PubMed

Plant Biotechnol J. 2023 Jun 30. doi: 10.1111/pbi.14112. Online ahead of print.ABSTRACTLow temperature is the main environmental factor affecting the yield, quality and geographical distribution of crops, which significantly restricts development of the fruit industry. The NAC (NAM, ATAF1/2 and CUC2) transcription factor (TF) family is involved in regulating plant cold tolerance, but the mechanisms underlying these regulatory processes remain unclear. Here, the NAC TF MdNAC104 played a positive role in modulating apple cold tolerance. Under cold stress, MdNAC104-overexpressing transgenic plants exhibited less ion leakage and lower ROS (reactive oxygen species) accumulation, but higher contents of osmoregulatory substances and activities of antioxidant enzymes. Transcriptional regulation analysis showed that MdNAC104 directly bound to the MdCBF1 and MdCBF3 promoters to promote expression. In addition, based on combined transcriptomic and metabolomic analyses, as well as promoter binding and transcriptional regulation analyses, we found that MdNAC104 stimulated the accumulation of anthocyanin under cold conditions by upregulating the expression of anthocyanin synthesis-related genes, including MdCHS-b, MdCHI-a, MdF3H-a and MdANS-b, and increased the activities of the antioxidant enzymes by promoting the expression of the antioxidant enzyme-encoding genes MdFSD2 and MdPRXR1.1. In conclusion, this study revealed the MdNAC104 regulatory mechanism of cold tolerance in apple via CBF-dependent and CBF-independent pathways.PMID:37387580 | DOI:10.1111/pbi.14112

Expert Rev Anti Infect Ther. 2023 Jun 30. doi: 10.1080/14787210.2023.2232112. Online ahead of print.ABSTRACTOBJECTIVES: Evaluation of the antifungal properties of Tamarix nilotica fractions against Candida albicans clinical isolates.METHODS: The in vitro antifungal potential was evaluated by agar well diffusion and broth microdilution methods. The antibiofilm potential was assessed by crystal violet, scanning electron microscopy (SEM), and qRT-PCR. The in vivo antifungal activity was evaluated by determining the burden in the lung tissues of infected mice, histopathological, immunohistochemical studies, and ELISA.RESULTS: Both the dichloromethane (DCM) and ethyl acetate (EtOAc) fractions had minimum inhibitory concentration (MIC) values of 64-256 and 128-1024 μg/mL, respectively. SEM examination showed that the DCM fraction decreased the biofilm formation capacity of the treated isolates. A significant decline in biofilm gene expression was observed in 33.33% of the DCM-treated isolates. A considerable decline in the CFU/g lung count in infected mice was observed, and histopathological examinations revealed that the DCM fraction maintained the lung tissue architecture. Immunohistochemical investigations indicated that the DCM fraction significantly (p < 0.05) decreased the expression of pro-inflammatory and inflammatory cytokines (TNF-α, NF-kB, COX-2, IL-6, and IL-1β) in the immunostained lung sections. The phytochemical profiling of DCM and EtOAc fractions was performed using Liquid chromatography-mass spectrometry (LC-ESI-MS/MS).CONCLUSION: T. nilotica DCM fraction could be a significant source of natural products with antifungal activity against C. albicans infections.PMID:37387417 | DOI:10.1080/14787210.2023.2232112

J Dent Res. 2023 Jun 30:220345231176522. doi: 10.1177/00220345231176522. Online ahead of print.ABSTRACTBone defect (BD) caused by trauma, infection, congenital defects, or neoplasia is a major cause of physical limitation. Distraction osteogenesis (DO) is a highly effective procedure for bone regeneration, while the concrete mechanism remains unknown. In this study, canine DO and BD models of the mandible were established. The results of micro-computed tomography and histological staining revealed that DO led to an increased mineralized volume fraction and robust new bone formation; in contrast, BD demonstrated incomplete bone union. Mesenchymal stem cells (MSCs) from DO and BD calluses were isolated and identified. Compared with BD-MSCs, DO-MSCs were found to have a stronger osteogenic capability. Single-cell RNA sequencing analysis was further performed to comprehensively define cell differences between mandibular DO and BD calluses. Twenty-six clusters of cells representing 6 major cell populations were identified, including paired related homeobox 1-expressing MSCs (PRRX1+MSCs), endothelial cells (ECs), T cells, B cells, neutrophils, and macrophages. Interestingly, 2 subpopulations in PRRX1+MSCs in the DO group were found to express the marker of neural crest cells (NCCs) and were associated with the process of epithelial-mesenchymal transition. The immunofluorescence assay was performed to further corroborate these results in vivo and in vitro, experimentally validating that continuous distraction maintained the PRRX1+MSCs in an embryonic-like state. Finally, we used CRISPR/Cas9 to knock out (KO) PRRX1 in the context of DO, which significantly blunted the capability of jawbone regeneration, resulting in a diminished NCC-like program and reduction of new bone volume. In addition, the ability of osteogenesis, cell migration, and proliferation in cultured PRRX1KO MSCs was inhibited. Taken together, this study provides a novel, comprehensive atlas of the cell fates in the context of DO regeneration, and PRRX1+MSCs act essential roles.PMID:37387366 | DOI:10.1177/00220345231176522

