PubMed

J Transl Med. 2024 Dec 24;22(1):1146. doi: 10.1186/s12967-024-05856-7.ABSTRACTBACKGROUND: Diabetic retinopathy (DR) is the most important complication of Type 2 Diabetes (T2D) in eyes. Despite its prevalence, the early detection and management of DR continue to pose considerable challenges. Our research aims to elucidate potent drug targets that could facilitate the identification of DR and propel advancements in its therapeutic strategies.METHODS: A broad multi-omics exploration of DR was presented to decipher the drug targets of DR and proliferative diabetic retinopathy (PDR). Transcriptome-Wide Association Studies (TWAS), fine-mapping and conditional analysis were applied to unearth potential tissue-specific gene associations with DR. Summary Data-based Mendelian Randomization (SMR) provided secondary analysis of high confidence genes. Cis-instrument of druggable genes were extracted from the eQTLGen Consortium and PsychENCODE, facilitating drug-target MR supported by colocalization analysis. Phenome-Wide Association Studies (PheWAS) was conducted on the high confidence genes. Metabolomic and immunomic MR-profiling further augmented our research as complement.RESULTS: TWAS identified multiple robust genetic loci in both DR and PDR (WFS1, RPS26, and SRPK1) through genetic associations across different tissues. Meanwhile, we have delineated both the commonalities and discrepancies between DR and PDR at the transcriptomic level, represented by DCLRE1B as the hub gene that DR progressed into PDR. SMR revealed 92 key DR-related genes and 55 PDR-related genes. HLA-DQ family genes have a frequent occurrence, while RPS26, WFS1 and SRPK1 were validated as the genetic network's linchpins. Drug-target MR casted ERBB3 and SRPK1 as candidate effector genes for DR and PDR susceptibility. In addition, metabolomics and immunomics analyses also revealed multifaceted pathogenic factors for DR.CONCLUSIONS: Our research offers targeted therapeutic insights for early-stage DR and facilitates multi-omic comparisons of it and PDR.PMID:39719581 | DOI:10.1186/s12967-024-05856-7

Cell Mol Life Sci. 2024 Dec 24;82(1):13. doi: 10.1007/s00018-024-05501-y.ABSTRACTImbalances in gut microbiota and their metabolites have been implicated in osteoporotic disorders. Trimethylamine-n-oxide (TMAO), a metabolite of L-carnitine produced by gut microorganisms and flavin-containing monooxygenase-3, is known to accelerate tissue metabolism and remodeling; however, its role in bone loss remained unexplored. This study investigates the relationship between gut microbiota dysbiosis, TMAO production, and osteoporosis development. We further demonstrate that the loss of beneficial gut microbiota is associated with the development of murine osteoporosis and alterations in the serum metabolome, particularly affecting L-carnitine metabolism. TMAO emerges as a functional metabolite detrimental to bone homeostasis. Notably, transplantation of mouse gut microbiota counteracts obesity- or estrogen deficiency-induced TMAO overproduction and mitigates key features of osteoporosis. Mechanistically, excessive TMAO intake augments bone mass loss by inhibiting bone mineral acquisition and osteogenic differentiation. TMAO activates the PERK and ATF4-dependent disruption of endoplasmic reticulum autophagy and suppresses the folding of ATF5, hindering mitochondrial unfolding protein response (UPRmt) in osteoblasts. Importantly, UPRmt activation by nicotinamide riboside mitigates TMAO-induced inhibition of mineralized matrix biosynthesis by preserving mitochondrial oxidative phosphorylation and mitophagy. Collectively, our findings revealed that gut microbiota dysbiosis leads to TMAO overproduction, impairing ER homeostasis and UPRmt, thereby aggravating osteoblast dysfunction and development of osteoporosis. Our study elucidates the catabolic role of gut microflora-derived TMAO in bone integrity and highlights the therapeutic potential of healthy donor gut microbiota transplantation to alter the progression of osteoporosis.PMID:39719538 | DOI:10.1007/s00018-024-05501-y

