PubMed

Clin Transl Gastroenterol. 2024 Sep 3. doi: 10.14309/ctg.0000000000000766. Online ahead of print.ABSTRACTINTRODUCTION: Altered gut microbiota may play a role in slow-transit constipation (STC). We conducted a study of gut microbiota composition and functionality in STC using metagenomic analyses.METHODS: We assembled a clinical cohort of 24 patients with STC physiology age- and sex-matched to 24 controls. We performed shotgun metagenomic sequencing followed by prediction of metabolite composition from functional profiles.RESULTS: In a middle-aged (mean 55.3 years), predominantly female cohort, there were no significant differences in α diversity indices, but permutational multivariate analysis of variance analysis showed significant between-group differences (R2=0.050, p<0.001) between STC patients and controls. Gordonibacter pamelaeae, Bifidobacterium longum, Firmicutes bacterium CAG 94, and Anaerotruncus colihominis were more abundant in STC, while Coprococcus comes and Roseburia intestinalis were more abundant in controls. Gut-derived metabolites varying in STC relative to controls were related to bile acid and cholesterol metabolism.DISCUSSION: We found a unique metagenomic and metabolomic signature of STC.PMID:39225513 | DOI:10.14309/ctg.0000000000000766

Future Microbiol. 2024 Sep 3:1-17. doi: 10.1080/17460913.2024.2386867. Online ahead of print.ABSTRACTAim: To explore the complex relationship between gut microbiota, obesity-related male reproductive impairments, and the NLRP3 inflammasome.Methods: A high-fat diet was administered to induce obesity in a mouse model, fecal microbiota transplantation or a high-dietary fiber diet (HDFD) was administered for 5 weeks to evaluate changes in parameters related to reproductive capacity, NLRP3, gut microbiota composition and metabolites in mice.Results: A high-fat diet induces obesity and decreases reproductive capacity in male mice. Fecal microbiota transplantation and HDFD can improve reproductive capacity in obese mice by adjusting the gut microbiota population to suppress the NLRP3/ASC/caspase-1 axis, thereby reducing IL-1β levels.Conclusion: This study offers a potential treatment for obesity-induced reproductive dysfunction by targeting the gut microbiota and the NLRP3 inflammasome pathway.PMID:39225491 | DOI:10.1080/17460913.2024.2386867

mSystems. 2024 Sep 3:e0059524. doi: 10.1128/msystems.00595-24. Online ahead of print.ABSTRACTAltered composition of the gut microbiota affects immunity and metabolism. This study previously found that eIF6 gene knockdown changes the composition of the intestinal flora in the eIF6 gene knockdown mouse model. Lactobacillus acidophilus is significantly increased in the model. This study was designed to investigate the role of L. acidophilus in the pathogenesis of atherosclerosis. Transcriptomic data from 117 patients with coronary artery disease (CAD) and 79 healthy individuals were obtained. ApoE-/- and ApoE-/-/eIF6+/- mice on normal chow diet or a high-fat diet were treated for 16 weeks; eIF6 deficiency was evaluated atherosclerosis. ApoE-/- mice on normal chow diet or a high-fat diet were treated with L. acidophilus by daily oral gavage for 16 weeks. Moreover, one group was treated with lipopolysaccharide at 12 weeks. The levels of eIF6, RNASE3, and RSAD2 were notably higher in the patients with CAD than in the healthy individuals. eIF6 deficiency altered the composition of gut microbiota. eIF6 deficiency reduced the atherosclerotic lesion formation in ApoE-/-/eIF6+/- mice compared with the ApoE-/- mice. The microbial sequencing and metabolomics analysis demonstrated some beneficial bacterial (L. acidophilus, Ileibacterium, and Bifidobacterium) and metabolic levels significantly had deference in ApoE-/-/eIF6+/- mice compared with the ApoE-/- mice. Correlational studies indicated that L. acidophilus had close correlations with low-density lipoprotein cholesterol, lesion area, and necrotic area. L. acidophilus inhibited high-fat diet-induced inflammation and atherosclerotic lesion, increasing the expression of tight junction proteins (ZO-1 and claudin-1) and reducing the gut permeability. However, lipopolysaccharide reversed the protective effect of L. acidophilus against atherosclerosis. eIF6 deficiency protected against atherosclerosis by regulating the composition of gut microbiota and metabolites. L. acidophilus attenuated atherosclerotic lesions by reducing inflammation and increasing gut permeability.IMPORTANCEeIF6 deficiency modulates the gut microbiota and multiple metabolites in atherosclerotic ApoE-/- mice. L. acidophilus was reduced in the gut of atherosclerotic ApoE-/- mice, but administration of Lactobacillus acidophilus reversed intestinal barrier dysfunction and vascular inflammation. Our findings suggest that targeting individual species is a beneficial therapeutic strategy to prevent inflammation and atherosclerosis.PMID:39225466 | DOI:10.1128/msystems.00595-24