Stud Health Technol Inform. 2023 Jun 29;305:432-435. doi: 10.3233/SHTI230524.ABSTRACTThe aim of metabolomics research is to identify the metabolites that play a role in various biological traits and diseases. This scoping review provides an overview of the current state of metabolomics studies that focus on the Qatari population. Our findings indicate that few studies have been conducted on this population, with a focus on diabetes, dyslipidemia, and cardiovascular disease. Blood samples were the primary source of metabolite identification, and several potential biomarkers for these diseases were proposed. To the best of our knowledge, this is the first scoping review that presents an overview of metabolomics studies in Qatar.PMID:37387058 | DOI:10.3233/SHTI230524

J Agric Food Chem. 2023 Jun 29. doi: 10.1021/acs.jafc.3c02562. Online ahead of print.ABSTRACTThe interaction of pectin and gut microbiota plays an important role in maintaining animal and human health, but this interaction is not fully understood. Here, the impact of pectin supplementation on substrate dynamics and gut microbiota (in the terminal ileum and feces) was integrally investigated in a fistula pig model. Our results showed that a pectin-supplemented diet (PEC) decreased the concentrations of starch, cellulose, and butyrate in feces but not in the terminal ileum. Metagenomic sequencing revealed that PEC had a low impact on the ileal microbiota but significantly increased plant polysaccharide-degrading genera (e.g., Bacteroides, Alistipes, and Treponema) in feces. Additionally, CAZyme profiling indicated that PEC reduced GH68 and GH8 for oligosaccharide degradation in the ileal microbiome, while it enriched GH5, GH57, and GH106 for degradation of carbohydrate substrates in feces. Metabolomic analysis confirmed that PEC increased metabolites involved in carbohydrate metabolism including glucuronate and aconitate. Collectively, pectin could promote complex carbohydrate substrate degradation in the hindgut via modulating the gut microbiota.PMID:37386754 | DOI:10.1021/acs.jafc.3c02562

Eur Respir J. 2023 Jun 29:2201374. doi: 10.1183/13993003.01374-2022. Online ahead of print.ABSTRACTBACKGROUND: Virus infections drive COPD exacerbations and progression. Anti-viral immunity centers on the activation of virus-specific CD8+ T cells by viral epitopes presented on MHC class I molecules of infected cells. These epitopes are generated by the immunoproteasome, a specialized intracellular protein degradation machine, which is induced by anti-viral cytokines in infected cells.METHODS: We here analysed the effects of CS on cytokine and virus-mediated induction of the immunoproteasome in vitro, ex vivo and in vivo using RNA and Western blot analyses. CD8+ T cell activation was determined in co-culture assays with CS-exposed Influenza A virus (IAV)-infected cells. Mass-spectrometry-based analysis of MHC class I-bound peptides uncovered the effects of CS on inflammatory antigen presentation in lung cells. IAV-specific CD8+ T cell numbers were determined in peripheral patients' blood using tetramer-technology.RESULTS: CS impaired the induction of the immunoproteasome by cytokine signaling and viral infection in lung cells in vitro, ex vivo and in vivo. CS also altered the peptide repertoire of antigens presented on MHC class I under inflammatory conditions. Importantly, MHC class I-mediated activation of IAV-specific CD8+ T cells was dampened by CS. COPD patients exhibited reduced numbers of circulating IAV-specific CD8+ T cells compared to healthy controls and asthmatics.CONCLUSION: Our data indicate that cigarette smoke interferes with MHC class I antigen generation and presentation and thereby contributes to impaired activation of CD8+ T cells upon virus infection. This adds important mechanistic insight on how cigarette smoke mediates increased susceptibility of smokers and COPD patients to viral infections.PMID:37385655 | DOI:10.1183/13993003.01374-2022