Transl Psychiatry. 2024 Dec 24;14(1):503. doi: 10.1038/s41398-024-03211-4.ABSTRACTEvidence suggests that complex interactions among the gut microbiome, metabolic abnormalities, and brain have important etiological and therapeutic implications in major depressive disorder (MDD). However, the influence of microbiome-gut-brain cross-talk on cognitive impairment in MDD remains poorly characterized. We performed serum metabolomic profiling on 104 patients with MDD and 77 healthy controls (HCs), and also performed fecal metagenomic sequencing on a subset of these individuals, including 79 MDD patients and 60 HCs. The findings were validated in a separate cohort that included 40 patients with MDD and 40 HCs using serum-targeted metabolomics. Abnormal bile acid metabolism was observed in patients with MDD, which is related to cognitive dysfunction. The following gut microbiota corresponded to changes in bile acid metabolism and enzyme activities involved in the bile acid metabolic pathway, including Lachnospiraceae (Blautia_massiliensis, Anaerostipes_hadrus, Dorea_formicigenerans, and Fusicatenibacter_saccharivorans), Ruminococcaceae (Ruminococcus_bromii, Flavonifractor_plautii, and Ruthenibacterium_lactatiformans), and Escherichia_coli. Furthermore, a combinatorial marker classifier that robustly differentiated patients with MDD from HCs was identified. In conclusion, this study provides insights into the gut-brain interactions in the cognitive phenotype of MDD, indicating a potential therapeutic strategy for MDD-associated cognitive impairment by targeting the gut microbiota and bile acid metabolism.PMID:39719433 | DOI:10.1038/s41398-024-03211-4

BMJ Open Ophthalmol. 2024 Dec 24;9(1):e001573. doi: 10.1136/bmjophth-2023-001573.ABSTRACTOBJECTIVE: Age-related macular degeneration (AMD) is one of the leading causes of irreversible visual impairment and blindness in the elderly. As AMD is a multifactorial disease, it is critical to explore useful biomarkers and pathological pathways underlying it. The purpose of this study is to summarise current metabolic profiles and further identify potential metabolic biomarkers and therapeutic targets in AMD, which could facilitate clinical diagnosis and treatment.METHODS AND ANALYSIS: Relevant metabolomics studies published before 10 December 2021 were generally reviewed from online resources by two investigators. Studies with sufficient information and data were included in this systematic review and repeatedly identified metabolites were extracted. Pathway and Kyoto Encyclopaedia of Genes and Genomes (KEGG) analyses were performed. The public Gene Expression Omnibus (GEO) database was used for coanalysis with differential metabolites to construct a pathway network via MetaboAnalyst V.5.0.RESULTS: 16 studies were included in our analysis. 24 metabolites were repeatedly detected and regarded as potential biomarkers for AMD. Pathway analysis implied a major role of phenylalanine, tyrosine and tryptophan pathways in AMD pathology. 11 KEGG pathways were enriched, meanwhile, 11 metabolic pathway clusters were identified by coanalysing the differential metabolites and gene profiles using the GEO database.CONCLUSION: In this study, we summarised 16 metabolomic studies on AMD, and 24 metabolites were identified as potential biofluid biomarkers. This provided novel insights into the pathogenic mechanisms underlying AMD. Further studies are warranted to validate and expand an effective pattern for AMD diagnosis and treatment.PMID:39719382 | DOI:10.1136/bmjophth-2023-001573

J Agric Food Chem. 2024 Dec 24. doi: 10.1021/acs.jafc.4c10753. Online ahead of print.ABSTRACTStropharia rugosoannulata, or wine-cap Stropharia, is a well-known edible mushroom cultivated globally. The pileipellis color is a crucial quality attribute of S. rugosoannulata, exhibiting significant variation throughout its developmental stages. However, the pigment types and regulatory mechanisms behind color variation remain unclear. The metabolome analysis found that the anthocyanin biosynthesis pathway was significantly enriched and anthocyanins accumulated steadily in fruiting bodies during three developmental stages. The pileipellis pigment was extracted, and HPLC-MS confirmed the presence of anthocyanins. Notably, significant differences in anthocyanin content were observed among the various colored varieties. Thus, anthocyanins contribute to the pileipellis color of S. rugosoannulata. Through further investigation, this study elucidated, for the first time, the relationship between the "SrNFYA-SrDRF2" regulatory module and anthocyanin accumulation. Combined multiomics assays and HPLC analysis revealed that auxin functions as a signaling molecule that regulates the accumulation of anthocyanins in the pileipellis. Subsequently, the hub gene of anthranilate synthase for auxin synthesis was identified as SrTRP1, and the transcription factor SrMYB1 was verified as a regulator of SrTRP1, influencing auxin accumulation. These findings provide a valuable resource for the targeted enhancement of the quality of S. rugosoannulata.PMID:39719358 | DOI:10.1021/acs.jafc.4c10753