Scand J Clin Lab Invest. 2024 Sep 3:1-10. doi: 10.1080/00365513.2024.2392241. Online ahead of print.ABSTRACTBreast cancer (BC) is among the most commonly diagnosed cancers. Besides mammography, breast ultrasonography and the routinely monitored protein markers, the variations of small molecular metabolites in blood may be of great diagnostic value. This study aimed to quantify specific metabolite markers with potential application in BC detection. The study enrolled 50 participants, 25 BC patients and 25 healthy controls (CTRL). Dried blood spots (DBS) were utilized as biological media and were quantified via a simplified liquid chromatography tandem mass spectrometry (LC-MS/MS) method, used in expanded newborn screening. The targeted metabolomic analysis included 12 amino acids and 32 acylcarnitines. Statistical analysis revealed a significant variation of metabolic profiles between BC patients and CTRL. Among the 44 metabolites, 18 acylcarnitines and 10 amino acids remained significant after Bonferroni correction, showing increase or decrease and enabled classification of BC patients and CTRL. The well-established LC-MS/MS protocol could provide results within few minutes. Therefore, the combination of an easy-to-handle material-DBS and LC-MS/MS protocol could facilitate BC screening/diagnosis and in the next step applied to other cancer patients, as well.PMID:39225029 | DOI:10.1080/00365513.2024.2392241

Front Plant Sci. 2024 Aug 19;15:1431148. doi: 10.3389/fpls.2024.1431148. eCollection 2024.ABSTRACTThe primary pharmacological components of Desmodium styracifolium (Osbeck.) Merr. are flavonoids, which have a broad range of pharmacological effects and are important in many applications. However, there have been few reports on the molecular mechanisms underlying flavonoid biosynthesis in the pharmacodynamic constituents of D. styracifolium. Flavonoid biosynthesis in D. styracifolium pharmacodynamic constituents has, however, been rarely studied. In this study, we investigated how salt stress, 6-BA (6-Benzylaminopurine) treatment, and PEG 6000-simulated drought stress affect flavonoid accumulation in D. styracifolium leaves. We integrated metabolomics and transcriptomic analysis to map the secondary metabolism regulatory network of D. styracifolium and identify key transcription factors involved in flavonoid biosynthesis. We then constructed overexpression vectors for the transcription factors and used them to transiently infiltrate Nicotiana benthamiana for functional validation. This experiment confirmed that the transcription factor DsMYB60 promotes the production of total flavonoids in Nicotiana tabacum L. leaves. This study lays the foundation for studying flavonoid biosynthesis in D. styracifolium at the molecular level. Furthermore, this study contributes novel insights into the molecular mechanisms involved in the biosynthesis of active ingredients in medicinal plants.PMID:39224850 | PMC:PMC11366580 | DOI:10.3389/fpls.2024.1431148

Front Plant Sci. 2024 Aug 19;15:1453031. doi: 10.3389/fpls.2024.1453031. eCollection 2024.ABSTRACTIn plants, sugar metabolism involves a complex interplay of genetic, molecular and environmental factors. To better understand the molecular mechanisms underlying these processes, we utilized a multi-layered approach that integrated transcriptomic and metabolomic datasets generated from multiple different varieties of sweet corn. Through this analysis, we found 2533 genes that were differentially expressed in the immature kernel tissues of sweet corn, including genes involved in transcriptional regulation, sugar metabolism, primary metabolism, and other processes associated with adaptability of sweet corn. We also detected 31 differential metabolites among the three types of sweet corn. Utilizing an integrated approach encompassing transcriptomics and eGWAS, we elucidated the transcriptional regulatory patterns governing these differential metabolites. Specifically, we delved into the transcriptional modulation of malate- and ubiquitin-associated genes across a range of sweet corn varieties, shedding new light on the molecular mechanisms underlying their regulation. This study provides a framework for future research aimed at improving the current understanding of sugar metabolism and regulatory gene networks in sweet corn, which could ultimately lead to the development of novel strategies for crop improvement.PMID:39224849 | PMC:PMC11366663 | DOI:10.3389/fpls.2024.1453031