Int J Antimicrob Agents. 2023 Jun 27:106907. doi: 10.1016/j.ijantimicag.2023.106907. Online ahead of print.ABSTRACTSalmonella enterica (SE) is a food-borne pathogen that poses a severe threat to both poultry production and human health. Antibiotics are critical for the initial treatment of bacterial infections. However, the overuse and misuse of antibiotics can result in the rapid evolution of antibiotic-resistant bacteria, while the discovery and development of new antibiotics are declining. Therefore, understanding antibiotic resistance mechanisms and developing novel control measures are highly valued. In the present study, GC-MS-based metabolomics analysis was performed to determine the metabolic profile of the gentamicin sensitive (SE-S) and resistant Salmonella enterica (SE-R). Fructose was identified as a crucial biomarker. Further analysis demonstrated a global depressed central carbon metabolism and energy metabolism in SE-R. The decrease in the pyruvate cycle reduces the production of NADH and ATP, ultimately causing a decrease in membrane potential, which contributes to gentamicin resistance. Exogenous fructose potentiated gentamicin's effectiveness in killing SE-R by promoting the pyruvate cycle, NADH, ATP and membrane potential, thereby increasing gentamicin intake. Additionally, fructose plus gentamicin improved the survival rate of chicken infected with gentamicin-resistant Salmonella in vivo. Given that metabolite structures are conserved across species, fructose identified from bacterial could be used as a biomarker for breeding for disease-resistance phenotypes in chicken. Therefore, we propose a novel strategy for fighting against antibiotic-resistant Salmonella enterica by exploring molecules suppressed by antibiotics and provide a new approach to find targets from the pathogen's perspective for chicken disease resistance breeding.PMID:37385564 | DOI:10.1016/j.ijantimicag.2023.106907

Exp Eye Res. 2023 Jun 27:109562. doi: 10.1016/j.exer.2023.109562. Online ahead of print.ABSTRACTCells communicate with each other using vesicles of varying sizes, including a specific repertoire known as exosomes. We isolated aqueous humor (AH)-derived vesicles using two different methods: ultracentrifugation and an exosome isolation kit. We confirmed a unique vesicle size distribution in the AH derived from control and primary open-angle glaucoma (POAG) patients using various techniques, including Nanotracker, dynamic light scattering, atomic force imaging, and electron microscopy. Bonafide vesicle and/or exosome markers were present by dot blot in both control and POAG AH-derived vesicles. Marker levels differed between POAG and control samples, while non-vesicle negative markers were absent in both. Quantitative labeled (iTRAQ) proteomics showed a reduced presence of a specific protein, STT3B, in POAG compared to controls, which was further confirmed using dot blot, Western blot, and ELISA assays. Along the lines of previous findings with AH profiles, we found vast differences in the total phospholipid composition of AH vesicles in POAG compared to controls. Electron microscopy further showed that the addition of mixed phospholipids alters the average size of vesicles in POAG. We found that the cumulative particle size of type I collagen decreased in the presence of Cathepsin D, which normal AH vesicles were able to protect against, but POAG AH vesicles did not. AH alone had no effect on collagen particles. We observed a protective effect on collagen particles with an increase in artificial vesicle sizes, consistent with the protective effects observed with larger control AH vesicles but not with the smaller-sized POAG AH vesicles. Our experiments suggest that AH vesicles in the control group provide greater protection for collagen beams compared to POAG, and their increased vesicle sizes are likely contributing factors to this protection.PMID:37385533 | DOI:10.1016/j.exer.2023.109562