Int J Biol Macromol. 2024 Dec 22:139113. doi: 10.1016/j.ijbiomac.2024.139113. Online ahead of print.ABSTRACTASPN-1, a novel glucan with a molecular weight of 33.31 kDa, was purified from Acanthopanax senticosus stems, characterized in structure, and evaluated for antitumor potential. The analysis of the structure of ASPN-1 revealed that it consisted of a backbone constructed from →4)-α-D-Glcp-(1 → glucosyls, branched at the O-3 position by an α-D-Glcp-(1 → residue and at the O-6 positions with α-D-Glcp-(1 → 6)-α-D-Glcp-(1 → and/or α-D-Glcp-(1 → residues. Surface morphological analysis revealed that ASPN-1 is an archetypal amorphous powder with an irregular network architecture composed of lamellar thin layers, filaments, and spherical particles. In vivo anti-tumor experiments indicated that ASPN-1 exerted inhibitory effects on CT26.WT mouse tumors by preserving immune function, elevating the production of IL-2, IFN-γ and TNF-α, and reducing production of TGF-β and IL-10. These findings indicated that ASPN-1, derived from A. senticosus, could potentially be used to treat colorectal carcinomas, acting through its immunomodulatory actions.PMID:39719239 | DOI:10.1016/j.ijbiomac.2024.139113

Amino Acids. 2024 Dec 24;57(1):3. doi: 10.1007/s00726-024-03433-2.ABSTRACTLittle is known about how blood free amino acids (FAAs) change in metabolic dysfunction-associated steatotic liver disease (MASLD). This study aims to identify the imbalance of FAAs in MASLD and explore its correction as a potential therapeutic target. We analyzed plasma FAAs data from 23,036 individuals with steatosis information from a biobank in Japan, and 310 patients with MASLD were enrolled. According to diagnostic criteria for steatotic liver disease (SLD) or cardiometabolic criteria (CC), we divided the subjects into five groups: MASLD, metabolic dysfunction and alcohol-associated liver disease (MetALD), CC-SLD-, CC + SLD-, and CC-SLD + . Twenty FAAs were compared among these groups and among MASLD patients with pathological information. Among the 20 FAAs, the levels of 16 FAAs increased in CC + SLD- according to the number of matches with CC items associated with insulin resistance (IR). Steatosis enhanced most of these changes but serine (Ser) and threonine (Thr) were unaffected. Glycine (Gly), Ser and Thr were significantly decreased in patients according to steatosis grade. We investigated the association between these FAAs imbalances and pathogenesis using MASLD mouse models. In mice fed a high-fat, fructose, and cholesterol (FFC) diet, metabolomics and RNA sequencing analyses indicated that abnormality in Gly, Ser, and Thr metabolism in the liver was associated with mitochondrial dysfunction and enhanced glycolysis via pyruvate. High-Gly, Ser, and Thr diet ameliorated pathogenesis of MASLD in leptin-deficient mice. Most FAAs increase due to cardiometabolic abnormalities, particularly IR. However, interventions targeting the metabolism of Gly, Ser, and Thr have the potential to improve MASLD.PMID:39718621 | DOI:10.1007/s00726-024-03433-2

