PubMed

J Vis Exp. 2023 Mar 31;(193). doi: 10.3791/65205.ABSTRACTThe brain secretome consists of proteins either actively secreted or shed from the cell surface by proteolytic cleavage in the extracellular matrix of the nervous system. These proteins include growth factor receptors and transmembrane proteins, among others, covering a broad spectrum of roles in the development and normal functioning of the central nervous system. The current procedure to extract the secretome from cerebrospinal fluid is complicated and time-consuming, and it is difficult to isolate these proteins from experimental animal brains. In this study, we present a novel protocol for isolating the brain secretome from mouse brain slice cultures. First, the brains were isolated, sliced, and cultured ex vivo. The culture medium was then filtered and concentrated for isolating proteins by centrifugation after a few days. Finally, the isolated proteins were resolved using sodium dodecyl-sulfate polyacrylamide gel electrophoresis (SDS-PAGE) and subsequently probed for purity characterization by western blot. This isolation procedure of the brain secretome from ex vivo brain slice cultures can be used to investigate the effects of the secretome on a variety of neurodevelopmental diseases, such as autism spectrum disorders.PMID:37067274 | DOI:10.3791/65205

Front Endocrinol (Lausanne). 2023 Mar 31;14:1166914. doi: 10.3389/fendo.2023.1166914. eCollection 2023.NO ABSTRACTPMID:37065744 | PMC:PMC10102633 | DOI:10.3389/fendo.2023.1166914

Nat Microbiol. 2023 Apr 17. doi: 10.1038/s41564-023-01355-5. Online ahead of print.ABSTRACTAnorexia nervosa (AN) is an eating disorder with a high mortality. About 95% of cases are women and it has a population prevalence of about 1%, but evidence-based treatment is lacking. The pathogenesis of AN probably involves genetics and various environmental factors, and an altered gut microbiota has been observed in individuals with AN using amplicon sequencing and relatively small cohorts. Here we investigated whether a disrupted gut microbiota contributes to AN pathogenesis. Shotgun metagenomics and metabolomics were performed on faecal and serum samples, respectively, from a cohort of 77 females with AN and 70 healthy females. Multiple bacterial taxa (for example, Clostridium species) were altered in AN and correlated with estimates of eating behaviour and mental health. The gut virome was also altered in AN including a reduction in viral-bacterial interactions. Bacterial functional modules associated with the degradation of neurotransmitters were enriched in AN and various structural variants in bacteria were linked to metabolic features of AN. Serum metabolomics revealed an increase in metabolites associated with reduced food intake (for example, indole-3-propionic acid). Causal inference analyses implied that serum bacterial metabolites are potentially mediating the impact of an altered gut microbiota on AN behaviour. Further, we performed faecal microbiota transplantation from AN cases to germ-free mice under energy-restricted feeding to mirror AN eating behaviour. We found that the reduced weight gain and induced hypothalamic and adipose tissue gene expression were related to aberrant energy metabolism and eating behaviour. Our 'omics' and mechanistic studies imply that a disruptive gut microbiome may contribute to AN pathogenesis.PMID:37069399 | DOI:10.1038/s41564-023-01355-5

Sci Rep. 2023 Apr 17;13(1):6261. doi: 10.1038/s41598-023-33442-2.ABSTRACTDiabetes is a main risk factor for kidney disease, causing diabetic nephropathy in close to half of all patients with diabetes. Metabolism has recently been identified to be decisive in cell fate decisions and repair. Here we used mass spectrometry imaging (MSI) to identify tissue specific metabolic dysregulation, in order to better understand early diabetes-induced metabolic changes of renal cell types. In our experimental diabetes mouse model, early glomerular glycocalyx barrier loss and systemic metabolic changes were observed. In addition, MSI targeted at small molecule metabolites and glycero(phospho)lipids exposed distinct changes upon diabetes in downstream nephron segments. Interestingly, the outer stripe of the outer medullar proximal tubular segment (PT_S3) demonstrated the most distinct response compared to other segments. Furthermore, phosphatidylinositol lipid metabolism was altered specifically in PT_S3, with one of the phosphatidylinositol fatty acid tails being exchanged from longer unsaturated fatty acids to shorter, more saturated fatty acids. In acute kidney injury, the PT_S3 segment and its metabolism are already recognized as important factors in kidney repair processes. The current study exposes early diabetes-induced changes in membrane lipid composition in this PT_S3 segment as a hitherto unrecognized culprit in the early renal response to diabetes.PMID:37069341 | DOI:10.1038/s41598-023-33442-2

