Integrative Molecular Phenotyping
INTEGRATIVE MOLECULAR
PHENOTYPING
WHEELOCK LABORATORY
DEPARTMENT OF MEDICAL
BIOCHEMISTRY AND BIOPHYSICS
WHEELOCK LABORATORY
DEPARTMENT OF MEDICAL
BIOCHEMISTRY AND BIOPHYSICS
WHEELOCK LABORATORY
DEPARTMENT OF MEDICAL
BIOCHEMISTRY AND BIOPHYSICS
WHEELOCK LABORATORY
DEPARTMENT OF MEDICAL
BIOCHEMISTRY AND BIOPHYSICS
WHEELOCK LABORATORY
DEPARTMENT OF MEDICAL
BIOCHEMISTRY AND BIOPHYSICS
WHEELOCK LABORATORY
WHEELOCK LABORATORY
DEPARTMENT OF MEDICAL
BIOCHEMISTRY AND BIOPHYSICS
WHEELOCK LABORATORY
DEPARTMENT OF MEDICAL
BIOCHEMISTRY AND BIOPHYSICS
WHEELOCK LABORATORY
DEPARTMENT OF MEDICAL
BIOCHEMISTRY AND BIOPHYSICS
WHEELOCK LABORATORY
DEPARTMENT OF MEDICAL
BIOCHEMISTRY AND BIOPHYSICS
WHEELOCK LABORATORY
DEPARTMENT OF MEDICAL
BIOCHEMISTRY AND BIOPHYSICS
WHEELOCK LABORATORY

PubMed

Changes in the gut microbiota and derived fecal metabolites may play a role in tacrolimus-induced diabetes in mice

Mon, 23/12/2024 - 12:00
Future Microbiol. 2024 Dec 22:1-10. doi: 10.1080/17460913.2024.2444761. Online ahead of print.ABSTRACTAIMS: A notable scarcity of research has focused on examining alterations in gut microbiota and its metabolites within tacrolimus (TAC)-induced diabetes models.METHODS: Tacrolimus-induced changes in glucose and lipid metabolism indices were analyzed through different routes of administration. The potential role of gut microbiota and its metabolites in TAC-induced diabetes was investigated using 16S rRNA sequencing and non-targeted metabolomics.RESULTS: After intraperitoneal(ip) and oral(po) administration of TAC, the α-diversity index of gut microbiota was significantly increased. The gut microbiota of the three groups of mice was significantly separated, and there were significant changes in composition and functional genes. Fecal metabolites changed significantly after TAC administration by different routes, and 53 metabolites (38 down-regulated and 15 up-regulated) were identified (CON vs. TACip). Similarly, 29 metabolites (8 down-regulated and 21 up-regulated) were identified (CON vs. TACpo). KEGG pathway analysis identified 4 and 13 significantly altered metabolic pathways, respectively. Correlation analysis suggested that microbiota and metabolites were involved in the pathogenesis of TAC-induced diabetes.CONCLUSION: This study investigated the alterations in gut microbiota and fecal metabolites in TAC-induced diabetic mice and evaluated the correlation between these changes. These findings provide valuable insights into potential biomarkers in the development of TAC-induced diabetes.PMID:39711145 | DOI:10.1080/17460913.2024.2444761

Spatial proteomics toward cellular resolution

Mon, 23/12/2024 - 12:00
Expert Rev Proteomics. 2024 Dec 22. doi: 10.1080/14789450.2024.2445809. Online ahead of print.ABSTRACTINTRODUCTION: Spatial biology is an emerging interdisciplinary field facilitating biological discoveries through the use of spatial omics technologies. Recent advancements in spatial transcriptomics, spatial genomics (e.g. genetic mutations and epigenetic marks), multiplexed immunofluorescence, and spatial metabolomics/lipidomics has enabled high-resolution spatial profiling of gene expression, genetic variation, protein expression, and metabolites/lipids profiles in tissue. These developments contribute to a deeper understanding of the spatial organization within tissue microenvironments at the molecular level.AREAS COVERED: This report provides an overview of the untargeted, bottom-up mass spectrometry (MS)-based spatial proteomics workflow. It highlights recent progress in tissue dissection, sample processing, bioinformatics, and liquid chromatography (LC)-MS technologies that are advancing spatial proteomics toward cellular resolution.EXPERT OPINION: The field of untargeted MS-based spatial proteomics is rapidly evolving and holds great promise. To fully realize the potential of spatial proteomics, it is critical to advance data analysis and develop automated and intelligent tissue dissection at the cellular or subcellular level, along with high-throughput LC-MS analyses of thousands of samples. Achieving these goals will necessitate significant advancements in tissue dissection technologies, LC-MS instrumentation, and computational tools.PMID:39710940 | DOI:10.1080/14789450.2024.2445809

Ghost Peaks of Aromatic Metabolites Induced by Corona Discharge Artifacts in LC-ESI-MS/MS

Mon, 23/12/2024 - 12:00
J Mass Spectrom. 2025 Jan;60(1):e5102. doi: 10.1002/jms.5102.ABSTRACTLC-ESI-MS/MS is a preferred method for detecting and identifying metabolites, including those that are unpredictable from the genome, especially in basal metazoans like Cnidaria, which diverged earlier than bilaterians and whose metabolism is poorly understood. However, the unexpected appearance of a "ghost peak" for dopamine, which exhibited the same m/z value and MS/MS product ion spectrum during an analysis of Nematostella vectensis, a model cnidarian, complicated its accurate identification. Understanding the mechanism by which "ghost peaks" appear is crucial to accurately identify the monoamine repertoire in early animals so as to avoid misassignments. Verification experiments showed that in-source oxidation of tyramine, which produced an intense signal, was responsible for this "ghost peak." This artifact commonly occurs among aromatic compounds with high signal intensities and appears at the same m/z as their respective in vivo oxidized metabolites. In metabolomics, spectra contain diverse signals from complex biological mixtures, making it difficult to recognize artifact peaks. To prevent misassignments, despite +16 Da differences, adequate chromatographic separation of metabolites from their respective in vivo oxidation precursors is necessary. Whereas both electrolysis and gas-phase corona discharge can cause in-source oxidation in ESI, corona discharge proved to be the dominant factor. Additionally, the presence of multiple oxygen atom sources was suggested by the voltage-dependent mass shift of +16 Da to +18 Da of the "ghost peak" when using 18O-labeled water as a solvent. Accurate metabolite identification using LC-ESI-MS/MS requires accounting for in-source products that can mimic in vivo products.PMID:39710888 | DOI:10.1002/jms.5102

International Symposium on Ruminant Physiology: Maternal nutrient supply: Impacts on physiological and whole animal outcomes in offspring

Sun, 22/12/2024 - 12:00
J Dairy Sci. 2024 Dec 20:S0022-0302(24)01424-3. doi: 10.3168/jds.2024-25788. Online ahead of print.ABSTRACTDemands for animal products are projected to increase in the future, and animal production is key to agricultural sustainability and food security; consequently, enhancing ruminant livestock production efficiencies in sustainable ways is a major goal for the livestock industry. Developmental programming is the concept that various stressors, including compromised maternal nutrition during critical developmental windows will result in both short- and long-term changes in the offspring. Ruminant models of developmental programming indicate that compromised maternal nutrition, including global under and over-nutrition, macronutrients, and specific micronutrients, including amino acids (Met and Arg), vitamins (folate, B12, and choline), and minerals (sulfur, cobalt, and selenium) can alter offspring outcomes. Data also suggest that maternal histotrophic composition, placental function, and likely fetal nutrient supply are altered by compromised maternal nutrition. Likewise, in offspring, visceral organ mass and function, metabolism, growth, and reproduction are affected. Findings from multi-omics approaches demonstrate that compromised maternal nutrition alters transcript abundance, metabolomic profiles, and multiple metabolic pathways. The underlying mechanisms of developmental programming are driven by epigenetic events, which depend on one-carbon metabolism and micronutrient supply. Current findings indicate that developmental programming in ruminants is real, that maternal nutrition can be a major driver of developmental programming, and that genomic and metabolomic changes in offspring are modulated by altered maternal nutrition during critical windows of development. Research needs in the area of developmental programming in ruminants include: enhanced understanding of the underlying mechanisms, practical relevance to production systems, impacts on short- and long-term animal health including longevity, interrelationships between maternal and paternal influences, intergenerational impacts, and interrelationships with the host microbiome. Additionally, strategic supplementation and precision nutrition approaches should be developed to foster the positive and mitigate the negative aspects of developmental programming to improve the efficiency and sustainability of ruminant livestock production systems.PMID:39710263 | DOI:10.3168/jds.2024-25788

"Assembly Theory" in Life Origin Models: A Critical Review

Sun, 22/12/2024 - 12:00
Biosystems. 2024 Dec 20:105378. doi: 10.1016/j.biosystems.2024.105378. Online ahead of print.ABSTRACTAny homeostatic protometabolism would have required orchestration of disparate biochemical pathways into integrated circuits. Extraordinarily specific molecular assemblies were also required at the right time and place. Assembly Theory conflated with its cousins-Complexity Theory, Chaos theory, Quantum Mechanics, Irreversible Nonequilibrium Thermodynamics and Molecular Evolution theory- collectively have great naturalistic appeal in hopes of their providing the needed exquisite steering and controls. They collectively offer the best hope of circumventing the need for active selection required to formally orchestrate bona fide formal organization (as opposed to the mere self-ordering of chaos theory) (Abel and Trevors, 2006b). This paper focuses specifically on AT's contribution to naturalistic life-origin models.PMID:39710183 | DOI:10.1016/j.biosystems.2024.105378

Effects of seasonal climates and MIPS1 mutations on soybean germination through multi-omics analysis

Sun, 22/12/2024 - 12:00
BMC Plant Biol. 2024 Dec 23;24(1):1231. doi: 10.1186/s12870-024-05957-x.ABSTRACTThis study delves into the combined effects of seasonal climate variations and MIPS1 gene mutations on the germination rates of soybean cultivars TW-1 and TW75. Through comprehensive metabolomic and transcriptomic analyses, we identified key KEGG pathways significantly affected by these factors, including starch and sucrose metabolism, lipid metabolism, and amino acid biosynthesis. These pathways were notably disrupted during the spring, leading to an imbalance in metabolic reserves critical for seedling development. Additionally, MIPS1 gene mutations further altered these pathways, exacerbating the metabolic disturbances. Our results underscore the intricate network of environmental and genetic interactions influencing soybean seed vigor and underscore the importance of understanding these pathways to enhance agricultural resilience and seed quality in fluctuating climates.PMID:39710639 | DOI:10.1186/s12870-024-05957-x

Maternal probiotic exposure enhances CD8 T cell protective neonatal immunity and modulates offspring metabolome to control influenza virus infection

Sun, 22/12/2024 - 12:00
Gut Microbes. 2025 Dec;17(1):2442526. doi: 10.1080/19490976.2024.2442526. Epub 2024 Dec 22.ABSTRACTMaternal gut microbiota composition contributes to the status of the neonatal immune system and could influence the early life higher susceptibility to viral respiratory infections. Using a novel protocol of murine maternal probiotic supplementation, we report that perinatal exposure to Lacticaseibacillus rhamnosus (L.rh) or Bifidobacterium animalis subsp. lactis (B.lac) increases the influenza A/PR8 virus (IAV) clearance in neonates. Following either supplementation, type 1 conventional dendritic cells (cDC1) were amplified in the lymph nodes leading to an enhanced IAV antigen-experienced IFN-γ producing effector CD8 T cells in neonates and IAV-specific resident memory CD8 T cells in adulthood. This was compatible with a higher protection of the offspring upon a secondary infection. Interestingly, only mice born to L.rh supplemented mothers further displayed an increased activation of IFN-γ producing virtual memory CD8 T cells and a production of IL-10 by CD4 and CD8 T cells that could explain a better control of the lung damages upon infection. In the offspring and the mothers, no disturbance of the gut microbiota was observed but, as analyzed through an untargeted metabolomic approach, both exposures modified neonatal plasma metabolites. Among them, we further demonstrated that genistein and 3-(3-hydroxyphenyl)propionic acid recapitulate viral clearance or cDC1 activation in neonates exposed to IAV. We conclude that maternal L.rh or B.lac supplementation confers the neonates specific metabolomic modulations with a better CD8 T cell-mediated immune protection against IAV infection.PMID:39710590 | DOI:10.1080/19490976.2024.2442526

Multifunctional dietary approach reduces intestinal inflammation in relation with changes in gut microbiota composition in subjects at cardiometabolic risk: the SINFONI project

Sun, 22/12/2024 - 12:00
Gut Microbes. 2025 Dec;17(1):2438823. doi: 10.1080/19490976.2024.2438823. Epub 2024 Dec 22.ABSTRACTThe development of cardiometabolic (CM) diseases is associated with chronic low-grade inflammation, partly linked to alterations of the gut microbiota (GM) and reduced intestinal integrity. The SINFONI project investigates a multifunctional (MF) nutritional strategy's impact combining different bioactive compounds on inflammation, GM modulation and CM profile. In this randomized crossover-controlled study, 30 subjects at CM-risk consumed MF cereal-products, enriched with polyphenols, fibers, slowly-digestible starch, omega-3 fatty acids or Control cereal-products (without bioactive compounds) for 2 months. Metabolic endotoxemia (lipopolysaccharide (LPS), lipopolysaccharide-binding protein over soluble cluster of differentiation-14 (LBP/sCD14), systemic inflammation and cardiovascular risk markers, intestinal inflammation, CM profile and response to a one-week fructose supplementation, were assessed at fasting and post mixed-meal. GM composition and metabolomic analysis were conducted. Mixed linear models were employed, integrating time (pre/post), treatment (MF/control), and sequence/period. Compared to control, MF intervention reduced intestinal inflammation (fecal calprotectin, p = 0.007) and endotoxemia (fasting LPS, p < 0.05), without alteration of systemic inflammation. MF decreased serum branched-chain amino acids compared to control (p < 0.05) and increased B.ovatus, B.uniformis, A.butyriciproducens and unclassified Christensenellaceae.CAG-74 (p < 0.05). CM markers were unchanged. A 2-month dietary intervention combining multiple bioactive compounds improved intestinal inflammation and induced GM modulation. Such strategy appears as an effective strategy to target low-grade inflammation through multi-target approach.PMID:39710576 | DOI:10.1080/19490976.2024.2438823

