vaccine research emerged following the advent of genomics technology, which changed the paradigm of vaccine development by utilizing the complete genomic data of microorganisms against them. It became possible to identify genes related to disease virulence, genetic patterns linked to disease virulence, as well as the genetic components that supported immunity and favorable vaccine responses. Complete genomic databases, and advancements in transcriptomics, metabolomics, structural genomics, proteomics, immunomics, pan-genomics, synthetic genomics, and population biology have allowed researchers to identify potential vaccine candidates and predict their effects in patients. New vaccines have been created against diseases for which previously there were no vaccines available, and existing vaccines have been improved. This review highlights the key issues and explores the evolution of vaccines. The increasing volume of IPB genomic data, and their application in novel genome-based techniques for vaccine development, were also examined, along with their characteristics, and the opportunities and obstacles involved. Critically, the application of genomics technology has helped researchers rapidly select and evaluate candidate antigens. Novel vaccines capable of addressing the limitations associated with conventional vaccines have been developed and pressing healthcare issues are being addressed.PMID:36678781 | DOI:10.3390/pharmaceutics15010152

Pharmaceuticals (Basel). 2023 Jan 8;16(1):88. doi: 10.3390/ph16010088.ABSTRACTThe Stephania tetrandra-Astragalus membranaceus herbal pair (FH) is a classic herbal pair widely used in the treatment of nephrotic syndrome (NS). The effects of Stephania tetrandra (FJ) and Astragalus membranaceus (HQ) on NS have been reported, but the mechanism of their combination on the improvement of NS are still unclear. The NS model was established by injecting adriamycin into the tail vein. FH intervention reduced the levels of serum triglyceride, total cholesterol, interleukin-6 (IL-6), blood urea nitrogen (BUN), urinary protein, and the gene expression levels of aquaporin 2 (AQP2) and arginine vasopressin (AVP) in NS rats. In addition, FH improved kidney injury in NS rats by inhibiting the expression of interleukin 13 (IL-13), phospho-signal transducers, and activators of transcription 6 (p-STAT6), Bax, cleaved-caspase3, while promoting the expression of Bcl-2. By comprehensive comparison of multiple indexes, the effects of FH on lipid metabolism, glomerular filtration rate, and inflammation were superior to that of FJ and HQ. Metabonomic studies showed that, compared with FJ and HQ, FH intervention significantly regulated tricarboxylic acid (TCA) cycle, cysteine and methionine metabolism, and alanine, aspartic acid and glutamic acid metabolism. Pearson correlation analysis showed that succinic acid and L-aspartic acid were negatively correlated with urinary protein, cystatin C (Cys C) and BUN (p &lt; 0.05). In summary, FH could reduce renal injury and improve NS through inhibiting the IL-13/STAT6 signal pathway, regulating endogenous metabolic pathways, such as TCA cycle, and inhibiting the expression of AQP2 and AVP genes. This study provides a comprehensive strategy to reveal the mechanism of FH on the treatment of NS, and also provides a reasonable way to clarify the compatibility of traditional Chinese medicine.PMID:36678585 | DOI:10.3390/ph16010088

Pharmaceuticals (Basel). 2022 Dec 23;16(1):20. doi: 10.3390/ph16010020.ABSTRACTChagas disease is caused by the protozoan Trypanosoma cruzi (T. cruzi). It remains the major parasitic disease in Latin America and is spreading worldwide, affecting over 10 million people. Hundreds of new compounds with trypanosomicidal action have been identified from different sources such as synthetic or natural molecules, but they have been deficient in several stages of drug development (toxicology, scaling-up, and pharmacokinetics). Previously, we described a series of compounds with simple structures, low cost, and environmentally friendly production with potent trypanosomicidal activity in vitro and in vivo. These molecules are from three different families: thiazolidenehydrazines, diarylideneketones, and steroids. From this collection, we explored their capacity to inhibit the triosephosphate isomerase and cruzipain of T. cruzi. Then, the mechanism of action was explored using NMR metabolomics and computational molecular dynamics. Moreover, the mechanism of death was studied by flow cytometry. Consequently, five compounds, 314, 793, 1018, 1019, and 1260, were pre-clinically studied and their pharmacologic profiles indicated low unspecific toxicity. Interestingly, synergetic effects of diarylideneketones 793 plus 1018 and 793 plus 1019 were evidenced in vitro and in vivo. In vivo, the combination of compounds 793 plus 1018 induced a reduction of more than 90% of the peak of parasitemia in the acute murine model of Chagas disease.PMID:36678516 | DOI:10.3390/ph16010020