Chemosphere. 2023 Jun 27:139302. doi: 10.1016/j.chemosphere.2023.139302. Online ahead of print.ABSTRACTSorption regulates the dispersion of pesticides from cropped areas to surrounding water bodies as well as their persistence. Assessing the risk of water contamination and evaluating the efficiency of mitigation measures, requires fine-resolution sorption data and a good knowledge of its drivers. This study aimed to assess the potential of a new approach combining chemometric and soil metabolomics to estimate the adsorption and desorption coefficients of a range of pesticides. It also aims to identify and characterise key components of soil organic matter (SOM) driving the sorption of these pesticides. We constituted a dataset of 43 soils from Tunisia, France and Guadeloupe (West Indies), covering extensive ranges of texture, organic carbon and pH. We performed untargeted soil metabolomics by liquid chromatography coupled with high-resolution mass spectrometry (UPLC-HRMS). We measured the adsorption and desorption coefficients of three pesticides namely glyphosate, 2,4-D and difenoconazole for these soils. We developed Partial Least Square Regression (PLSR) models for the prediction of the sorption coefficients from the RT-m/z matrix and conducted further ANOVA analyses to identify, annotate and characterise the most significant constituents of SOM in the PLSR models. The curated metabolomics matrix yielded 1213 metabolic markers. The prediction performance of the PLSR models was generally high for the adsorption coefficients Kdads (0.3 < R2 < 0.8) and for the desorption coefficients Kfdes (0.6 < R2 < 0.8) but low for ndes (0.03 < R2 < 0.3). The most significant features in the predictive models were annotated with a confidence level of 2 or 3. The molecular descriptors of these putative compounds suggest that the pool of SOM compounds driving glyphosate sorption is reduced compared to 2,4-D and difenoconazole, and these compounds are generally more polar. This approach can provide estimates of the adsorption and desorption coefficients of pesticides, including polar pesticide, for contrasted pedoclimates.PMID:37385484 | DOI:10.1016/j.chemosphere.2023.139302

Phytochemistry. 2023 Jun 27:113777. doi: 10.1016/j.phytochem.2023.113777. Online ahead of print.ABSTRACTThe undifferentiated cambial meristematic cell (CMC) has been recognized as a value-added production platform for plant natural products in comparison to the dedifferentiated plant cell line (DDC). In a time-based approach at 0, 24, 48, and 72 h, the present study aimed at investigating the phytochemical metabolome of methyl jasmonate (MeJA)-elicited CMC cultures derived from sweet basil (Ocimum basilicum L.), including primary and secondary metabolites analyzed using GC/TOF-MS post-silylation and RP-UPLC-C18-FT-MS/MS, respectively, as well as the analysis of aroma composition using headspace SPME-GC-MS. The results revealed a stress response in primary metabolism manifested by an increase in amino and organic acids reaching their maximum levels after 48 (1.3-fold) and 72 (1.7-fold) h, respectively. In addition, phenolic acids (e.g., sagerinic acid, rosmarinic acid, and 3-O-methylrosmarinic acid) followed by flavonoid aglycones (e.g., salvigenin and 5,6,4'-trihydroxy-7,3'-dimethoxyflavone) were the most abundant with prominent increases at 48 (1.2-fold) and 72 (2.1-fold) h, respectively. The aroma was intensified by the elicitation along the time, especially after 48 and 72 h. Furthermore, multivariate data analyses, including principal component analysis (PCA) and orthogonal partial least squares discriminant analysis (OPLS-DA) confirmed elicitation effect, especially post 48 and 72 h. The study further assessed the effect of MeJA elicitation on the antioxidant and polyphenolic content. The cultures at 48 h demonstrated a significant (p < 0.05) antioxidant activity concurrently with correlation with total polyphenolic content using Pearson's correlation. Our study provides new insights to the elicitation impact on primary and secondary metabolism, in addition to aroma profile, to orchestrate the stress response and in relation to antioxidant effect.PMID:37385363 | DOI:10.1016/j.phytochem.2023.113777