Ecotoxicol Environ Saf. 2024 Dec 22;290:117579. doi: 10.1016/j.ecoenv.2024.117579. Online ahead of print.ABSTRACTThe effects of chlormequat chloride, a typical plant growth regulator, on the medicinal herb Corydalis yanhusuo were investigated. A standardized field experiment was conducted to investigate the molecular mechanisms and variations in active compounds resulting from chlormequat chloride treatment. Samples of C. yanhusuo were collected under controlled conditions and at varying doses of chlormequat chloride. The differential compounds identified in both control and treated groups of C. yanhusuo were primarily alkaloids, as determined by non-targeted metabolomics analysis. The metabolite content was determined through the precise quantification of 12 enriched alkaloidal compounds across various categories of C. yanhusuo using targeted metabolomics. A comprehensive metabolomics evaluation method was developed that focuses on pharmacodynamically active compounds. Transcriptomic analysis also facilitates the identification of differential genes and enzymes associated with alkaloid production between the two groups. Chlormequat chloride significantly increased the yield of C. yanhusuo, but the content of the quantitatively abundant alkaloids decreased. It was suggested that the level of cytochrome P450 enzymes, primarily involved in the biosynthesis of benzylisoquinoline alkaloids, was inhibited by chlormequat chloride. In conclusion, this study revealed a dose-dependent effect of chlormequat chloride on C. yanhusuo and its associated molecular mechanisms as determined by omics analysis.PMID:39718287 | DOI:10.1016/j.ecoenv.2024.117579

Prostaglandins Leukot Essent Fatty Acids. 2024 Dec 16;204:102662. doi: 10.1016/j.plefa.2024.102662. Online ahead of print.ABSTRACTLipid dyshomeostasis and neuroinflammation are key hallmarks of neuropsychiatric and neurodegenerative disorders, including major depressive disorder and Alzheimer's disease. In particular, polyunsaturated fatty acids (PUFAs) and their derivatives called oxylipins gained specific interest in this context, especially considering their capacity to orchestrate neuroinflammatory responses via direct modulation of microglia. The hippocampus and hypothalamus are crucial brain regions for regulating mood and cognition that are implicated in a variety of neuropsychiatric and neurodegenerative disorders and there is ample evidence for the sex-bias in risks for the development as well as sex-bias in the presentation of such psychiatric diseases, including the neuroinflammatory response. To better understand the local PUFA/oxylipin profiles and microglia responses in disease, we here assessed their brain region and sex-dependent profiles in homeostatic brains. In 2-month-old male and female mice, we measured non-esterified (free) PUFA/oxylipin profiles using liquid chromatography-tandem mass spectrometry and characterized microglia morphology via immunohistochemistry. The hypothalamus and hippocampus exhibit a different free PUFA/oxylipin profile, independent of sex. The hippocampus was characterized by a higher density of complex Iba1+ microglial cells than the hypothalamus, without sex effects. Hypothalamic microglial morphology correlated more strongly with free PUFA- and oxylipin species than hippocampal microglia, correlating with species from both the N-3 and N-6 PUFA metabolization pathways, while hippocampal microglial parameters correlated only with N-6 pathway-related species. Our findings provide a basis for future studies to investigate the relationship between PUFAs, their derivatives and neuroinflammation in the context of diseases.PMID:39718073 | DOI:10.1016/j.plefa.2024.102662

Int J Med Mushrooms. 2025;27(1):1-11. doi: 10.1615/IntJMedMushrooms.2024056428.ABSTRACTMeripilus giganteus, commonly known as the giant polypore, is a significant basidiomycete fungus with notable ecological role and potential medicinal applications. Studies on this fungus have revealed its multifaceted bioactive properties, including antioxidant, antimicrobial, anticancer, immunosuppressive, and neuroprotective effects. Through the production of ligninolytic enzymes such as laccase, M. giganteus holds promise for bioremediation and biofuel production. Given these promising findings, further research is warranted, including genome sequencing, proteomic, and metabolomic approaches, to fully elucidate its bioactive pathways and maximize its biotechnological potential.PMID:39717914 | DOI:10.1615/IntJMedMushrooms.2024056428