Biochemistry (Mosc). 2023 Jan;88(Suppl 1):S52-S74. doi: 10.1134/S0006297923140043.ABSTRACTUnder suboptimal growth conditions, bacteria can transit to the dormant forms characterized by a significantly reduced metabolic activity, resistance to various stress factors, and absence of cell proliferation. Traditionally, the dormant state is associated with the formation of highly differentiated cysts and spores. However, non-spore-forming bacteria can transfer to the dormant-like hypobiotic state with the generation of less differentiated cyst-like forms (which are different from spores). This review focuses on morphological and biochemical changes occurred during formation of dormant forms of mycobacteria in particular pathogenic M. tuberculosis (Mtb) caused latent forms of tuberculosis. These forms are characterized by the low metabolic activity, the absence of cell division, resistance to some antibiotics, marked morphological changes, and loss of ability to grow on standard solid media ("non-culturable" state). Being produced in vitro, dormant Mtb retained ability to maintain latent infection in mice. After a long period of dormancy, mycobacteria retain a number of stable proteins with a potential enzymatic activity which could participate in maintaining of low-level metabolic activity in period of dormancy. Indeed, the metabolomic analysis showed significant levels of metabolites in the dormant cells even after a long period of dormancy, which may be indicative of residual metabolism in dormant mycobacteria. Special role may play intracellularly accumulated trehalose in dormant mycobacteria. Trehalose appears to stabilize dormant cells, as evidenced by the direct correlation between the trehalose content and cell viability during the long-term dormancy. In addition, trehalose can be considered as a reserve energy substrate consumed during reactivation of dormant mycobacteria due to the ATP-dependent conversion of trehalase from the latent to the active state. Another feature of dormant mycobacteria is a high representation of proteins participating in the enzymatic defense against stress factors and of low-molecular-weight compounds protecting cells in the absence of replication. Dormant mycobacteria contain a large number of hydrolyzing enzymes, which, on the one hand, ensure inactivation of biomolecules damaged by stress. On the other hand, the products of these enzymatic reactions can be used for the maintenance of energy state and vital activity of bacterial cells during their long-term survival in the dormant state, i.e., for creating a situation that we propose to refer to as the "catabolic survival". In general, dormant non-replicating mycobacterial cells can be described as morphologically altered forms that contain principal macromolecules and are stabilized and protected from the damaging factors by an arsenal of proteins and low-molecular-weight compounds. Because of the presumable occurrence of metabolic reactions in such cells, this form of survival should be referred to as hypobiosis.PMID:37069114 | DOI:10.1134/S0006297923140043