Food Chem Toxicol. 2023 Jun 27:113908. doi: 10.1016/j.fct.2023.113908. Online ahead of print.ABSTRACTTriclocarban (TCC) is an antibacterial component widely used in personal care products with potential toxicity possessing public health issues. Unfortunately, enterotoxicity mechanisms of TCC exposure remain largely unknown. Using a combination of 16S rRNA gene sequencing, metabolomics, histopathological and biological examinations, this study systematically explored the deteriorating effects of TCC exposure on a dextran sulfate sodium (DSS)-induced colitis mouse model. We found that TCC exposure at different doses significantly aggravated colitis phenotypes including shortened colon length and altered colonic histopathology. Mechanically, TCC exposure further disrupted intestinal barrier function, manifested by significant downregulation of the number of goblet cells, mucus layer thickness and expression of junction proteins (MUC-2, ZO-1, E-cadherin and Occludin). The gut microbiota composition and its metabolites such as short-chain fatty acids (SCFAs) and tryptophan metabolites were also markedly altered in DSS-induced colitis mice. Consequently, TCC exposure markedly exacerbated colonic inflammatory status of DSS-treated mice by activating NF-κB pathway. These findings provided new evidence that TCC could be an environmental hazards for development of IBD or even colon cancer.PMID:37385329 | DOI:10.1016/j.fct.2023.113908

Comput Methods Programs Biomed. 2023 Jun 17;240:107681. doi: 10.1016/j.cmpb.2023.107681. Online ahead of print.ABSTRACTBACKGROUND AND OBJECTIVE: Mechanistic-based Model simulations (MM) are an effective approach commonly employed, for research and learning purposes, to better investigate and understand the inherent behavior of biological systems. Recent advancements in modern technologies and the large availability of omics data allowed the application of Machine Learning (ML) techniques to different research fields, including systems biology. However, the availability of information regarding the analyzed biological context, sufficient experimental data, as well as the degree of computational complexity, represent some of the issues that both MMs and ML techniques could present individually. For this reason, recently, several studies suggest overcoming or significantly reducing these drawbacks by combining the above-mentioned two methods. In the wake of the growing interest in this hybrid analysis approach, with the present review, we want to systematically investigate the studies available in the scientific literature in which both MMs and ML have been combined to explain biological processes at genomics, proteomics, and metabolomics levels, or the behavior of entire cellular populations.METHODS: Elsevier Scopus®, Clarivate Web of Science™ and National Library of Medicine PubMed® databases were enquired using the queries reported in Table 1, resulting in 350 scientific articles.RESULTS: Only 14 of the 350 documents returned by the comprehensive search conducted on the three major online databases met our search criteria, i.e. present a hybrid approach consisting of the synergistic combination of MMs and ML to treat a particular aspect of systems biology.CONCLUSIONS: Despite the recent interest in this methodology, from a careful analysis of the selected papers, it emerged how examples of integration between MMs and ML are already present in systems biology, highlighting the great potential of this hybrid approach to both at micro and macro biological scales.PMID:37385142 | DOI:10.1016/j.cmpb.2023.107681

J Pharm Biomed Anal. 2023 Jun 24;234:115546. doi: 10.1016/j.jpba.2023.115546. Online ahead of print.ABSTRACTAn ultrahigh-performance liquid chromatography coupled with ion mobility quadrupole time-of-flight mass spectrometry method was developed for the separation and identification of phenols, organic acids, flavonoids and curcumin in different species of ginger. The parameters affecting the separation and response of liquid chromatography, including the stationary phase and mobile phase, were systematically investigated and optimized. To further identify the differential metabolites in the six types of samples, a chemometric approach was introduced. Principal component analysis, cluster analysis and partial least squares discriminant analysis were used to identify the major components in the samples and to compare the compositional differences between the various samples. In addition, antioxidant experiments were designed to investigate the differences in antioxidant activity among the six ginger samples. The method showed good linearity (R2 ≥0.9903), satisfactory precision (RSD% ≤ 4.59 %), low LOD (0.35-25.86 ng/mL) and acceptable recovery (78-109 %) and reproducibility (RSD% ≤ 4.20 %). Therefore, the method has great potential for application in the compositional analysis and quality control of ginger.PMID:37385094 | DOI:10.1016/j.jpba.2023.115546