Water Res X. 2024 Dec 2;26:100290. doi: 10.1016/j.wroa.2024.100290. eCollection 2025 Jan 1.ABSTRACTHydrophobic organic pollutants in aqueous environments are challenging to biodegrade due to limited contact between microorganisms, the pollutants and the electron acceptor, particularly under anaerobic or anoxic conditions. Here, we propose a novel strategy that uses inexpensive, dual-function elemental sulfur (S0) to enhance biodegradation. Using petroleum hydrocarbons as the target pollutants, we demonstrated that hydrophobic and nonpolar S° can concentrate hydrocarbons while simultaneously serving as an electron acceptor to enrich hydrocarbon-degrading bacteria. The permeable reactive barrier filled with S0 effectively removed petroleum hydrocarbons. In addition to rapid adsorption, we discovered, for the first time, that petroleum hydrocarbons underwent efficient biodegradation through the reduction of S0. Specifically, n-alkanes were degraded by 80 % to 90 % and polycyclic aromatic hydrocarbons by 40 % to 95 %. These degradation rates were 17 % to 30 % and 26 % to 43 % higher, respectively, compared to those observed without S0. Consecutive subcultures combined with untargeted metabolomics analysis revealed that bacteria capable of dissimilatory sulfur reduction enhanced the fermentation process. These bacteria provided electrons to the metabolic network, which facilitated the mineralization of petroleum hydrocarbons. Our findings highlight the significant potential of S° for removing hydrophobic organic pollutants in oxygen-free environments, demonstrate the feasibility of integrating adsorption, biodegradation, and electron supply to enhance pollutant removal.PMID:39717821 | PMC:PMC11664143 | DOI:10.1016/j.wroa.2024.100290

Front Vet Sci. 2024 Dec 9;11:1501630. doi: 10.3389/fvets.2024.1501630. eCollection 2024.ABSTRACTMetabolomics is a science that takes small molecular metabolites in organisms as the research object and determines the dynamic changes of metabolites at the overall level through a variety of modern analytical techniques. At present, metabolomics technology has been widely used in biological significance interpretation, food safety and quality, breeding, disease diagnosis, functional compound identification, and other fields. Its application in poultry science has also become the focus of widespread attention. With the sustainable development of analytical techniques, metabolomics has great potential in the application of poultry science. In this paper, the research progress of metabolomics in poultry growth and development, genetics and breeding, egg quality, meat quality, and disease is reviewed and concluded, which is expected to provide scientific ideas for the research of metabolomics in poultry.PMID:39717790 | PMC:PMC11663919 | DOI:10.3389/fvets.2024.1501630

Curr Res Food Sci. 2024 Nov 29;10:100938. doi: 10.1016/j.crfs.2024.100938. eCollection 2025.ABSTRACTRadish is an important vegetable worldwide, with wide medicinal functions and health benefits. The quality of radish, strongly affected by phytochemicals like flavonoids and glucosinolates, are quite different depending on the radish varieties. However, the comprehensive accumulation profiles of secondary metabolites and their molecular regulatory mechanisms in different radish cultivars remain unclear thus far. Herein, we comprehensively analyzed the secondary metabolite and gene expression profiles of the flesh and skin of four popular radish varieties with different flesh and/or skin colors, using UPLC-MS/MS-based metabolomics and transcriptomics approach combined with RT-qPCR. The results showed that altogether 352 secondary metabolites were identified in radish, of which flavonoids and phenolic acids accounted for 60.51% of the total. The flesh and skin of each variety exhibited distinct metabolic profiles, making them unique in coloration, flavor, taste, and nutritional quality. The differential metabolites were mostly enriched in flavonoid biosynthesis, flavone and flavonol biosynthesis, phenylpropanoid biosynthesis, and glucosinolate biosynthesis pathway. Further, 19 key genes regulating the differential accumulation of flavonoids among different radish varieties were identified, such as RsCHS, RsCCOAMT, RsF3H, RsFLS, RsCYP75B1, RsDFR, and RsANS that were significantly upregulated in red-colored radish tissue. Also, 10 key genes affecting the differential accumulation of glucosinolates among different varieties were identified, such as RsCYP83B1, RsSUR1, and RsST5a that were significantly increased in the skin of green radish. Moreover, systematical biosynthetic pathways of flavonoids and glucosinolates and co-expression networks between genes and metabolites were constructed based on integrative analysis between metabolomics and transcriptomics. Our findings provide a novel insight into the mechanisms of radish quality formation, thereby providing a molecular basis for breeding and cultivation of radish with excellent nutritional quality.PMID:39717680 | PMC:PMC11665663 | DOI:10.1016/j.crfs.2024.100938

Ecol Evol. 2024 Dec 22;14(12):e70751. doi: 10.1002/ece3.70751. eCollection 2024 Dec.ABSTRACTAnimal gut microbiota play important roles in host immunity, nutrient metabolism, and energy acquisition. The gut microbiota and its metabolic products interact with the host in many different ways, influencing gut homoeostasis and health. Teratoscincus roborowskii is an endemic species which displays special frugivorous behavior, and it has been observed consuming grapes. To explore the effects of grape intake on the gut microbiota and metabolites of T. roborowskii, 16S rRNA sequencing and liquid chromatography mass spectrometry metabolomics were applied to investigate the gut microbiota and metabolite profiles of T. roborowskii fed with mealworms (LC group) and a mixture of mealworms and grapes (FG group). Our results demonstrated that a notable shift in microbiota composition occurred, particularly in terms of an increase in the probiotic Lactococcus in the FG group. The metabolite analysis revealed a significant enrichment of the pathways related to glucose metabolism in the FG group. In addition, the digestive enzyme activity analysis showed that the α-amylase and cellulase activities in the FG group were significantly higher than those of the LC group, which was consistent with the food type. A strong correlation between diet, gut microbiota, and fecal metabolites was observed, which may imply that different diets promote the establishment of host intestinal adaptation strategies. Our study provides a theoretical basis for host health and the scientific captive breeding of the desert lizards T. roborowskii.PMID:39717646 | PMC:PMC11663733 | DOI:10.1002/ece3.70751

Food Chem X. 2024 Dec 2;24:102063. doi: 10.1016/j.fochx.2024.102063. eCollection 2024 Dec 30.ABSTRACTNongxiangxing Baijiu is the most famous Baijiu flavor in China, and its characteristic style is closely related to Nongxiangxing Daqu used in fermentation. However, there are few reports about the difference of Daqu quality between seasonal variations. In this study, precipitation and temperature drove changes in microbial communities that resulted in differences in the flavor of Daqu produced in different seasons. For example, the average daily temperature in summer was as high as 27.29 ± 2.24 °C, which was significantly higher than other seasons (p < 0.01). Bacillus was abundant in the Daqu produced in this season, while tetramethylpyrazine flavor was more prominent, up to 1556.95 ± 153.92 μg/kg. Metabolomics studies identified major pathways associated with the weak flavor of spring_Daqu. In addition, LEFSe analysis revealed the marked microorganisms in different seasons. These results revealed the differences in seasonal Daqu, thus contributing to the scientific and rational use of Daqu.PMID:39717403 | PMC:PMC11665295 | DOI:10.1016/j.fochx.2024.102063

J Pharm Anal. 2024 Nov;14(11):101024. doi: 10.1016/j.jpha.2024.101024. Epub 2024 Jun 26.ABSTRACTTriclocarban (TCC) is a common antimicrobial agent that has been widely used in medical care. Given the close association between TCC treatment and metabolic disorders, we assessed whether long-term treatment to TCC at a human-relevant concentration could induce nephrotoxicity by disrupting the metabolic levels in a mouse model. Matrix-assisted laser desorption/ionization mass spectrometry imaging (MALDI-MSI) was applied to investigate the alterations in the spatial distributions and abundances of TCC, endogenous and exogenous metabolites in the kidney after TCC treatment. The results showed that TCC treatment induced the changes in the organ weight, organ coefficient and histopathology of the mouse kidney. MSI data revealed that TCC accumulated in all regions of the kidney, while its five metabolites mainly distributed in the cortex regions. The abundances of 79 biomolecules associated with pathways of leukotriene E4 metabolism, biosynthesis and degradation of glycerophospholipids and glycerolipids, ceramide-to-sphingomyelin signaling were significantly altered in the kidney after TCC treatment. These biomolecules showed distinctive distributions in the kidney and displayed a favorable spatial correlation with the pathological damage. This work offers new insights into the related mechanisms of TCC-induced nephrotocicity and exhibits the potential of MALDI-MSI-based spatial metabolomics as a promising approach for the risk assessment of agents in medical care.PMID:39717194 | PMC:PMC11664399 | DOI:10.1016/j.jpha.2024.101024

J Clin Hypertens (Greenwich). 2024 Dec 24. doi: 10.1111/jch.14961. Online ahead of print.ABSTRACTResistant hypertension (RH) may cause severe target organ damage and poses significant challenges in the field of hypertension prevention and treatment. Mining biological characteristics is crucial for exploring the pathogenesis of RH and for early diagnosis and treatment. Although several single-omics studies have been conducted on RH, its complex pathogenesis has only been partially elucidated. In this study, metabolomics, proteomics, and transcriptomics were jointly analyzed in healthy subjects and patients with hypertension and RH. The multi-omics analysis found that differential substances of RH were enriched in the HIF-1 signaling pathway and that differential substances such as ascorbic acid, reduced glutathione (GSH), choline, citric acid, transferrin receptor (TfR), Egl-9 family hypoxia-inducible factor 2 (EGLN2), and glutathione peroxidase 1 (GPX1) were screened out. The results of intergroup comparisons were as follows: RH versus N: ascorbic acid (Fold Change (FC):0.42, p < 0.01), GSH (FC:0.65, p < 0.05), choline (FC:1.32, p < 0.05), citric acid (FC:0.48, p < 0.001), TfR (FC2.32, p < 0.001), GPX1 (FC:16.02, p < 0.001), EGLN2 (FC:0.76, p < 0.001); RH versus EH: ascorbic acid (FC:0.52, p < 0.05), GSH (FC:0.55, p < 0.05), choline (FC:1.28, p < 0.05), citric acid (FC:0.59, p < 0.001), TfR (FC:1.71, p < 0.001), GPX1 (FC:2.11, p < 0.05), EGLN2 (FC:0.76, p < 0.05). These differential substances may reflect the biology of RH. This study provides multi-omics analysis for a deeper understanding of the complex molecular characteristics of RH, providing new insights into the pathogenesis, early diagnosis, and precise treatment of the disease.PMID:39716980 | DOI:10.1111/jch.14961

Brain. 2024 Dec 24:awae413. doi: 10.1093/brain/awae413. Online ahead of print.ABSTRACTConvergent data, across species, paint a compelling picture of the critical role of the gut and its resident microbiota in several brain functions and disorders. The chemicals mediating communication along these sophisticated highways of the brain-gut-microbiome (BGM) axis include both microbiota metabolites and classical neurotransmitters. Amongst the latter, GABA is fundamental to brain function where it mediates the majority of neuronal inhibition. Until recently, GABA's role and specific molecular targets in the periphery within the BGM axis had received limited attention. Yet, GABA is produced by neuronal and non-neuronal elements of the BGM, and recently GABA-modulating bacteria have been identified as key players in GABAergic gut systems, indicating that GABA-mediated signalling is likely to transcend not only physiological boundaries, but also species. We review available evidence with a view to better understand how GABA facilitates integration of molecularly and functionally disparate systems to bring about overall homeostasis, and how GABA perturbations within the BGM axis can give rise to multi-system medical disorders, thereby magnifying the disease burden and the challenges for patient care. Analysis of transcriptomic databases revealed significant overlaps between GABAAR subunits expressed in the human brain and gut. However, in the gut, there are notable expression profiles for a select number of subunits that have received limited attention to date but could be functionally relevant for BGM axis homeostasis. GABAergic signalling, via different receptor subtypes, directly regulates BGM homeostasis by modulating the excitability of neurons within brain centres responsible for gastrointestinal (GI) function, in a sex-dependent manner, potentially revealing mechanisms underlying the greater prevalence of GI disturbances in females. Apart from such top-down regulation of the BGM axis, a diverse group of cell types, including enteric neurons, glia, enteroendocrine cells, immune cells and bacteria - integrate peripheral GABA signals to influence brain functions and potentially contribute to brain disorders. We propose several priorities for this field, including the exploitation of available technologies to functionally dissect components of these GABA pathways within the BGM, with a GI and brain-behaviour-disease focus. Furthermore, in silico ligand-receptor docking analyses, using relevant bacterial metabolomic datasets, coupled with advances in knowledge of GABAAR 3D structures, could uncover new ligands with novel therapeutic potential. Finally, targeted design of dietary interventions is imperative to advance their therapeutic potential to support GABA homeostasis across the BGM axis.PMID:39716883 | DOI:10.1093/brain/awae413