Neurology. 2023 Apr 17:10.1212/WNL.0000000000207264. doi: 10.1212/WNL.0000000000207264. Online ahead of print.ABSTRACTBACKGROUND AND OBJECTIVES: In the United States, the risk of stroke is greater among Black compared to White individuals. However, the reasons for the difference in stroke incidence are not fully elucidated. We aimed to identify metabolites that account for higher prevalent hypertension and incident ischemic stroke among Black adults.METHODS: We used a stroke case-cohort nested within the REasons for Geographic and Racial Differences in Stroke (REGARDS) study. Targeted metabolomic profiling of 162 plasma metabolites was performed by liquid chromatography-tandem mass spectrometry. We identified metabolites that were associated with prevalent hypertension, incident ischemic stroke, and mediated the relationship between hypertension and ischemic stroke by weighted logistic regression, Cox proportional hazard model, and inverse odds ratio weighting mediation analysis respectively.RESULTS: Incident ischemic stroke cases adjudicated through April 1, 2019 (n=1,075) were included in the study. The random cohort sample was derived from the full cohort using stratified sampling (n=968). Among 162 metabolites, gluconic acid was associated with prevalent hypertension in Black adults (OR=1.86, 95% CI=1.39-2.47, P=2.58x10-5) but not in White adults (OR=1.00, 95% CI=0.80-1.24, P=0.97; P for interaction=4.57x10-4). Gluconic acid also demonstrated an association with incident ischemic stroke among Black participants (HR=1.53, 95% CI=1.28-1.81, P=1.76x10-6) but not White participants (HR=1.16, 95% CI=1.00-1.34, P=0.057; P for interaction=0.019). In mediation analysis, gluconic acid mediated 25.4% (95% CI=4.1%-46.8%, P=0.02) of the association between prevalent hypertension and incident ischemic stroke among Black individuals. Specific socioeconomic factors were linked to elevated gluconic acid level among Black adults in multivariable analysis, including a Southern dietary pattern (β=0.18, 95% CI=0.08-0.28, P<0.001), lower educational attainment (β=0.45, 95% CI=0.19-0.72, P=0.001), and a lack of exercise (β=0.26, 95% CI=0.01-0.51, P=0.045).DISCUSSION: Gluconic acid is associated with prevalent hypertension and incident ischemic stroke and mediates the relationship between hypertension and ischemic stroke in Black but not White adults. Gluconic acid is a biomarker that is associated with social determinants of health including Southern diet, low educational attainment, and low physical activity.PMID:37068957 | DOI:10.1212/WNL.0000000000207264

Annu Rev Anal Chem (Palo Alto Calif). 2023 Apr 17. doi: 10.1146/annurev-anchem-091222-112115. Online ahead of print.ABSTRACTThis article critically reviews analytical method validation and quality control applied to the environmental chemistry field. The review focuses on the determination of organic micropollutants (OMPs), specifically emerging contaminants and pesticides, in the aquatic environment. The analytical technique considered is (gas and liquid) chromatography coupled to mass spectrometry (MS), including high-resolution MS for wide-scope screening purposes. An analysis of current research practices outlined in the literature has been performed, and key issues and analytical challenges are identified and critically discussed. It is worth emphasizing the lack of specific guidelines applied to environmental analytical chemistry and the minimal regulation of OMPs in waters, which greatly affect method development and performance, requirements for method validation, and the subsequent application to samples. Finally, a proposal is made for method validation and data reporting, which can be understood as starting points for further discussion with specialists in environmental analytical chemistry. Expected final online publication date for the Annual Review of Analytical Chemistry, Volume 16 is June 2023. Please see http://www.annualreviews.org/page/journal/pubdates for revised estimates.PMID:37068748 | DOI:10.1146/annurev-anchem-091222-112115

J Adv Res. 2023 Apr 15:S2090-1232(23)00116-9. doi: 10.1016/j.jare.2023.04.010. Online ahead of print.ABSTRACTINTRODUCTION: Major depressive disorder (MDD) in adolescents is a widespread and growing global public health concern with unique characteristics and pathophysiological mechanisms that are distinct from MDD in adults.OBJECTIVE: The purpose of our work was to address this knowledge gap about the unique characteristics and pathophysiological mechanisms of adolescent depression from a microbiota-gut-brain (MGB) axis perspective.METHOD: Ten healthy male cynomolgus macaques (Macaca fascicularis) were paired into five pairs based on age and body weight, and two cynomolgus macaques from each pair were randomly allocated to chronic unpredictable mild stress group, or unstressed control group. At endpoint, microbe composition from cecum, ascending colon, transverse colon, and descending colon were analyzed by metagenome sequencing, and the metabolite profiles of MGB axis including central (prefrontal cortex, hippocampus and amygdala) and peripheral (plasma, gut and feces of cecum, ascending colon, transverse colon and descending colon) samples were analyzed by metabolomic profiling. Then, we compare the gut microbiome and metabolic signatures in MGB axis between adolescent and adult depressed macaques.RESULTS: The microbial composition and gut-brain metabolic signatures were widely divergent between adolescent and adult depressed macaques, though the phylum Firmicutes and lipid metabolism pathways were persistently altered in both populations. Purine and arginine biosynthesis metabolism were a specific hallmark of adolescent depressed macaques, while fatty acyl metabolism was specially altered in adult. These differential metabolic pathways in adolescent and adult depressed macaques were mainly mapped into the prefrontal cortex and hippocampus, respectively. Notably, the genus Clostridium and Haemophilus, characteristically disturbed in adolescent depressed macaques but not in adult, were also significantly associated with the majority of purine metabolites in MGB axis.CONCLUSION: These findings provide a new framework describing divergent pathophysiological mechanisms between adolescent and adult depression, and may open new windows for more effective treatment strategies of adolescent depression.PMID:37068733 | DOI:10.1016/j.jare.2023.04.010