Front Plant Sci. 2024 Aug 14;15:1436429. doi: 10.3389/fpls.2024.1436429. eCollection 2024.ABSTRACTINTRODUCTION: Red spider mite (Tetranychus urticae) infestation (SMI) is a detrimental factor for roses grown indoors. Although predatory mite (Neoseiulus californicus) antagonism (PMA) is often utilized to alleviate SMI damage, little is known about the defensive response of greenhouse-grown roses to SMI and the molecular mechanism by which PMA protects roses.METHODS: To determine the transcriptome and metabolome responses of roses to SMI and PMA, the leaves of a rose cultivar ("Fairy Zixia/Nightingale") were infested with T. urticae, followed by the introduction of predator mite. Leaf samples were collected at various time points and subjected to transcriptome and metabolome analyses.RESULTS: We found that 24 h of SMI exerted the most changes in the expression of defense-related genes and metabolites in rose leaves. KEGG pathway analysis of differentially expressed genes (DEGs) and metabolites revealed that rose responses to SMI and PMA were primarily enriched in pathways such as sesquiterpenoid and triterpenoid biosynthesis, benzoxazinoid biosynthesis, stilbenoid, diarylheptanoid and gingerol biosynthesis, phytosterol biosynthesis, MAPK signaling pathway, phenylpropanoid biosynthesis, and other pathways associated with resistance to biotic stress. Rose reacted to SMI and PMA by increasing the expression of structural genes and metabolite levels in phytosterol biosynthesis, mevalonate (MVA) pathway, benzoxazinoid biosynthesis, and stilbenoid biosynthesis. In addition, PMA caused a progressive recover from SMI, allowing rose to revert to its normal growth state. PMA restored the expression of 190 essential genes damaged by SMI in rose leaves, including transcription factors DRE1C, BH035, MYB14, EF110, WRKY24, NAC71, and MY108. However, after 144 h of PMA treatment, rose responsiveness to stimulation was diminished, and after 192 h, the metabolic levels of organic acids and lipids were recovered in large measure.CONCLUSION: In conclusion, our results offered insights on how roses coordinate their transcriptome and metabolome to react to SMI and PMA, therefore shedding light on how roses, T. urticae, and N. californicus interact.PMID:39224847 | PMC:PMC11368075 | DOI:10.3389/fpls.2024.1436429

Front Cell Infect Microbiol. 2024 Aug 19;14:1393432. doi: 10.3389/fcimb.2024.1393432. eCollection 2024.ABSTRACTINTRODUCTION: The immune response regulates the severity of COVID-19 (sCOVID-19). This study examined the cause-and-effect relationship between immune cell traits (ICTs) and the risk of severe COVID-19. Additionally, we discovered the potential role of plasma metabolome in modulating this risk.METHODS: Employing data from a genome-wide association study (GWAS), we conducted a two-sample Mendelian randomization (MR) assessment of 731 genetic ICTs and sCOVID-19 (5,101 cases, 1,383,241 controls) incidence. The MR analysis was utilized to further quantitate the degree of plasma metabolome-mediated regulation of immune traits in sCOVID-19.RESULTS: The inverse variance weighted method recognized 2 plasma metabolites (PMs) responsible for casual associations between immune cells and sCOVID-19 risk. These included Tridecenedioate (C13:1-DC) which regulated the association between CD27 on IgD- CD38br (OR 0.804, 95% CI 0.699-0.925, p = 0.002) and sCOVID-19 risk (mediated proportion: 18.7%); arginine to citrulline ratio which controlled the relationship of CD39 on monocyte (OR 1.053, 95% CI 1.013-1.094, p = 0.009) with sCOVID-19 risk (mediated proportion: -7.11%). No strong evidence that genetically predicted sCOVID-19 influenced the aforementioned immune traits.CONCLUSION: In this study, we have successfully identified a cause-and-effect relationship between certain ICTs, PMs, and the likelihood of contracting severe COVID-19. Our findings can potentially improve the accuracy of COVID-19 prognostic evaluation and provide valuable insights into the underlying mechanisms of the disease.PMID:39224704 | PMC:PMC11366714 | DOI:10.3389/fcimb.2024.1393432

Food Chem X. 2024 Aug 6;23:101719. doi: 10.1016/j.fochx.2024.101719. eCollection 2024 Oct 30.ABSTRACTZhoupigan (Citrus reticulata cv. Manau Gan) is a local citrus variety in China. Its peel, known as Zangju peel (ZJP). The metabolic profile and bioactivity of ZJP have not been adequately studied, resulting in underutilization of ZJP and a serious waste of resources. In this study, GC-MS identified 46 components in ZJP, which defined ZJP's distinct aroma. Furthermore, UPLC-ESI-MS/MS detected 1506 metabolites in ZJP, and the differential metabolites were primarily involved in the biosynthesis of flavonoids and phenylacetone. Additionally, 56 key differential metabolites with metabolic pathways were identified. ZJP had significant antioxidant activity and the enzyme inhibitory activity ranking as pancreatic lipase (IC50 = 3.71 mg/mL) > α-glucosidase (IC50 = 6.28 mg/mL) > α-amylase (IC50 = 8.02 mg/mL). This study aimed to evaluate the potential of ZJP as natural antioxidant and functional food source and to serve as foundation for the further development of ZJP products with specific functional attributes.PMID:39224696 | PMC:PMC11367054 | DOI:10.1016/j.fochx.2024.101719

Front Cell Dev Biol. 2024 Aug 19;12:1431173. doi: 10.3389/fcell.2024.1431173. eCollection 2024.ABSTRACTDuring the metamorphosis of anuran amphibians, the tail resorption process is a necessary and crucial change. One subject that has received relatively little or no attention is the expression patterns of proteins and metabolites in the different tail portions during metamorphosis, especially in highland amphibians. The mechanisms of tail resorption in three portions (the tip, middle and root) of the tail were investigated in N. pleskei G43 tadpole based on two omics (proteomic and metabolomic). Integrin αVβ3 was found to be high expressed in the distal portion of the tail, which could improve the sensitiveness to thyroid hormones in the distal portion of the tail. Muscle regression displayed a spatial pattern with stronger regression in distal and weaker one in proximal portion. