PubMed

Aquat Toxicol. 2024 Nov 13;277:107164. doi: 10.1016/j.aquatox.2024.107164. Online ahead of print.ABSTRACTNitrite is a toxic substance found in rearing water that affects shrimp health. The hepatopancreas is an important digestive, immune, and metabolic organ in the shrimp. In this study, shrimps (Litopenaeus vannamei) were separately exposed to 1 and 5 mg/L nitrite stress for 48 h, and the toxicity of nitrite in the hepatopancreas was explored by integrating histology, physiological indicators, energy metabolism, and metabolomics. Nitrite stress induced morphological changes and stress responses in the hepatopancreas. Specifically, physiology-related indices, such as the relative gene expression levels of antioxidants (ROMO1, Nrf2, GPx), endoplasmic reticulum stress (Bip, IRE1 and XBP1), and immune genes (ALF, Pen-3, Lys) were decreased, whereas the gene expression of apoptosis (Casp-3), detoxification (CYP450), and glutamic oxaloacetic transaminase (GOT) activity were increased. The activities of osmotic adjustment-related enzymes (NKA, CMA, and ATPase) also decreased. Energy metabolism-related indices, such as pyruvate and hepatic glycogen contents, increased, whereas glucose, lactic acid, triglyceride, and ATP contents and ATPase activity decreased, and the relative gene expression levels of carbohydrate metabolism (PDH, HK, and LDH) and electron-transport chain genes (CytC, COI and CCO) decreased, and the expressions of lipid metabolism (AMPK, SREBP, and FAS), tricarboxylic acid cycle (MDH, CS, IDH and FH) genes were also disturbed. The metabolic pattern of the hepatopancreas was affected by nitrite stress. Glycine, serine, and threonine metabolism were highly affected, and more functional amino acids varied in the 5 mg/L nitrite stress group. These results reveal the toxic effects of nitrite stress on the stress response, physiology, energy metabolism, and metabolite homeostasis in the hepatopancreas of shrimp. Several potential metabolite biomarker candidates were identified for toxicological evaluation.PMID:39561610 | DOI:10.1016/j.aquatox.2024.107164

J Hazard Mater. 2024 Nov 12;481:136470. doi: 10.1016/j.jhazmat.2024.136470. Online ahead of print.ABSTRACTTo reveal the disruption caused by herbicides and the mechanisms of algal interactions on interspecific competitive strategies at a metabolic and population level, this study established short-term (7 d) and long-term (21 d) Scenedesmus-Microcystis competition coculture systems and investigated the toxicity of acetochlor (ACT) on algae competition. Scenedesmus obliquus (EC50 6.586 μg/L) is three orders of magnitude more sensitive to ACT than Microcystis aeruginosa (EC50 19,539 μg/L), placing it at a competitive disadvantage in environments with ACT pollution. Short-term coculture tests (ACT concentrations from 0 to 12.5 μg/L) showed that ACT suppresses S. obliquus growth and competition, while M. aeruginosa initially showed compensatory growth, which was negated by ACT. Metabolomics revealed that interspecies competition and ACT affect fatty acid synthesis and nitrogen assimilation metabolism of both microalgae, suggesting species differences in the mode of action (MOA) of ACT toxicity and resource competition strategies, respectively. ACT weakens the ability of M. aeruginosa to compete for nitrogen and synthesize microcystin under competitive stress. ACT biotransformation can be conducted across species. In an algal culture system with equal initial biomass, the 7 d ACT degradation rate increased by 24.9 % and 123.8 % with coculture of the two algae compared with monocultures of S. obliquus and M. aeruginosa, respectively. In long-term experiments, the degradation rate increased by 19.0 % and 8.9 % in cocultures compared with the monocultures. Lotka-Volterra models showed that competitive inhabitation was alleviated, implying that the competition interspecies relationship is beneficial for the coexistence of both algal populations under ACT stress.PMID:39561538 | DOI:10.1016/j.jhazmat.2024.136470

J Neurol Sci. 2024 Nov 10;467:123303. doi: 10.1016/j.jns.2024.123303. Online ahead of print.ABSTRACTThe study examined changes in the plasma proteome, metabolome, and lipidome of N = 14 patients with relapsing-remitting multiple sclerosis (RRMS) initiating treatment with ocrelizumab, assayed at baseline, 6 months, and 12 months. Analyses of >4000 circulating biomarkers identified depletion of B-cell associated proteins as the early effect observed following ocrelizumab (OCR) initiation, accompanied by the reduction in plasma abundance of cytokines and cytotoxic proteins, markers of neuronaxonal damage, and biologically active lipids including ceramides and lysophospholipids, at 6 months. B-cell depletion was accompanied by decreases in B-cell receptor and cytokine signaling but a pronounced increase in circulating plasma B-cell activating factor (BAFF). This was followed by an upregulation of a number of signaling and metabolic pathways at 12 months. Patients with higher baseline brain MRI lesion load demonstrated both higher levels of cytotoxic and structural proteins in plasma at baseline and more pronounced biomarker change trajectories over time. Digital cytometry identified a putative increase in myeloid cells and a pro-inflammatory subset of T-cells. Therapeutic effects of ocrelizumab extend beyond CD20-mediated B-cell lysis and implicate metabolic reprogramming, juxtaposing the early normalization of immune activation, cytokine signaling and metabolite and lipid turnover in periphery with changes in the dynamics of immune cell activation or composition. We identify BAFF increase following CD20 depletion as a tentative compensatory mechanism that contributes to the reconstitution of targeted B-cells, necessitating further research.PMID:39561535 | DOI:10.1016/j.jns.2024.123303

J Chromatogr B Analyt Technol Biomed Life Sci. 2024 Nov 13;1249:124372. doi: 10.1016/j.jchromb.2024.124372. Online ahead of print.ABSTRACTSymptoms of ulcerative colitis (UC) are like "intestinal carbuncle" in Chinese medicine. The aqueous extract of Sargentodoxa cuneata (AESc) has good therapeutic effects on UC, but the underlying mechanism needs to be further elucidated. The mechanism of AESc against UC was studied based on metabolomics and bioinformatics in mice with UC. Dextran sodium sulfate was applied to induce a mouse model of UC. After the intervention of AESc, the general condition of the animals was recorded, and efficacy-related indicators were measured. Information on serum metabolites was determined. Multivariate analysis combined with bioinformatics methods were used to identify the differential metabolites. Furthermore, "metabolite-target-disease" network was obtained, and differential metabolites of UC were screened, and further analysis of the metabolites were performed. Molecular docking validation was also carried out. AESc improved general conditions such as blood in stool, hair of animals, and weight loss, reduced disease activity index scores and shortening of colon length in mice with UC. A total of 3445 serum metabolites were obtained, and 64 differentiated metabolites of AESc against UC were screened. Enrichment analysis showed that arachidonic acid metabolism, bile secretion, drug metabolism-other enzymes, and tyrosine metabolism were associated with AESc in the treatment of UC. In addition, based on "metabolite-target-disease" network, the serum metabolites cholylleucine, 9,10,13-TriHOME, birabresib, anthramycin methyl ether, trans-hexadec-2-enoyl carnitine, and lucidumol A were found to have the therapeutic potential for UC. Further, 14 core targets were obtained, and lipids and atherosclerosis, rheumatoid arthritis and multiple immune-inflammatory pathways were associated with AESc for the treatment of UC. AESc corrects serum metabolic disturbances in UC mice, and multiple serum metabolites have therapeutic potential for UC. AESc may treat UC by regulating biological processes such as lipid metabolism, amino acid metabolism, thereby restoring normal physiological function of the intestine.PMID:39561468 | DOI:10.1016/j.jchromb.2024.124372