Environ Res. 2023 Apr 15:115921. doi: 10.1016/j.envres.2023.115921. Online ahead of print.ABSTRACTTitanium dioxide (TiO2) is a common additive in foods, medicines, and personal care products. In recent years, nano-scale particles in TiO2 additives have been an increasing concern due to their potential adverse effects on human health, especially gut health. The objective of this study was to determine the impact of titanium dioxide nanoparticles (TiO2 NPs, 30 nm) on beneficial gut bacteria and host response from a metabolomics perspective. In the in vitro study, four bacterial strains, including Lactobacillus reuteri, Lactobacillus gasseri, Bifidobacterium animalis, and Bifidobacterium longum were subjected to the treatment of TiO2 NPs. The growth kinetics, cell viability, cell membrane permeability, and metabolomics response were determined. TiO2 NPs at the concentration of 200 μg/mL showed inhibitory effects on the growth of all four strains. The confocal microscope results indicated that the growth inhibitory effects could be associated with cell membrane damage caused by TiO2 NPs to the bacterial strains. Metabolomics analysis showed that TiO2 NPs caused alterations in multiple metabolic pathways of gut bacteria, such as tryptophan and arginine metabolism, which were demonstrated to play crucial roles in regulating gut and host health. In the in vivo study, mice were fed with TiO2 NPs (0.1 wt% in diet) for 8 weeks. Mouse urine was collected for metabolomics analysis and the tryptophan metabolism pathway was also significantly affected in TiO2 NPs-fed mice. Moreover, four neuroprotective metabolites were significantly reduced in both in vitro bacteria and in vivo urine samples. Overall, this study provides insights into the potential adverse effects of TiO2 NPs on gut bacteria and the metabolic responses of both bacteria and host. Further research is needed to understand the causality between gut bacteria composition and the metabolism pathway, which is critical to monitor the gut-microbiome mediated metabolome changes in toxicological assessment of food components.PMID:37068726 | DOI:10.1016/j.envres.2023.115921

NanoImpact. 2023 Apr 15:100464. doi: 10.1016/j.impact.2023.100464. Online ahead of print.ABSTRACTNanomaterial have shown excellent properties in the food industry. Although iron oxides are often considered safe and widely used as food additives, the toxicity of nano‑iron oxide remains unclear. Here we established a subchronic exposure mouse model by gavage, tested the biodistribution of nano‑iron oxide, and explored the mechanism of liver injury caused by it through disturbance of the gut-liver axis. Oral intake of nano‑iron oxide will likely disrupt the small intestinal epithelial barrier, induce hepatic lipid metabolism disorders through the gut-liver axis, and cause hepatic damage accompanied with hepatic iron deposition. Nano‑iron oxide mainly caused hepatic lipid metabolism disorder by perturbing glycerophospholipid metabolism and the sphingolipid metabolism pathways, with the total abundance of phosphatidylcholine (PC) and phosphatidylethanolamine (PE) tending to decrease while that of triglyceride tended to increase, in a time- and dose-dependent manner. The imbalanced lipid homeostasis could cause damage via membrane disruption, lipid accumulation, and lipotoxicity. This data provides information about the subchronic toxicity of nano‑iron oxide, highlights the importance of gut-liver axis in the hepatotoxicity.PMID:37068656 | DOI:10.1016/j.impact.2023.100464