Food Chem. 2023 Jun 25;427:136729. doi: 10.1016/j.foodchem.2023.136729. Online ahead of print.ABSTRACTThe potential mechanisms about the health risks of endogenous 3-MCPD remain elusive. Here, we researched the influences of 3-MCPD on the metabolic landscape of digested goat infant formulas via integrative UHPLC-Q-Orbitrap HRMS-MS/MS-based peptidomics and metabolomics (%RSDs ≤ 7.35 %, LOQ 2.99-58.77 μg kg-1). Digested goat infant formulas under 3-MCPD-interference caused metabolic perturbation by down-regulating levels of peptides VGINYWLAHK (5.98-0.72 mg kg-1) and HLMCLSWQ (3.25-0.72 mg kg-1) pertained to health-promoting bioactive components, and accelerated the down-regulation of non-essential amino acids (AAs, l-tyrosine 0.88-0.39 mg kg-1, glutamic acid 8.83-0.88 μg kg-1, and d-aspartic acid 2.93-0.43 μg kg-1), semi-essential AA (l-arginine 13.06-8.12 μg kg-1) and essential AAs (l-phenylalanine 0.49-0.05 mg kg-1) that provide nutritional value. Peptidomics and metabolomics interactions elucidated that 3-MCPD altered the stability of α-lactalbumin and d-aspartate oxidase in a dose-dependent manner, and affected the flavor perception of goat infant formulas, leading to a decline of nutritional value of goat infant formulas.PMID:37385056 | DOI:10.1016/j.foodchem.2023.136729

Diabetol Metab Syndr. 2023 Jun 29;15(1):141. doi: 10.1186/s13098-023-01116-8.ABSTRACTBACKGROUND: Heart failure with preserved ejection fraction (HFpEF) is a common disease with high morbidity and lacks effective treatment. We investigated the protective effects of the long-term application of the sodium-glucose cotransporter 2 inhibitor (SGLT2i) dapagliflozin on diabetes-associated HFpEF in a rat model. Serum proteomics and metabolomics analysis were also conducted in type 2 diabetic patients with HFpEF treated with dapagliflozin.METHODS: Male Zucker diabetic fatty (ZDF) rats were used as a model of diabetic cardiomyopathy. From weeks 16 to 28, animals were given a vehicle or dapagliflozin (1 mg/kg) once daily. Primary blood biochemistry indices, echocardiography, histopathology, and cardiac hemodynamics were determined during the study period. The key markers of myocardial fibrosis, nitro-oxidative stress, inflammation, apoptosis, autophagy, and AMPK/mTOR signaling were examined. Additionally, healthy controls and individuals with type 2 diabetes were enrolled and 16 serum samples from 4 groups were randomly selected. Serum proteome and metabolome changes after dapagliflozin treatment were analyzed in diabetic individuals with HFpEF.RESULTS: Dapagliflozin effectively prevented the development of HFpEF in rats with diabetes by mitigating nitro-oxidative stress, pro-inflammatory cytokines, myocardial hypertrophy, and fibrosis, reducing apoptosis, and restoring autophagy through AMPK activating and mTOR pathway repressing. Proteomics and metabolomics revealed that cholesterol and high-density lipoprotein particle metabolism, nicotinate and nicotinamide metabolism, arginine biosynthesis, and cAMP and peroxisome proliferator-activated receptor (PPAR) signaling are the major disturbed pathways in HFpEF patients treated with dapagliflozin.CONCLUSION: Long-term treatment with dapagliflozin significantly prevented the development of HFpEF in diabetic rats. Dapagliflozin could be a promising therapeutic strategy in managing HFpEF individuals with type 2 diabetes.PMID:37386620 | DOI:10.1186/s13098-023-01116-8