G3 (Bethesda). 2024 Nov 19:jkae195. doi: 10.1093/g3journal/jkae195. Online ahead of print.ABSTRACTPeppermint, Mentha × piperita L., is a hexaploid (2n = 6x = 72) and the predominant cultivar of commercial mint oil production in the US. This cultivar is threatened because of high susceptibility to the fungal disease verticillium wilt, caused by Verticillium dahliae. This report details the first draft polyploid chromosome-level genome assembly for this mint species. The "Mitcham" genome resource will broaden comparative studies of disease resistance, essential oil biosynthesis, and hybridization events within the genus Mentha. It will also be a valuable contribution to the body of phylogenetic studies involving Mentha and other genera that contain species with varying ploidy levels.PMID:39561240 | DOI:10.1093/g3journal/jkae195

Cell Rep. 2024 Nov 18;43(11):114976. doi: 10.1016/j.celrep.2024.114976. Online ahead of print.ABSTRACTCore components of the N-glycosylation pathway are known, but the metabolic and post-translational mechanisms regulating this pathway in normal and disease states remain elusive. Using a multi-omic approach in zebrafish, we discovered a mechanism whereby O-GlcNAcylation directly impacts the expression and abundance of two rate-limiting proteins in the N-linked glycosylation pathway. We show in a model of an inherited glycosylation disorder PMM2-CDG, congenital disorders of glycosylation that phosphomannomutase deficiency is associated with increased levels of UDP-GlcNAc and protein O-GlcNAcylation. O-GlcNAc modification increases the transcript and protein abundance of both NgBR and Dpagt1 in pmm2m/m mutants. Modulating O-GlcNAc levels, NgBR abundance, or Dpagt1 activity exacerbated the cartilage phenotypes in pmm2 mutants, suggesting that O-GlcNAc-mediated increases in the N-glycosylation machinery are protective. These findings highlight nucleotide-sugar donors as metabolic sensors that regulate two spatially separated glycosylation pathways, demonstrating how their coordination is relevant to disease severity in the most common congenital disorder of glycosylation.PMID:39561044 | DOI:10.1016/j.celrep.2024.114976

Nutr Neurosci. 2024 Nov 19:1-12. doi: 10.1080/1028415X.2024.2425565. Online ahead of print.ABSTRACTThe relevance of lifestyle, including diet and exercise, has been associated with improved learning and memory capacity, delayed age-related cognitive decline, and a reduced risk of neurodegeneration. Most neurodegenerative diseases are defined as complex multifactorial disorders in which genetic and environmental factors greatly contribute to their onset. Although inflammatory cells produce reactive oxygen species (ROS), oxidative stress itself might exert pro-inflammatory effects and an uncontrolled response could lead to a state of chronic inflammation. Anti-inflammatory dietary approaches unify the disciplines of nutrition, immunity, and neurology. Personalized dietary interventions will be developed based on an individual's genetic makeup, metabolic profile, and gut microbiota composition, thanks to advances in genomics, metabolomics, and microbiome research. The relevance of dietary patterns in decreasing inflammation relies on the role of specific antioxidant nutrients, which might contribute to a decrease in the levels of ROS. This review aims to summarize recent advancements in neuroscience and immunology that have revealed the crucial role that diet and the immune system play in brain function and disease progression. Nutrition influences the immune system, and in turn, the immune system impacts neurological health. This bidirectional relationship suggests that targeted nutritional interventions could modulate immune responses to delay or mitigate the progression of neurodegenerative diseases potentially. This approach focuses on the use of specific nutrients and dietary components that influence the immune system and inflammatory pathway. Key elements of immunonutrition include omega-3 fatty acids, antioxidants, vitamins and various bioactive compounds found in foods.PMID:39561029 | DOI:10.1080/1028415X.2024.2425565

Environ Sci Technol. 2024 Nov 19. doi: 10.1021/acs.est.4c07188. Online ahead of print.ABSTRACTTire wear particles (TWPs), generated from tire abrasion, contribute significantly to environmental contamination. The toxicity of TWPs to organisms has raised significant concerns, yet their effects on terrestrial plants remain unclear. Here, we investigated the long-term impact of pristine and naturally aged TWPs on water spinach (Ipomoea aquatica) and its rhizospheric soil. The results indicated that natural aging reduced the toxicity of TWPs, as evidenced by decreased levels of polycyclic aromatic hydrocarbons (PAHs) in soil and TWPs themselves. Consequently, aged TWPs were found to enhance the plant growth and chlorophyll content, whereas pristine TWPs increased the plant stress. Furthermore, aged TWPs improved soil organic matter (SOM) and total organic carbon (TOC), thereby boosting the microbial enzymes involved in nitrogen cycling. Metabolomic analysis revealed that aged TWPs upregulated key pathways related to carbon and nitrogen metabolism, enhancing plant growth and stress responses. Additionally, rhizosphere bacterial diversity was higher under aged TWPs, favoring nutrient-cycling taxa such as Acidobacteriota and Nitrospirota. Pristine TWPs may lead to overproliferation of certain dominant species, thereby reducing microbial diversity in soil, which could ultimately compromise the soil health. These findings contribute to a deeper understanding of the mechanisms underlying TWP toxicity in plants and highlight the necessity for further research on the impact of aged TWPs across various plant species over different exposure durations for comprehensive risk assessment.PMID:39561015 | DOI:10.1021/acs.est.4c07188

J Clin Invest. 2024 Nov 19:e177824. doi: 10.1172/JCI177824. Online ahead of print.ABSTRACTThe glioblastoma (GBM) microenvironment is enriched in immunosuppressive factors that potently interfere with the function of cytotoxic T lymphocytes. Cancer cells can directly impact the immune system, but the mechanisms driving these interactions are not completely clear. Here we demonstrate that the polyamine metabolite spermidine (SPD) is elevated in the GBM tumor microenvironment. Exogenous administration of SPD drives tumor aggressiveness in an immune-dependent manner in pre-clinical mouse models via reduction of CD8+ T cell frequency and reduced cytotoxic function. Knockdown of ornithine decarboxylase, the rate-limiting enzyme in spermidine synthesis, did not impact cancer cell growth in vitro but did result in extended survival. Furthermore, glioblastoma patients with a more favorable outcome had a significant reduction in spermidine compared to patients with a poor prognosis. Our results demonstrate that spermidine functions as a cancer cell-derived metabolite that drives tumor progression by reducing CD8+ T cell number and function.PMID:39561012 | DOI:10.1172/JCI177824

Arch Gynecol Obstet. 2024 Nov 19. doi: 10.1007/s00404-024-07828-0. Online ahead of print.ABSTRACTThere is a general lack of awareness regarding how the mode of delivery can significantly influence the omics composition of biological samples such as umbilical cord blood and amniotic fluid. To address this, we analyzed the impact of delivery mode on proteomic and metabolomic profiles in a cohort of 40 healthy pregnant women without complications, including 16 who had vaginal delivery (VD), 16 who underwent elective cesarean delivery by maternal request (CS), and 8 who had intrapartum cesarean section (Intra_CS). Using label-free liquid chromatography-tandem mass spectrometry (LC-MS/MS) for proteomic and untargeted metabolomic analyses, we compared amniotic fluid and cord blood samples across delivery modes. The amniotic fluid proteomic and metabolomic profiles of CS women exhibited clear separation from those of VD individuals, whereas only the proteomic profiles of the Intra_CS group differed when compared to the CS group. In cord blood, metabolomic profiles differed between CS and VD women, but proteomic profiles showed no separation. These findings highlight the significant impact of delivery mode on omics profiles, particularly amniotic fluid proteomics and metabolomics, and cord blood metabolomics. Larger studies are needed to validate these findings and expand their generalizability to broader populations.PMID:39560725 | DOI:10.1007/s00404-024-07828-0

J Neurol. 2024 Nov 19. doi: 10.1007/s00415-024-12722-5. Online ahead of print.NO ABSTRACTPMID:39560724 | DOI:10.1007/s00415-024-12722-5

Proc Natl Acad Sci U S A. 2024 Nov 26;121(48):e2407842121. doi: 10.1073/pnas.2407842121. Epub 2024 Nov 19.ABSTRACTThe human lens is composed of a monolayer of lens epithelial cells (LECs) and elongated fibers that align tightly but are separated by the plasma membrane. The integrity of the lens plasma membrane is crucial for maintaining lens cellular structure, homeostasis, and transparency. Glutathione peroxidase 4 (GPX4), a selenoenzyme, plays a critical role in protecting against lipid peroxidation. This study aims to elucidate the role of GPX4 in lens plasma membrane stability during lens development using in vitro, ex vivo, and in vivo systems. Our findings reveal that GPX4 deficiency triggers lens epithelial apoptosis-independent but ferroptosis-mediated cell death. Blocking lens GPX4 activity during ex vivo culture induces lens opacification, LEC death, and disruption of lens fiber cell arrangement. Deletion of lens-specific Gpx4 results in significant unsaturated phospholipid loss and an increase in oxidized phospholipids. Consequently, lenses with Gpx4 deficiency exhibit massive disruption of lens fiber cell structure, significant loss of LECs via ferroptosis, and formation of newborn cataracts. Remarkably, administering the lipid peroxidation inhibitor, liproxstatin-1, to pregnant mothers at embryonic days 9.5 significantly prevents lipid peroxidation, LEC death, and lens developmental defects. Our study unveils the crucial role of GPX4 in lens development and transparency, and also provides a successful intervention approach to prevent lens developmental defects through lipid peroxidation inhibition.PMID:39560644 | DOI:10.1073/pnas.2407842121

J Periodontal Res. 2024 Nov 19. doi: 10.1111/jre.13363. Online ahead of print.ABSTRACTAIMS: This research sought to assess the efficacy of Bacillus subtilis (B. subtilis) R0179 and explore potential metabolites in mitigating experimental periodontitis in mice induced by Porphyromonas gingivalis (P. gingivalis) ATCC 33277.METHODS: B. subtilis R0179 was administered to 8-week-old male C57BL/6J mice with periodontitis. Oral load of P. gingivalis ATCC 33277 and periodontal tissue loss were quantified. The cell-free supernatant (CFS) was separated to assess its anti-P. gingivalis effect. Proteomic and metabolomic analyses identified potential antibacterial components in the CFS, further evaluated for anti-P. gingivalis effects.RESULTS: B. subtilis R0179 significantly reduced P. gingivalis ATCC 33277 levels and mitigated periodontal tissue loss in mice. The CFS, rather than inactivated B. subtilis R0179 cells, exhibited antibacterial activity. Proteomic and metabolomic analyses identified mesaconate and citraconate as key antibacterial agents. Disk diffusion assays confirmed the efficacy of mesaconate against P. gingivalis, while citraconate had no effect. Mesaconate showed a dose-dependent reduction in P. gingivalis ATCC 33277 population and periodontal tissue loss in mice.CONCLUSION: These findings highlight B. subtilis R0179 and its metabolite mesaconate as promising candidates for therapeutic development against periodontitis by inhibiting P. gingivalis ATCC 33277 effectively.PMID:39560450 | DOI:10.1111/jre.13363