Int J Biol Macromol. 2023 Apr 15:124436. doi: 10.1016/j.ijbiomac.2023.124436. Online ahead of print.ABSTRACTNAC (NAM, ATAF1/2 and CUC2) transcription factors (TFs) are a class of TFs families unique to plants, which not only play an important role in the growth and developmental stages of plants but also function in response to stress and regulation of secondary metabolite biosynthesis. However, there are few studies on NAC genes in the medicinal plant Isatis indigotica. In this study, 96 IiNAC genes were identified based on the whole-genome data of I. indigotica, distributed in seven chromosomes and three contigs. IiNAC genes were structurally conserved and divided into 15 subgroups. Cis-elements were identified in the promoter region of the IiNAC gene in response to plant growth and development, abiotic stresses and hormones. In addition, transcriptome and metabolome data of I. indigotica leaves under salt stress were analyzed to construct a network of IiNAC gene co-expression and metabolite association. Ten differentially expressed IiNAC genes were co-expressed with 109 TFs, and Gene Ontology (GO) and Kyoto Encyclopedia of Genes and Genomes (KEGG) enrichment analyses revealed that most of these genes were associated with plant growth and development and abiotic stress responses. Eleven IiNAC genes were positively associated with 72 metabolites. Eleven IiNAC genes were positively or negatively associated with 47 metabolites through 37 TFs. Commonly associated secondary metabolites include two terpenoids, abscisic acid and bilobalide, two flavonoids, dihydrokaempferol and syringaldehyde, a coumarin, 7-methoxycoumarin, an alkaloid, lupinine, and quinone dihydrotanshinone I. This study provides important data to support the identification of the NAC gene family in I. indigotica and the regulatory functions of IiNAC genes in metabolites under salt stress.PMID:37068542 | DOI:10.1016/j.ijbiomac.2023.124436

J Chromatogr B Analyt Technol Biomed Life Sci. 2023 Mar 30;1222:123686. doi: 10.1016/j.jchromb.2023.123686. Online ahead of print.ABSTRACTBACKGROUND AND AIMS: Alzheimer's disease (AD), the most common type of dementia, is hard to recognize early, resulting in delayed treatment and poor outcome. At present, there is neither reliable, non-invasive methods to diagnose it accurately and nor effective drugs to recover it. Discovery and quantification of novel metabolite markers in plasma of AD patients and investigation of the correlation between the markers and AD assessment scores.MATERIALS AND METHODS: Untargeted liquid chromatography-mass spectrometry (LC-MS)-based metabolomics with LC-quadrupole- time-of-flight (Q-TOF) was performed in plasma samples of age-matched AD patients and healthy controls. The potential markers were further quantified with targeted multiple reaction monitoring (MRM) approach.RESULTS: Among the candidates, progesterone, and 3-indoleacetic acid (3-IAA) were successfully identified and then validated in 50 plasma samples from 25 AD patients and 25 matched normal controls with MRM approach. As a result, 3-IAA was significantly altered in AD patients and correlated with some AD assessment scores.CONCLUSION: By using untargeted LC-MS metabolomic and LC-MRM approaches to analyze plasma metabolites of AD patients and normal subjects, 3-IAA was discovered and quantified to be significantly altered in AD patients and correlated with several AD assessment scores.PMID:37068461 | DOI:10.1016/j.jchromb.2023.123686

Biomed Pharmacother. 2023 Mar 28;162:114614. doi: 10.1016/j.biopha.2023.114614. Online ahead of print.ABSTRACTThe continuing heavy toll of the COVID-19 pandemic necessitates development of therapeutic options. We adopted structure-based drug repurposing to screen FDA-approved drugs for inhibitory effects against main protease enzyme (Mpro) substrate-binding pocket of SARS-CoV-2 for non-covalent and covalent binding. Top candidates were screened against infectious SARS-CoV-2 in a cell-based viral replication assay. Promising candidates included atovaquone, mebendazole, ouabain, dronedarone, and entacapone, although atovaquone and mebendazole were the only two candidates with IC50s that fall within their therapeutic plasma concentration. Additionally, we performed Mpro assays on the top hits, which demonstrated inhibition of Mpro by dronedarone (IC50 18 µM), mebendazole (IC50 19 µM) and entacapone (IC50 9 µM). Atovaquone showed only modest Mpro inhibition, and thus we explored other potential mechanisms. Although atovaquone is Dihydroorotate dehydrogenase (DHODH) inhibitor, we did not observe inhibition of DHODH at the respective SARS-CoV-2 IC50. Metabolomic profiling of atovaquone treated cells showed dysregulation of purine metabolism pathway metabolite, where ecto-5'-nucleotidase (NT5E) was downregulated by atovaquone at concentrations equivalent to its antiviral IC50. Atovaquone and mebendazole are promising candidates with SARS-CoV-2 antiviral activity. While mebendazole does appear to target Mpro, atovaquone may inhibit SARS-CoV-2 viral replication by targeting host purine metabolism.PMID:37068330 | DOI:10.1016/j.biopha.2023.114614