Differential impact of impaired steryl ester biosynthesis on the metabolome of tomato fruits and seeds

Sun, 22/12/2024 - 12:00
Physiol Plant. 2025 Jan-Feb;177(1):e70022. doi: 10.1111/ppl.70022.ABSTRACTSteryl esters (SE) are a storage pool of sterols that accumulates in cytoplasmic lipid droplets and helps to maintain plasma membrane sterol homeostasis throughout plant growth and development. Ester formation in plant SE is catalyzed by phospholipid:sterol acyltransferase (PSAT) and acyl-CoA:sterol acyltransferase (ASAT), which transfer long-chain fatty acid groups to free sterols from phospholipids and acyl-CoA, respectively. Comparative mass spectrometry-based metabolomic analysis between ripe fruits and seeds of a tomato (Solanum lycopersicum cv Micro-Tom) mutant lacking functional PSAT and ASAT enzymes (slasat1xslpsat1) shows that disruption of SE biosynthesis has a differential impact on the metabolome of these organs, including changes in the composition of free and glycosylated sterols. Significant perturbations were observed in the fruit lipidome in contrast to the mild effect detected in the lipidome of seeds. A contrasting response was also observed in phenylpropanoid metabolism, which is down-regulated in fruits and appears to be stimulated in seeds. Comparison of global metabolic changes using volcano plot analysis suggests that disruption of SE biosynthesis favours a general state of metabolic activation that is more evident in seeds than fruits. Interestingly, there is an induction of autophagy in both tissues, which may contribute along with other metabolic changes to the phenotypes of early seed germination and enhanced fruit tolerance to Botrytis cinerea displayed by the slasat1xslpsat1 mutant. The results of this study reveal unreported connections between SE metabolism and the metabolic status of plant cells and lay the basis for further studies aimed at elucidating the mechanisms underlying the observed effects.PMID:39710490 | DOI:10.1111/ppl.70022

Microplastics Aggravate the Adverse Effects of Methylmercury than Inorganic Mercury on Zebrafish (Danio rerio)

Sun, 22/12/2024 - 12:00
Environ Pollut. 2024 Dec 20:125559. doi: 10.1016/j.envpol.2024.125559. Online ahead of print.ABSTRACTThe potential health risks of microplastics (MPs) and their combined exposure with heavy metals such as mercury (Hg) in aquatic environment are increasingly concerned recently. In this work, zebrafish embryos were exposed to different levels of polystyrene microplastics (PS-MPs, ∼0.1 μm) coupled with Hg(II) or/and MeHg at 20 μg/L, to investigate the tissue biodistribution and accumulation of PS-MPs and Hg species, and their interaction, as well as embryo toxicity, oxidative stress and metabolic profiles. With zebrafish embryo development, PS-MPs were ingested and then primarily translocated to yolk sac, liver, and intestinal tissues, further acted as a significant vector for improving the bioaccumulation of MeHg vs. Hg(II). Whatever single or combined exposure of PS-MPs and Hg species, embryo disorders, such as delayed hatching, developmental abnormalities, and motor behavioral, and increased oxidative stress indications were obviously found. Herein, PS-MPs + MeHg aggravated oxidative stress compared with MeHg alone, which might been relevant to the highly accumulation of Hg level in zebrafish larvae induced by PS-MPs. Non-targeted metabolomics results proved PS-MPs involvement disturbed lipid metabolism, amino acid metabolism, and energy metabolism compared with alone Hg(II) or MeHg exposure, of which excessive energy metabolism by activating the glycolysis process was found in PS-MPs + MeHg treatment. This work reveals the enhancement efficacy of PS-MPs on MeHg induced toxicity and adverse stress, further proving the differentiated effect of elemental chemical forms with microplastics. In the future, elemental species must be considered for the combined toxicity evaluation and ecological risk assessments of microplastics and heavy metals.PMID:39710179 | DOI:10.1016/j.envpol.2024.125559