mSystems. 2024 Nov 19:e0085624. doi: 10.1128/msystems.00856-24. Online ahead of print.ABSTRACTCoral reefs are experiencing unprecedented loss in coral cover due to increased incidence of disease and bleaching events. Thus, understanding mechanisms of disease susceptibility and resilience, which vary by species, is important. In this regard, untargeted metabolomics serves as an important hypothesis-building tool enabling the delineation of molecular factors underlying disease susceptibility or resilience. In this study, we characterize metabolomes of four species of visually healthy stony corals, including Meandrina meandrites, Orbicella faveolata, Colpophyllia natans, and Montastraea cavernosa, collected at least a year before stony coral tissue loss disease reached the Dry Tortugas, Florida, and demonstrate that both symbiont and host-derived biochemical pathways vary by species. Metabolomes of Meandrina meandrites displayed minimal intraspecies variability and the highest biological activity against coral pathogens when compared to other species in this study. The application of advanced metabolite annotation methods enabled the delineation of several pathways underlying interspecies variability. Specifically, endosymbiont-derived vitamin E family compounds, betaine lipids, and host-derived acylcarnitines were among the top predictors of interspecies variability. Since several metabolite features that contributed to inter- and intraspecies variation are synthesized by the endosymbiotic Symbiodiniaceae, which could be a major source of these compounds in corals, our data will guide further investigations into these Symbiodiniaceae-derived pathways.IMPORTANCE: Previous research profiling gene expression, proteins, and metabolites produced during thermal stress have reported the importance of endosymbiont-derived pathways in coral bleaching resistance. However, our understanding of interspecies variation in these pathways among healthy corals and their role in diseases is limited. We surveyed the metabolomes of four species of healthy corals with differing susceptibilities to the devastating stony coral tissue loss disease and applied advanced annotation approaches in untargeted metabolomics to determine the interspecies variation in host and endosymbiont-derived pathways. Using this approach, we propose the survey of immune markers such as vitamin E family compounds, acylcarnitines, and other metabolites to infer their role in resilience to coral diseases. As time-resolved multi-omics datasets are generated for disease-impacted corals, our approach and findings will be valuable in providing insight into the mechanisms of disease resistance.PMID:39560405 | DOI:10.1128/msystems.00856-24

Anal Methods. 2024 Nov 19. doi: 10.1039/d4ay01569j. Online ahead of print.ABSTRACTScreening differential metabolites is of great significance in biomarker discovery in metabolomics research. However, it is susceptible to unwanted variations introduced during experiments. Previous normalization methods have improved the accuracy of inter-group classification by eliminating systematic errors. Nonetheless, the classification ability of differential metabolites obtained through these methods still requires further enhancement, and the reproducibility evaluation on importance rankings of differential metabolites is often disregarded. The EigenRF algorithm was developed as an improvement over the previous metabolomics normalization method referred to as EigenMS, which aims to normalize metabolomics data. Furthermore, scoring metrics, including the local consistency (LC) and overall difference (OD) scores, were introduced to evaluate the reproducibility of importance rankings of differential metabolites from a dual perspective. After conducting validation on three publicly accessible datasets, the EigenRF method has demonstrated enhanced classification ability of differential metabolites as well as improved reproducibility. In summary, EigenRF enhances the reliability of differential metabolites in metabolomics research, benefiting the further exploration of molecular mechanisms underlying biological alterations in complex matrices. The EigenRF algorithm was implemented in an R package: https://www.github.com/YangHuaLab/EigenRF.PMID:39560372 | DOI:10.1039/d4ay01569j

Cancer Rep (Hoboken). 2024 Nov;7(11):e70042. doi: 10.1002/cnr2.70042.ABSTRACTBACKGROUND: Detection of cancer at the early stage currently offers the only viable strategy for reducing disease-related morbidity and mortality. Various approaches for multi-cancer early detection are being explored, which largely rely on capturing signals from circulating analytes shed by tumors into the blood. The fact that biomarker concentrations are limiting in the early stages of cancer, however, compromises the accuracy of these tests. We, therefore, adopted an alternate approach that involved interrogation of the serum metabolome with machine learning-based data analytics. Here, we monitored for modulations in metabolite patterns that correlated with the presence or absence of cancer. Results obtained confirmed the efficacy of this approach by demonstrating that it could detect a total of 15 cancers in women with an average accuracy of about 99%.AIMS: To further increase the scope of our test, we conducted an investigator-initiated clinical trial involving a total of 6445 study participants, which included both cancer patients and non-cancer volunteers. Our goal here was to maximize the number of cancers that could be detected, while also covering cancers in both females and males.METHODS AND RESULTS: Metabolites extracted from individual serum samples were profiled by ultra-performance liquid chromatography coupled to a high-resolution mass spectrometer using an untargeted protocol. After processing, the data were analyzed by our cancer detection machine-learning algorithm to differentiate cancer from non-cancer samples. Results revealed that our test platform could indeed detect a total of 30 cancers, covering both females and males, with an average accuracy of ~98%. Importantly, the high detection accuracy remained invariant across all four stages of the cancers.CONCLUSION: Thus, our approach of integrating untargeted metabolomics with machine learning-powered data analytics offers a powerful strategy for early-stage multi-cancer detection with high accuracy.TRIAL REGISTRATION: Registration No: CTRI/2023/03/050316.PMID:39559978 | DOI:10.1002/cnr2.70042