Brief Bioinform. 2023 Apr 17:bbad141. doi: 10.1093/bib/bbad141. Online ahead of print.ABSTRACTImaging mass spectrometry (IMS) is one of the powerful tools in spatial metabolomics for obtaining metabolite data and probing the internal microenvironment of organisms. It has dramatically advanced the understanding of the structure of biological tissues and the drug treatment of diseases. However, the complexity of IMS data hinders the further acquisition of biomarkers and the study of certain specific activities of organisms. To this end, we introduce an artificial intelligence tool, SmartGate, to enable automatic peak selection and spatial structure identification in an iterative manner. SmartGate selects discriminative m/z features from the previous iteration by differential analysis and employs a graph attention autoencoder model to perform spatial clustering for tissue segmentation using the selected features. We applied SmartGate to diverse IMS data at multicellular or subcellular spatial resolutions and compared it with four competing methods to demonstrate its effectiveness. SmartGate can significantly improve the accuracy of spatial segmentation and identify biomarker metabolites based on tissue structure-guided differential analysis. For multiple consecutive IMS data, SmartGate can effectively identify structures with spatial heterogeneity by introducing three-dimensional spatial neighbor information.PMID:37068309 | DOI:10.1093/bib/bbad141

Kidney360. 2023 Apr 17. doi: 10.34067/KID.0000000000000129. Online ahead of print.ABSTRACTBACKGROUND: Chronic kidney disease of a nontraditional etiology (CKDnt) is responsible for high mortality in Central America, although its causes remain unclear. Evidence of kidney dysfunction has been observed among youth, suggesting that early kidney damage contributing to CKDnt may initiate in childhood.METHODS: Urine specimens of Nicaraguan adolescents 12-23 years without CKDnt (n=136) were analyzed by proton nuclear magnetic resonance (1H-NMR) spectroscopy for 50 metabolites associated with kidney dysfunction. Urinary metabolite levels were compared by CKiD U25 estimated glomerular filtration rate (eGFR), regional CKDnt prevalence, sex, age, and family history of CKDnt using supervised statistical methods and pathway analysis in MetaboAnalyst. Magnitude of associations and changes over time were assessed through multivariable linear regression.RESULTS: In adjusted analyses, glycine concentrations were higher among youth from high-risk regions (β=0.82, (95% CI: 0.16, 1.85); p=0.01). Pyruvate concentrations were lower among youth with low eGFR (β= -0.36; (95% CI:-0.57, -0.04); p=0.03) and concentrations of other citric acid (TCA) cycle metabolites differed by key risk factors. Over four years, participants with low eGFR experienced greater declines in 1-methylnicotinamide and 2-oxoglutarate and greater increases in citrate and guanidinoacetate concentrations.CONCLUSION: Urinary concentration of glycine, a molecule associated with thermoregulation and kidney function preservation, was higher among youth in high-risk CKDnt regions, suggestive of greater heat exposure or renal stress. Lower pyruvate concentrations were associated with low eGFR, and citric acid cycle metabolites like pyruvate likely relate to mitochondrial respiration rates in the kidneys. Participants with low eGFR experienced longitudinal declines in concentrations of 1-methylnicotinamide, an anti-inflammatory metabolite associated with anti-fibrosis in tubule cells. These findings merit further consideration in research on the origins of CKDnt.PMID:37068179 | DOI:10.34067/KID.0000000000000129

Crit Rev Food Sci Nutr. 2023 Apr 17:1-17. doi: 10.1080/10408398.2023.2199425. Online ahead of print.ABSTRACTFermented foods are important components of the human diet. There is increasing awareness of abundant nutritional and functional properties present in fermented foods that arise from the transformation of substrates by microbial communities. Thus, it is significant to unravel the microbial communities and mechanisms of characteristic flavor formation occurring during fermentation. There has been rapid development of high-throughput and other omics technologies, such as metaproteomics and metabolomics, and as a result, there is growing recognition of the importance of integrating these approaches. The successful applications of multi-omics approaches and bioinformatics analyses have provided a solid foundation for exploring the fermentation process. Compared with single-omics, multi-omics analyses more accurately delineate microbial and molecular features, thus they are more apt to reveal the mechanisms of fermentation. This review introduces fermented foods and an overview of single-omics technologies - including metagenomics, metatranscriptomics, metaproteomics, and metabolomics. We also discuss integrated multi-omics and bioinformatic analyses and their role in recent research progress related to fermented foods, as well as summarize the main potential pathways involved in certain fermented foods. In the future, multilayered analyses of multi-omics data should be conducted to enable better understanding of flavor formation mechanisms in fermented foods.PMID:37068005 | DOI:10.1080/10408398.2023.2199425

Cancer Discov. 2023 Apr 17:OF1-OF20. doi: 10.1158/2159-8290.CD-22-0872. Online ahead of print.ABSTRACTCancer-related alterations of the p53 tetramerization domain (TD) abrogate wild-type (WT) p53 function. They result in a protein that preferentially forms monomers or dimers, which are also normal p53 states under basal cellular conditions. However, their physiologic relevance is not well understood. We have established in vivo models for monomeric and dimeric p53, which model Li-Fraumeni syndrome patients with germline p53 TD alterations. p53 monomers are inactive forms of the protein. Unexpectedly, p53 dimers conferred some tumor suppression that is not mediated by canonical WT p53 activities. p53 dimers upregulate the PPAR pathway. These activities are associated with lower prevalence of thymic lymphomas and increased CD8+ T-cell differentiation. Lymphomas derived from dimeric p53 mice show cooperating alterations in the PPAR pathway, further implicating a role for these activities in tumor suppression. Our data reveal novel functions for p53 dimers and support the exploration of PPAR agonists as therapies.SIGNIFICANCE: New mouse models with TP53R342P (monomer) or TP53A347D (dimer) mutations mimic Li-Fraumeni syndrome. Although p53 monomers lack function, p53 dimers conferred noncanonical tumor-suppressive activities. We describe novel activities for p53 dimers facilitated by PPARs and propose these are "basal" p53 activities.PMID:37067911 | DOI:10.1158/2159-8290.CD-22-0872

Neurochem Res. 2023 Apr 17. doi: 10.1007/s11064-023-03937-5. Online ahead of print.ABSTRACTEpilepsy is a chronic brain disease and often occurs suddenly for no reason. Eucommiae folium (EF), an edible herb, can be used in the treatment of various kinds of brain diseases in clinic. From the perspective of safety and efficacy, EF is especially suitable for the treatment of chronic brain diseases. With the help of biolabels, this study was aimed to explore the value and feasibility of EF in the treatment of epilepsy. Proteomics and metabolomics were used to explore the biolabels of EF intervention in brain tissues. Bioinformatics was then applied to topologically analyze its neuroprotective effects and mechanisms and material basis based on biolabels, which were validated in an animal model. The biolabel-led research revealed that EF may exert the therapeutic potential to treat brain diseases through the interaction between multiple compounds and multiple targets, among which its therapeutic potential for epilepsy is particularly prominent. In the pentylenetetrazole-induction model, EF and four active compounds (oleamide, catechol, chlorogenic acid, and kaempferol) protected epileptic hippocampal neurons (Nissl and FJB staining) against mitochondrial dysfunction (MYH6, MYL3, and MYBPC3, etc.) and calcium overload (TNNI3, TNNC1, and TNNT2, etc.) through the hypertrophic cardiomyopathy pathway. This study provides new evidence and insights for the neuroprotective effects of EF, in which four active compounds may be potential drug candidates for the treatment of epilepsy.PMID:37067737 | DOI:10.1007/s11064-023-03937-5

Amino Acids. 2023 Apr 17. doi: 10.1007/s00726-023-03255-8. Online ahead of print.ABSTRACTDiabetes mellitus (DM) is a severe chronic diseases with a global prevalence of 9%, leading to poor health and high health care costs, and is a direct cause of millions of deaths each year. The rising epidemic of diabetes and its complications, such as retinal and peripheral nerve disease, is a huge burden globally. A better understanding of the molecular pathways involved in the development and progression of diabetes and its complications can facilitate individualized prevention and treatment. High diabetes mellitus incidence rate is caused mainly by lack of non-invasive and reliable methods for early diagnosis, such as plasma biomarkers. The incidence of diabetes and its complications in the world still grows so it is crucial to develop a new, faster, high specificity and more sensitive diagnostic technologies. With the advancement of analytical techniques, metabolomics can identify and quantify multiple biomarkers simultaneously in a high-throughput manner, and effective biomarkers can greatly improve the efficiency of diabetes and its complications. By providing information on potential metabolic pathways, metabolomics can further define the mechanisms underlying the progression of diabetes and its complications, help identify potential therapeutic targets, and improve the prevention and management of T2D and its complications. The application of amino acid metabolomics in epidemiological studies has identified new biomarkers of diabetes mellitus (DM) and its complications, such as branched-chain amino acids, phenylalanine and arginine metabolites. This study focused on the analysis of metabolic amino acid profiling as a method for identifying biomarkers for the detection and screening of diabetes and its complications. The results presented are all from recent studies, and in all cases analyzed, there were significant changes in the amino acid profile of patients in the experimental group compared to the control group. This study demonstrates the potential of amino acid profiles as a detection method for diabetes and its complications.PMID:37067568 | DOI:10.1007/s00726-023-03255-8

Microbiol Spectr. 2023 Apr 17:e0040923. doi: 10.1128/spectrum.00409-23. Online ahead of print.ABSTRACTEndometritis is a common cow disease characterized by inflammation of endometrium, which leads to infertility or low fertility of cows and brings huge economic losses to the dairy industry. Tau interferon (IFN-τ) has many important biological functions, including an anti-inflammatory effect. The present study aimed to survey the effects of IFN-τ administration on gut microflora and body metabolism in mice with endometritis and to explore the potential relationship. The results indicated that IFN-τ obviously alleviated the damage and ultrastructural changes of mouse endometrium induced by Escherichia coli and enhanced tight junction protein's expression level. Through analysis by 16S rRNA gene sequencing, we found that IFN-τ, especially at 12 h, could regulate the composition of gut microbiota associated with Pediococcus, Staphylococcus, and Enterorhabdus in E. coli-induced mouse endometritis. Through histometabonomics, it was found that endometritis was related to 11 different metabolites and 4 potential metabolic pathways. These metabolites and metabolic pathways were major participants in metabolic pathways, cysteine and methionine metabolism, arachidonic acid metabolism, and pyrimidine metabolism. Correlation analysis of gut microbiota with uterine tissue metabolomics showed that changes in metabolic pathways might be affected by gut microbiota, such as Enterorhabdus in mouse endometritis. The above results indicated that the anti-inflammatory mechanism of IFN-τ might be reduction of the abundance of Enterorhabdus in the gut microbiota, affecting the expression level of important metabolites in uterine tissue and thus playing an anti-inflammatory role. IMPORTANCE The change in intestinal flora has been the focus of many disease studies in recent years, but the pathogenetic effect of interferon on endometritis is still unclear. The results of this study showed that IFN-τ alleviated the damage in mouse endometritis induced by E. coli and improved the endometrial tissue barrier. Its functional mechanism may be reduction of the abundance of Enterorhabdus in the intestinal microbiota, affecting the expression level of important metabolites in uterine tissue and thus playing an anti-inflammatory role.PMID:37067455 | DOI:10.1128/spectrum.00409-23