Gut microbiome and obesity in late adolescence: a case-control study in "Children of 1997" birth cohort

Sun, 22/12/2024 - 12:00
Ann Epidemiol. 2024 Dec 20:S1047-2797(24)00280-1. doi: 10.1016/j.annepidem.2024.12.009. Online ahead of print.ABSTRACTPURPOSE: Although the gut microbiome is important in human health, its relation to adolescent obesity remains unclear. Here we assessed the associations of the gut microbiome with adolescent obesity in a case-control study.METHODS: In the "Children of 1997" birth cohort, participants with and without obesity at ~17.4 years were 1:1 matched on sex, physical activity, parental education and occupation (n=312). Fecal gut microbiome composition and pathways were assessed via shotgun metagenomic sequencing. The association of microbiota species with obesity was evaluated using conditional logistic regression. We explored the association of the obesity-relevant species with adolescent metabolomics using multivariable linear regression, and causal relationships with type 2 diabetes using Mendelian randomization analysis.RESULTS: Gut microbiota in the adolescents with obesity exhibited lower richness (p=0.031) and evenness (p=0.014) compared to controls. Beta diversity revealed differences in the microbiome composition in two groups (p=0.034). Lower relative abundance of Clostridium spiroforme, Clostridium phoceensis and Bacteroides uniformis were associated with higher obesity risk (q<0.15). Lower Bacteroides uniformis was associated with higher branched-chain amino acid, potentially contributing to higher type 2 diabetes risk.CONCLUSION: Adolescents with obesity had a distinct gut microbiota profile compared to the controls, possibly linked to metabolic pertubation and related diseases.PMID:39710013 | DOI:10.1016/j.annepidem.2024.12.009

Investigation of the Potential Material Basis and Mechanism of Astragali Radix Against Adriamycin-Induced Nephropathy Model Rat by (1)H NMR and MS-Based Untargeted Metabolomics Analysis

Sun, 22/12/2024 - 12:00
Biomed Chromatogr. 2025 Jan;39(1):e6054. doi: 10.1002/bmc.6054.ABSTRACTAstragali Radix (AR) is one of the monarch drugs of Fangji Huangqi decoction and has the effects of inducing diuresis to alleviate edema, tonifying and strengthening the body. However, there is a paucity of research regarding the effective fraction and the underlying metabolic mechanism of AR on nephrotic syndrome (NS). This work aims to elucidate the potential mechanisms of AR treating NS, as well as to identify effective part and components. Firstly, body weight, kidney index, 24-h urea protein, and biochemical parameters were used to confirm the kidney injury. The most effective part of AR was determined based on the indicators above. Then, 1H NMR, UHPLC-QTOF/MS, and GC-MS-based metabolomic approaches were used to investigate differential metabolites closely associated with the effective part against NS. A "C-T-P-D" network (a network diagram of "TCM prescription-herbs-components-targets-metabolites-pathways-disease") was constructed by intersecting the targets of differential metabolites with those of AR treating NS. The efficacy indicators determined the n-butanol part of AR as the best effective part. Multiplatform metabolomics and network pharmacology study indicated that the potential mechanism for treating NS may be related to targets (MIF, SRC, and GBA) and metabolic pathways (citrate cycle, glyoxylate and dicarboxylate metabolism, alanine, aspartate and glutamate metabolism, and glycolysis/gluconeogenesis).PMID:39709944 | DOI:10.1002/bmc.6054

Positive impact of DPP-4 or SGLT2 inhibitors on mild cognitive impairment in type 2 diabetes patients on metformin therapy: A metabolomic mechanistic insight

Sun, 22/12/2024 - 12:00
Biomed Pharmacother. 2024 Dec 21;182:117771. doi: 10.1016/j.biopha.2024.117771. Online ahead of print.ABSTRACTMild cognitive impairment is increasingly recognized as a complication of type 2 diabetes (T2D). Although currently no disease-modifying treatments for cognitive disorders exist, interest surged in potential neuroprotective effects of newer anti-diabetic drugs. This study investigates the impact of newer anti-diabetic drug classes, dipeptidyl peptidase-4 (DPP-4i) and sodium-glucose cotransporter-2 inhibitors (SGLT2i) - on cognitive decline in T2D patients on metformin therapy. A prospective observational cohort study was conducted, with a follow-up duration of 6 months. The study compared the cognitive performance of T2D patients on metformin monotherapy to those on a combination of metformin with DPP-4i or SGLT2i, using the Montreal Cognitive Assessment Battery. A group of healthy volunteers served as a reference. At baseline, patients receiving combination therapy had a cognitive performance comparable to that of healthy volunteers, while those on metformin monotherapy scored lower. These differences persisted for patients who completed the follow-up, though there was no change within group. Baseline differences were independent of glycemic control, blood lipids, renal function, and serum inflammatory markers. Comprehensive metabolomics and lipidomics revealed that T2D patients on metformin monotherapy exhibited enriched purine, glutathione and sphingolipid metabolism, with alterations in xanthine, L-pyroglutamic acid, and several sphingomyelins. These changes suggest increased oxidative stress in T2D, mitigated in the combination therapy group, as evidenced by total serum antioxidant capacity. As such, we conclude that the combination of DPP-4i or SGLT2i with metformin positively impacts cognitive function in T2D patients by modulating metabolic pathways rather than improving glycemic control, peripheral diabetic complications, or systemic inflammation.PMID:39709941 | DOI:10.1016/j.biopha.2024.117771

Polysaccharides from Yupingfeng granules ameliorated cyclophosphamide-induced immune injury by protecting intestinal barrier

Sun, 22/12/2024 - 12:00
Int Immunopharmacol. 2024 Dec 21;146:113866. doi: 10.1016/j.intimp.2024.113866. Online ahead of print.ABSTRACTImmune injury is the main side effect caused by cyclophosphamide and the disruption of the intestinal barrier may be an important cause. Yupingfeng granules have been reported to have immunomodulatory effects and polysaccharides are important components of them. This study aimed to investigate the ameliorative effect of polysaccharides from Yupingfeng granules (YPFP) on cyclophosphamide induced immune injury and reveal their potential mechanisms based on its protective effect on the intestine. YPFP were isolated and preliminarily characterized. Pharmacodynamic evaluation revealed that YPFP treatment could effectively mitigate lesions of immune organs, ameliorate white blood cells and downregulate IL-10 level. Further, the protective effect of intestinal barrier on the basis of intestinal tight junctions, MUC-2, microflora, endogenous metabolites, pathways and immune cells was discussed to outline mechanisms. The results showed that YPFP repaired the integrity of intestinal epithelium, enhanced the abundance of Muribaculaceae_unclassified, Bacteroide and Muribaculum, downgraded the abundance of Lachnospiraceae_NK4A136_group, improved the excretion of lipids and bile acids especially 3-oxo-LCA, increased the content of SCFAs in feces and inhibited the expression of key proteins of PI3K-AKT and MAPK-JUN pathways. More importantly, Th17 and Treg balance was remodeled after YPFP administration, which might be related to certain differential metabolites and pathways enriched by metabolomics. This study provides a rich understanding of YPFP and lays a foundation for further development of Yupingfeng granules. It was shown for the first time that the immunomodulatory effect of YPFP might be involved in multiple mechanisms of intestinal homeostasis. YPFP could be regarded as an immunomodulator to alleviate immune damage caused by cyclophosphamide.PMID:39709910 | DOI:10.1016/j.intimp.2024.113866

Metagenomics and metabolomics to investigate the effect of Amygdalus mongolica oil on intestinal microbiota and serum metabolites in rats

Sun, 22/12/2024 - 12:00
Phytomedicine. 2024 Dec 17;136:156335. doi: 10.1016/j.phymed.2024.156335. Online ahead of print.ABSTRACTBACKGROUND: Renal fibrosis (RF) is an inevitable consequence of multiple manifestations of progressive chronic kidney diseases (CKDs). Mechanism of Amygdalus mongolica (Maxim.) in the treatment of RF needs further investigation.PURPOSE: The study further investigated the potential mechanism of A. mongolica in the treatment of RF.METHODS: A rat model of RF was induced by unilateral ureteral obstruction (UUO), followed by treatment with varying dosages of A. mongolica oil for 4 weeks. Body weight was measured weekly. We detected serum levels of interleukin (IL)-6, IL-1β, type Ⅲ procollagen (Col-Ⅲ), type IV collagen (Col-Ⅳ), laminin (LN), hyaluronidase (HA), and tissue levels of albumin (ALB), blood urea nitrogen (BUN), creatinine (Cre), superoxide dismutase (SOD), malondialdehyde (MDA), and hydroxyproline (HYP). Shotgun metagenomics analyzed the composition of the intestinal microbiota. High-performance liquid chromatography coupled with a quadrupole-exactive mass spectrometer (HPLC-Q-Exactive-MS) monitored changes in metabolite levels in serum and gut. Multiple reaction monitoring-mass spectrometry (MRM-MS) determined the levels of amino acids in serum.RESULTS: A. mongolica oil significantly alleviated indicators related to RF (p < 0.05). A. mongolica oil reduced the ratio of Firmicutes to Bacteroidetes and restored the balance of intestinal microbiota in rats with RF. A. mongolica oil modulated levels of metabolites in gut content and serum. It regulated 11 metabolic pathways including arachidonic acid metabolism. Targeted metabolomics of amino acids showed that 17 amino acids were significantly changed by A. mongolica oil, including L-glycine, L-serine and L-glutamine.CONCLUSION: A. mongolica oil regulates intestinal microbiota and metabolites, restoring amino acid metabolism to treat RF.PMID:39709798 | DOI:10.1016/j.phymed.2024.156335

Model organisms for investigating the functional involvement of NRF2 in non-communicable diseases

Sun, 22/12/2024 - 12:00
Redox Biol. 2024 Dec 16;79:103464. doi: 10.1016/j.redox.2024.103464. Online ahead of print.ABSTRACTNon-communicable chronic diseases (NCDs) are most commonly characterized by age-related loss of homeostasis and/or by cumulative exposures to environmental factors, which lead to low-grade sustained generation of reactive oxygen species (ROS), chronic inflammation and metabolic imbalance. Nuclear factor erythroid 2-like 2 (NRF2) is a basic leucine-zipper transcription factor that regulates the cellular redox homeostasis. NRF2 controls the expression of more than 250 human genes that share in their regulatory regions a cis-acting enhancer termed the antioxidant response element (ARE). The products of these genes participate in numerous functions including biotransformation and redox homeostasis, lipid and iron metabolism, inflammation, proteostasis, as well as mitochondrial dynamics and energetics. Thus, it is possible that a single pharmacological NRF2 modulator might mitigate the effect of the main hallmarks of NCDs, including oxidative, proteostatic, inflammatory and/or metabolic stress. Research on model organisms has provided tremendous knowledge of the molecular mechanisms by which NRF2 affects NCDs pathogenesis. This review is a comprehensive summary of the most commonly used model organisms of NCDs in which NRF2 has been genetically or pharmacologically modulated, paving the way for drug development to combat NCDs. We discuss the validity and use of these models and identify future challenges.PMID:39709790 | DOI:10.1016/j.redox.2024.103464

Forensic metabolomics: Tracing cyanide-induced metabolic changes in fatalities

Sun, 22/12/2024 - 12:00
Forensic Sci Int. 2024 Dec 17;367:112350. doi: 10.1016/j.forsciint.2024.112350. Online ahead of print.ABSTRACTAccurate detection of cyanide exposure is crucial, particularly in forensic science. However, cyanide's high volatility and potential biochemical conversions in biological samples pose challenges for direct detection, complicating the determination of cause of death. Identifying alternative cyanide metabolites as markers may mitigate false negatives and positives, extending the detection window in poisoning cases. This study aimed to evaluate metabolic changes induced by cyanide exposure in forensic cases using a multi-platform approach, including metabolomics and lipidomics analyses via liquid and gas chromatography coupled with high-resolution mass spectrometry. Results demonstrated clear discrimination between cyanide-exposed and control groups through OPLS-DA models. A total of 92 altered metabolites were identified in cyanide-exposed individuals compared to controls. Significant changes in metabolites primarily included glycerophospholipids (30.7 %), glycerolipids (14 %), fatty acyls (12.9 %), sphingolipids (8.0 %), amino acids and analogs (8.0 %), among others. Cyanide intoxication disrupted multiple metabolic pathways, including mitochondrial β-oxidation, acylcarnitine accumulation, a shift towards gluconeogenesis in amino acid metabolism, and ammonia homeostasis disturbance, affecting both ammonia recycling and the urea cycle. These pathways are essential for cellular energy production. The altered metabolic profiles provide insight into cyanide poisoning pathways, potentially aiding the development of new forensic diagnostic strategies. The area under the receiver operating characteristic curve was used to assess each model's predictive value. Findings suggest that metabolites such as phosphate and 3-hydroxybutyric acid could serve as diagnostic biomarkers in lethal cyanide poisoning cases. Future studies must evaluate these potential biomarkers' effectiveness in different fatal victim cohorts and validate the suggested panel through a targeted approach.PMID:39709742 | DOI:10.1016/j.forsciint.2024.112350

Microbial diversity and metabolomics analysis of colon contents exposed to cadmium and polystyrene microplastics