Plant J. 2024 Nov 19. doi: 10.1111/tpj.17149. Online ahead of print.ABSTRACTCotton stands as a pillar in the textile industry due to its superior natural fibers. Lignin, a complex polymer synthesized from phenylalanine and deposited in mature cotton fibers, is believed to be essential for fiber quality, although the precise effects remain largely unclear. In this study, we characterized two ubiquitously expressed cinnamyl alcohol dehydrogenases (CAD), GhCAD37A and GhCAD37D (GhCAD37A/D), in Gossypium hirsutum. GhCAD37A/D possess CAD enzymatic activities, to catalyze the generation of monolignol products during lignin biosynthesis. Analysis of transgenic cotton knockout and overexpressing plants revealed that GhCAD37A/D are important regulators of fiber quality, positively impacting breaking strength but negatively affecting fiber length and elongation percentage by modulating lignin biosynthesis in fiber cells. Moreover, GhCAD37A/D are shown to modulate anther vitality and affect stem lodging trait in cotton by influencing lignin biosynthesis in the vascular bundles of anther and stem, respectively. Additionally, our study revealed that Ghcad37A/D knockout plants displayed red stem xylem, likely due to the overaccumulation of aldehyde intermediates in the phenylpropanoid metabolism pathway, as indicated by metabolomics analysis. Thus, our work illustrates that GhCAD37A/D are two important enzymes of lignin biosynthesis in different cotton organs, influencing fiber quality, anther vitality, and stem lodging.PMID:39559968 | DOI:10.1111/tpj.17149

Drug Des Devel Ther. 2024 Nov 13;18:5161-5182. doi: 10.2147/DDDT.S478072. eCollection 2024.ABSTRACTBACKGROUND: Modified Suanmei-Tang (MST) comprises four plants common to both traditional Chinese medicine and culinary applications, and it can potentially alleviate metabolic-associated fatty liver disease (MAFLD) triggered by a high-fat diet (HFD).PURPOSE: This research aims to investigate the impact and underlying mechanisms of MST in ameliorating MAFLD caused by an HFD.METHODS: UHPLC-Q-Orbitrap-MS/MS was used to determine the constituents of MST and to evaluate its effects on MAFLD mouse models. Transcriptomics, network pharmacology, and bioinformatics analysis (including Kyoto Encyclopedia of Genes and Genomes and Gene Set Enrichment Analysis) were utilized to further clarify the mechanisms by which MST acts on MAFLD. The experimental methods included ELISA, real time quantitative PCR (RT-qPCR), Western blot, immunohistochemistry, molecular docking, and metabolomics. Transcriptomics was integrated with metabolomics to find correlations between differentially expressed genes and metabolites, and crucial genes were validated through RT-qPCR.RESULTS: A total of 23 components of MST were identified. The formulation was found to alleviate metabolic disorders, obesity, insulin resistance, inflammation, and oxidative stress in mice with MAFLD. The findings indicate that MST promoted autophagy by suppressing phosphorylation in the PI3K/AKT/mTOR pathway and enhancing lipid management in the livers of MAFLD mice.CONCLUSION: MST could effectively improve lipid metabolism disorders and liver lipid deposition in MAFLD mice, and its mechanism might be related to regulating the PI3K/AKT/mTOR pathway to improve autophagy.PMID:39559790 | PMC:PMC11572505 | DOI:10.2147/DDDT.S478072