Nutrients. 2023 Jan 15;15(2):456. doi: 10.3390/nu15020456.ABSTRACTGiven the increasing prevalence of obesity, the white-to-beige adipocyte conversion has attracted interest as a target for obesity treatment. Gamma-aminobutyric acid (GABA) treatment can reduce obesity, but the underlying mechanism remains unclear. Here, we aimed to investigate the mechanism by which GABA triggers weight loss by improving the beiging of inguinal white adipose tissue (iWAT) and the role of gut microbiota in this process. The results showed that GABA reduced body weight and adipose inflammation and promoted the expression of thermogenic genes in the iWAT. The 16S rRNA sequence analysis of gut microbiota showed that GABA treatment increased the relative abundance of Bacteroidetes, Akkermansia, and Romboutsia and reduced that of Firmicutes and Erysipelatoclostridium in obese mice. Additionally, serum metabolomic analysis revealed that GABA treatment increased 3-hydroxybutyrate and reduced oxidized lipid levels in obese mice. Spearman's correlation analysis showed that Akkermansia and Romboutsia were negatively associated with the levels of oxidized lipids. Fecal microbiota transplantation analysis confirmed that the gut microbiota was involved in the white-to-beige adipocyte reconstruction by GABA. Overall, our findings suggest that GABA treatment may promote iWAT beiging through the gut microbiota in obese mice. GABA may be utilized to protect obese people against metabolic abnormalities brought on by obesity and gut dysbiosis.PMID:36678326 | DOI:10.3390/nu15020456

Nutrients. 2023 Jan 14;15(2):440. doi: 10.3390/nu15020440.ABSTRACTThe concentration of water-soluble vitamins (except folic acid and vitamin B12) is not routinely measured, which may lead to undiagnosed deficiencies among hemodialysis (HD) patients. The aim of the study was to assess the blood concentration of water-soluble vitamins in HD patients in comparison with healthy subjects and to assess the impact of diabetes mellitus (DM) coexistence on the concentration of these vitamins. The two-center study included 142 HD patients and a control group of 31 healthy subjects. Vitamins concentration was determined using high-performance liquid chromatography (HPLC). Vitamin B1, B6, and B12 levels were significantly lower in the HD group than in the control group (p &lt; 0.001). Vitamin B1 and B2 were negatively correlated with blood urea nitrogen (BUN) levels before HD (R = -0.39, R = -0.38; p &lt; 0.05). Vitamin B3, B12, and C were positively correlated with the albumin concentration (R = 0.26, R = 0.27, R = 0.28; p &lt; 0.05). Among diabetic patients, only the concentration of vitamin B1 was lower than among non-diabetic patients. The concentration of water-soluble vitamins may be related to the adequacy of dialysis, the time of laboratory determination since the last dialysis, diet, coexistence of other diseases, use of drugs, and dietary supplements in individual patients.PMID:36678310 | DOI:10.3390/nu15020440

Nutrients. 2023 Jan 11;15(2):367. doi: 10.3390/nu15020367.ABSTRACTShort-chain fatty acids (SCFAs) are important metabolites of the gut microbiota. The aim is to analyze the influence of perinatal factors, which can affect the gut microbiota, on the concentrations of fecal SCFAs over the first two years of life. Gas chromatography was used to analyze SCFA in a total of 456 fecal samples from 86 children. Total SCFA concentrations increased until 12 months and stabilized after that. Antibiotic treatment during pregnancy was associated with an increase in acetic acid, propionic acid and total SCFA in meconium and a decrease in the same SCFAs at 6 months. Butyric acid was increased after Caesarean delivery until 1 month. In formula-fed children, propionic acid (at 1 month) and butyric acid and total SCFA (at 12 months) were increased. Acetic and linear butyric acids and total SCFAs were also increased at 12 months in children born vaginally that were also formula-fed. Higher butyric acid was observed in children of mothers with normal pre-pregnancy weight and adequate weight gain during pregnancy. Butyric acid was also elevated in 6-month-old infants with a higher body weight (≥85th percentile). Acetic acid concentrations were significantly higher in 2-year-old females vs. males. We conclude that perinatal factors are linked to changes in fecal SCFAs and further long-term epidemiological studies are warranted.PMID:36678236 | DOI:10.3390/nu15020367

Nutrients. 2023 Jan 5;15(2):282. doi: 10.3390/nu15020282.ABSTRACTBreastfeeding is the gold standard for early nutrition. Metabolites from the one-carbon metabolism pool are crucial for infant development. The aim of this study is to compare the breast-milk one-carbon metabolic profile to other biofluids where these metabolites are present, including cord and adult blood plasma as well as cerebrospinal fluid. Breast milk (n = 142), cord blood plasma (n = 23), maternal plasma (n = 28), aging adult plasma (n = 91), cerebrospinal fluid (n = 92), and infant milk formula (n = 11) samples were analyzed by LC-MS/MS to quantify choline, betaine, methionine, S-adenosylmethionine, S-adenosylhomocysteine, total homocysteine, and cystathionine. Differences between groups were visualized by principal component analysis and analyzed by Kruskal-Wallis test. Correlation analysis was performed between one-carbon metabolites in human breast milk. Principal component analysis based on these metabolites separated breast milk samples from other biofluids. The S-adenosylmethionine (SAM) concentration was significantly higher in breast milk compared to the other biofluids and was absent in infant milk formulas. Despite many significant correlations between metabolites in one-carbon metabolism, there were no significant correlations between SAM and methionine or total homocysteine. Together, our data indicate a high concentration of SAM in breast milk, which may suggest a strong demand for this metabolite during infant early growth while its absence in infant milk formulas may indicate the inadequacy of this vital metabolic nutrient.PMID:36678154 | DOI:10.3390/nu15020282