Sun, 22/12/2024 - 12:00
Ecotoxicol Environ Saf. 2024 Dec 21;290:117585. doi: 10.1016/j.ecoenv.2024.117585. Online ahead of print.ABSTRACTCadmium and microplastics, common pollutants, can accumulate in the body, impacting the intestinal barrier and harming livestock breeding. In order to explore the damage mechanism of cadmium and cadmium combined microplastic on the colon of mice, 60 mice were divided into three groups: The control group (0.2 mL of saline), cadmium group (Cd group, 0.2 mL of 4.8 mg/kg/d CdCl2) and mixed group (Mix group, 0.2 mL of mixed solution containing 4.8 mg/kg/d CdCl2 and 10.0 mg/d MPs) were fed for 42 d. The changes of colon histopathology were observed, and the changes of microbial diversity and metabolomics of colon contents were analyzed. Pathological sections of the colon showed abnormal mucosal hyperemia with mixed exposure compared to cadmium exposure. Microbial diversity analysis showed increased abundances of Enterococcus, Adlercreutzia, and Bifidobacterium in the Cd and Mix groups, with Dubosiella being the most significantly increased. Metabolomic analysis indicated significant differences in nucleotide and purine metabolism between the Cd and control groups, and in linoleic acid and bile acid metabolism between the Mix and control groups. The ABC transporter metabolites increased with Cd exposure, while the PPAR pathway metabolites were enriched with MPs exposure. Correlation analysis highlighted several key findings: Pasteurella exhibited a notably negative association with pantothenate. Conversely, Enterococcus demonstrated a significant positive link with palmitoylcarnitine. Additionally, both Adlercreutzia and norank_f_Eggerthellaceae showed a positive correlation with azelaic acid. These findings suggest that Cd and MPs disrupt intestinal microbiota and metabolic pathways, providing insights into potential treatments for such exposures.PMID:39709704 | DOI:10.1016/j.ecoenv.2024.117585

Metabolic Profile of Gut Microbiota and Levels of Trefoil Factors in Adults with Different Metabolic Phenotypes of Obesity

Sun, 22/12/2024 - 12:00
Mol Biol (Mosk). 2024 Jul-Aug;58(4):638-654.ABSTRACTObesity is associated with changes in the gut microbiota, as well as with increased permeability of the intestinal wall. In 130 non-obese volunteers, 57 patients with metabolically healthy obesity (MHO), and 76 patients with metabolically unhealthy obesity (MUHO), bacterial DNA was isolated from stool samples, and the 16S rRNA gene was sequenced. The metabolic profile of the microbiota predicted by PICRUSt2 (https://huttenhower.sph.harvard.edu/picrust/) was more altered in patients with MUHO than MHO. Obesity, especially MUHO, was accompanied by an increase in the ability of the gut microbiota to degrade energy substrates, produce energy through oxidative phosphorylation, synthesize water-soluble vitamins (B1, B6, B7), nucleotides, heme, aromatic amino acids, and protective structural components of cells. Such changes may be a consequence of the microbiota adaptation to the MUHO-specific conditions. Thus, a vicious circle is formed, when MUHO promotes the depletion of the gut microbiome, and further degeneration of the latter contributes to the pathogenesis of metabolic disorders. The concentration of the trefoil factor family (TFF) in the serum of the participants was also determined. In MHO and MUHO patients, the TFF2 and TFF3 levels were increased, but we did not find significant associations of these changes with the metabolic profile of the gut microbiota.PMID:39709568

Faecal metaproteomics analysis reveals a high cardiovascular risk profile across healthy individuals and heart failure patients

Sun, 22/12/2024 - 12:00
Gut Microbes. 2025 Dec;17(1):2441356. doi: 10.1080/19490976.2024.2441356. Epub 2024 Dec 22.ABSTRACTThe gut microbiota is a crucial link between diet and cardiovascular disease (CVD). Using fecal metaproteomics, a method that concurrently captures human gut and microbiome proteins, we determined the crosstalk between gut microbiome, diet, gut health, and CVD. Traditional CVD risk factors (age, BMI, sex, blood pressure) explained < 10% of the proteome variance. However, unsupervised human protein-based clustering analysis revealed two distinct CVD risk clusters (low-risk and high-risk) with different blood pressure (by 9 mmHg) and sex-dependent dietary potassium and fiber intake. In the human proteome, the low-risk group had lower angiotensin-converting enzymes, inflammatory proteins associated with neutrophil extracellular trap formation and auto-immune diseases. In the microbial proteome, the low-risk group had higher expression of phosphate acetyltransferase that produces SCFAs, particularly in fiber-fermenting bacteria. This model identified severity across phenotypes in heart failure patients and long-term risk of cardiovascular events in a large population-based cohort. These findings underscore multifactorial gut-to-host mechanisms that may underlie risk factors for CVD.PMID:39709554 | DOI:10.1080/19490976.2024.2441356

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