Front Pharmacol. 2024 Nov 4;15:1418063. doi: 10.3389/fphar.2024.1418063. eCollection 2024.ABSTRACTLomatogonium rotatum (LR) is a folk medicinal herb traditionally used as a lipid-lowering and anti-obesity agent; but its pharmacological mechanism is unclear. In this study, we assessed the alterations of LR on gut microbes and serum metabolites in obese mice and their associated mechanisms of modulation on visceral fat and serum lipid by integrating gut microbiota and metabolomics analyses. Mice were fed a high-fat diet (HFD) to generate obesity and were then given LR and Orlistat orally at different doses (0.18, 0.9, 1.8 g/kg for LR and 0.048 g/kg for Orlistat) for a duration of 9 weeks. The impact of LR on weight loss was assessed through the examination of fat deposition, serum lipid indices, liver indices, and HE pathohistology. The effects of LR on gut microbiota and serum metabolites in obese mice were then investigated by 16S rRNA sequencing technology and untargeted metabolomics, and correlation analysis was performed. LR significantly reduced body weight, feed intake, Lee's index, visceral fat accumulation, serum TG, TC, AST and ALT, and elevated serum HDL levels in obese mice. In addition, 16S rRNA sequencing results indicated that the LR intervention remodeled microbial diversity and composition, increased the relative abundance of gut microbes Bacteroidetes and Porphyromonadaceae in HFD-induced obese mice, and decreased the Deferribacteres, Firmicutes and the Firmicutes/Bacteroidetes ratio. Correlation analyses showed that LR regulation of L-tyrosine and hesperetin metabolism, as well as alterations in the metabolic pathways of Phenylalanine, tyrosine and tryptophan biosynthesis, were associated with the changes in abundance of Bacteroidetes, Firmicutes, Porphyromonadaceae and Deferribacteres. Our study demonstrated that LR has lipid lowering and visceral fat reduction effects and its function may be closely related to the improvement of the gut microbiota and its associated metabolites.PMID:39559734 | PMC:PMC11570273 | DOI:10.3389/fphar.2024.1418063

Front Immunol. 2024 Nov 4;15:1475528. doi: 10.3389/fimmu.2024.1475528. eCollection 2024.ABSTRACTSystemic sclerosis (SSc) is a rare and highly heterogeneous chronic autoimmune disease characterized by multi-organ and tissue fibrosis, often accompanied by a poor prognosis and high mortality rates. The primary pathogenic mechanisms of SSc are considered to involve tissue fibrosis, autoimmune dysfunction, and microvascular abnormalities. Recent studies have shed light on the gut microbiota (GM) and metabolites in SSc patients, revealing their association with gastrointestinal symptoms and disease phenotypes. However, further elucidation is needed on the specific mechanisms underlying the interactions between GM, metabolites, and the immune system and their roles in the pathogenesis of SSc. This review outlines the characteristics of GM and metabolites in SSc patients, exploring their interrelationships and analyzing their correlations with the clinical phenotypes of SSc. The findings indicate that while the α-diversity of GM in SSc patients resembles that of healthy individuals, notable differences exist in the β-diversity and the abundance of specific bacterial genera, which are closely linked to gastrointestinal symptoms. Moreover, alterations in the levels of amino acids and lipid metabolites in SSc patients are prominently observed and significantly associated with clinical phenotypes. Furthermore, this review delves into the potential immunopathological mechanisms of GM and metabolites in SSc, emphasizing the critical role of interactions between GM, metabolites, and the immune system in comprehending the immunopathological processes of SSc. These insights may offer new scientific evidence for the development of future treatment strategies.PMID:39559369 | PMC:PMC11570262 | DOI:10.3389/fimmu.2024.1475528