Microbiome. 2023 Jun 30;11(1):145. doi: 10.1186/s40168-023-01589-9.ABSTRACTBACKGROUND: Adolescent depression is becoming one of the major public health concerns, because of its increased prevalence and risk of significant functional impairment and suicidality. Clinical depression commonly emerges in adolescence; therefore, the prevention and intervention of depression at this stage is crucial. Recent evidence supports the importance of the gut microbiota (GM) in the modulation of multiple functions associated with depression through the gut-brain axis (GBA). However, the underlying mechanisms remain poorly understood. Therefore, in the current study, we aimed to screen the microbiota out from healthy and depressive adolescents, delineate the association of the targeted microbiota and the adolescent depression, address the salutary effects of the targeted microbiota on anti-depressive behaviors in mice involving the metabolism of the tryptophan (Trp)-derived neurotransmitters along the GBA.RESULTS: Here, we found the gut microbiota from healthy adolescent volunteers, first diagnosis patients of adolescent depression, and sertraline interveners after first diagnosis displayed significant difference, the relative abundance of Faecalibacterium, Roseburia, Collinsella, Blautia, Phascolarctobacterium, Lachnospiraceae-unclassified decreased in adolescent depressive patients, while restored after sertraline treatment. Of note, the Roseburia abundance exhibited a high efficiency in predicting adolescent depression. Intriguingly, transplantation of the fecal microbiota from healthy adolescent volunteers to the chronic restraint stress (CRS)-induced adolescent depressed mice significantly ameliorated mouse depressive behaviors, in which the Roseburia exerted critical roles, since its effective colonization in the mouse colon resulted in remarkably increased 5-HT level and reciprocally decreased kynurenine (Kyn) toxic metabolites quinolinic acid (Quin) and 3-hydroxykynurenine (3-HK) levels in both the mouse brain and colon. The specific roles of the Roseburia were further validated by the target bacteria transplantation mouse model, Roseburia intestinalis (Ri.) was gavaged to mice and importantly, it dramatically ameliorated CRS-induced mouse depressive behaviors, increased 5-HT levels in the brain and colon via promoting tryptophan hydroxylase-2 (TPH2) or -1 (TPH1) expression. Reciprocally, Ri. markedly restrained the limit-step enzyme responsible for kynurenine (indoleamine2,3-dioxygenase 1, IDO1) and quinolinic acid (3-hydroxyanthranilic acid 3,4-dioxygenase, 3HAO) generation, thereby decreased Kyn and Quin levels. Additionally, Ri. administration exerted a pivotal role in the protection of CRS-induced synaptic loss, microglial activation, and astrocyte maintenance.CONCLUSIONS: This study is the first to delineate the beneficial effects of Ri. on adolescent depression by balancing Trp-derived neurotransmitter metabolism and improving synaptogenesis and glial maintenance, which may yield novel insights into the microbial markers and therapeutic strategies of GBA in adolescent depression. Video Abstract.PMID:37386523 | DOI:10.1186/s40168-023-01589-9

Diabetol Metab Syndr. 2023 Jun 29;15(1):142. doi: 10.1186/s13098-023-01115-9.ABSTRACTBACKGROUND: Acute myocardial infarction (AMI) is the most prevalent cause of mortality and morbidity in patients with type 2 diabetes mellitus (T2DM). However, strict blood glucose control does not always prevent the development and progression of AMI. Therefore, the present study aimed to explore potential new biomarkers associated with the occurrence of AMI in T2DM patients.METHODS: A total of 82 participants were recruited, including the control group (n = 28), T2DM without AMI group (T2DM, n = 30) and T2DM with initial AMI group (T2DM + AMI, n = 24). The untargeted metabolomics using liquid chromatography-mass spectrometry (LC-MS) analysis was performed to evaluate the changes in serum metabolites. Then, candidate metabolites were determined using ELISA method in the validation study (n = 126/T2DM group, n = 122/T2DM + AMI group).RESULTS: The results showed that 146 differential serum metabolites were identified among the control, T2DM and T2DM + AMI, Moreover, 16 differentially-expressed metabolites were significantly altered in T2DM + AMI compared to T2DM. Amino acid and lipid pathways were the major involved pathways. Furthermore, three candidate differential metabolites, 12,13-dihydroxy-9Z-octadecenoic acid (12,13-diHOME), noradrenaline (NE) and estrone sulfate (ES), were selected for validation study. Serum levels of 12,13-diHOME and NE in T2DM + AMI were significantly higher than those in T2DM. Multivariate logistic analyses showed that 12,13-diHOME (OR, 1.491; 95% CI 1.230-1.807, P < 0.001) and NE (OR, 8.636; 95% CI 2.303-32.392, P = 0.001) were independent risk factors for AMI occurrence in T2T2DM patients. The area under receiver operating characteristic (ROC) curve (AUC) were 0.757 (95% CI 0.697-0.817, P < 0.001) and 0.711(95% CI 0.648-0.775, P < 0.001), respectively. The combination of both significantly improved the AUC to 0.816 (95% CI 0.763-0.869, P < 0.001).CONCLUSIONS: 12,13-diHOME and NE may lead to understanding the possible metabolic alterations associated with AMI onset in T2DM population and serve as promising risk factors and therapeutic targets.PMID:37386486 | DOI:10.1186/s13098-023-01115-9