Skelet Muscle. 2024 Dec 23;14(1):36. doi: 10.1186/s13395-024-00368-w.ABSTRACTDespite its notoriously mild phenotype, the dystrophin-deficient mdx mouse is the most common model of Duchenne muscular dystrophy (DMD). By mimicking a human DMD-associated metabolic comorbidity, hyperlipidemia, in mdx mice by inactivating the apolipoprotein E gene (mdx-ApoE) we previously reported severe myofiber damage exacerbation via histology with large fibro-fatty infiltrates and phenotype humanization with ambulation dysfunction when fed a cholesterol- and triglyceride-rich Western diet (mdx-ApoEW). Herein, we performed comparative lipidomic and metabolomic analyses of muscle, liver and serum samples from mdx and mdx-ApoEW mice using solution and high-resolution-magic angle spinning (HR-MAS) 1H-NMR spectroscopy. Compared to mdx and regular chow-fed mdx-ApoE mice, we observed an order of magnitude increase in lipid deposition in gastrocnemius muscle of mdx-ApoEW mice including 11-fold elevations in -CH3 and -CH2 lipids, along with pronounced elevations in serum cholesterol, fatty acid, triglyceride and phospholipids. Hepatic lipids were also elevated but did not correlate with the extent of muscle lipid infiltration or differences in serum lipids. This study provides the first lipometabolomic signature of severe mdx lesions exacerbated by high circulating lipids and lends credence to claims that the liver, the main regulator of whole-body lipoprotein metabolism, may play only a minor role in this process.PMID:39716324 | DOI:10.1186/s13395-024-00368-w

Arthritis Res Ther. 2024 Dec 23;26(1):227. doi: 10.1186/s13075-024-03429-z.ABSTRACTOBJECTIVE: Rheumatoid arthritis (RA) is a chronic inflammatory condition that, despite available approaches to manage the disease, lacks an efficient treatment and timely diagnosis. Using the most advanced omics technique, metabolomics and proteomics approach, we explored varied metabolites and proteins to identify unique metabolite-protein signatures involved in the disease pathogenesis of RA.METHODS: Untargeted metabolomics (n = 20) and proteomics (n = 60) of RA patients' plasma were carried out by HPLC/LC-MS/MS and SWATH, respectively and analyzed by Metaboanalyst. The targets of metabolite retrieved by PharmMapper were matched with SWATH data, and joint pathway analysis was carried out. An in-vitro study of metabolites in TNF-α induced SW982 cells was conducted by Western, RT-PCR, scratch, and ROS scavenging assay. The effect of GUDCA was also evaluated in the CIA rat model.RESULTS: A Total of 82 metabolites and 231 differential proteins were revealed. Porphyrin and chlorophyll pathway and its metabolite Glycoursodeoxycholic acid (GUDCA) was found to be significantly altered. In vitro analysis has shown that GUDCA reduces inflammation thus offering protection against ROS production and cell proliferation. PharmMapper analysis revealed that GUDCA was significantly linked with identified SWATH proteins insulin like growth factor-1(IGF1), and Transthyretin (TTR) and it upregulates the expression of IGF1 and downregulates the expression of TTR in both in vitro and in vivo models.CONCLUSION: GUDCA was found to possess antioxidative, antiproliferative properties and an effective anti-inflammatory property at a low dosage. It may be considered as a potential therapeutic option for reducing the inflammatory parameters associated with RA.PMID:39716302 | DOI:10.1186/s13075-024-03429-z