Mol Med. 2023 Jun 29;29(1):82. doi: 10.1186/s10020-023-00669-8.ABSTRACTBACKGROUND: Insulin resistance (IR) is an important determinant of glucose metabolic disturbance and placental dysplasia in gestational diabetes mellitus (GDM). Calcium/calmodulin dependent protein kinase IV (CAMK4) improves insulin IR induced by a high-fat diet (HFD). The current study sought to elucidate the role and potential mechanism of CAMK4 in GDM.METHODS: A GDM model was established in female C57BL/6J mice via HFD feeding for one week before mating and throughout gestation. The IR was elicited by 10-6 M insulin treatment for 48 h in HTR-8/SVneo cells and mouse primary trophoblast cells. The function of CAMK4 was investigated by transfection of overexpression plasmid in HTR-8/SVneo cells and infection of lentivirus loaded with CAMK4 encoding sequence in primary trophoblast cells. Real-time PCR, western blot, cell counting kit-8, transwell, wound healing, dual-luciferase reporter assay, and liquid chromatography/mass spectrometry-based untargeted metabolomics were performed to confirm the effects of CAMK4 on trophoblast cells.RESULTS: Decreased CAMK4 expression was found in the placenta of GDM mice. CAMK4 overexpression ameliorated IR-induced viability impairment, migratory and invasive capacity inhibition, autophagy blocking, insulin signaling inactivation and glucose uptake disorder in trophoblast cells. CAMK4 also transcriptionally activated orphan nuclear receptor NUR77, and the effects of CAMK4 were abrogated by silencing of NUR77. Metabolomics analysis revealed that CAMK4 overexpression caused alterations of amino acid, lipid and carbohydrate metabolism, which were important in GDM.CONCLUSION: Our results indicated that CAMK4/NUR77 axis may provide novel potential targets in GDM treatment.PMID:37386367 | DOI:10.1186/s10020-023-00669-8

Nat Aging. 2023 Jun 29. doi: 10.1038/s43587-023-00448-4. Online ahead of print.ABSTRACTTechnical advancements over the past two decades have enabled the measurement of the panoply of molecules of cells and tissues including transcriptomes, epigenomes, metabolomes and proteomes at unprecedented resolution. Unbiased profiling of these molecular landscapes in the context of aging can reveal important details about mechanisms underlying age-related functional decline and age-related diseases. However, the high-throughput nature of these experiments creates unique analytical and design demands for robustness and reproducibility. In addition, 'omic' experiments are generally onerous, making it crucial to effectively design them to eliminate as many spurious sources of variation as possible as well as account for any biological or technical parameter that may influence such measures. In this Perspective, we provide general guidelines on best practices in the design and analysis of omic experiments in aging research from experimental design to data analysis and considerations for long-term reproducibility and validation of such studies.PMID:37386258 | DOI:10.1038/s43587-023-00448-4

Sci Rep. 2023 Jun 29;13(1):10519. doi: 10.1038/s41598-023-37488-0.ABSTRACTResearch continues to identify genetic variation, environmental exposures, and their mixtures underlying different diseases and conditions. There is a need for screening methods to understand the molecular outcomes of such factors. Here, we investigate a highly efficient and multiplexable, fractional factorial experimental design (FFED) to study six environmental factors (lead, valproic acid, bisphenol A, ethanol, fluoxetine hydrochloride and zinc deficiency) and four human induced pluripotent stem cell line derived differentiating human neural progenitors. We showcase the FFED coupled with RNA-sequencing to identify the effects of low-grade exposures to these environmental factors and analyse the results in the context of autism spectrum disorder (ASD). We performed this after 5-day exposures on differentiating human neural progenitors accompanied by a layered analytical approach and detected several convergent and divergent, gene and pathway level responses. We revealed significant upregulation of pathways related to synaptic function and lipid metabolism following lead and fluoxetine exposure, respectively. Moreover, fluoxetine exposure elevated several fatty acids when validated using mass spectrometry-based metabolomics. Our study demonstrates that the FFED can be used for multiplexed transcriptomic analyses to detect relevant pathway-level changes in human neural development caused by low-grade environmental risk factors. Future studies will require multiple cell lines with different genetic backgrounds for characterising the effects of environmental exposures in ASD.PMID:37386098 | DOI:10.1038/s41598-023-37488-0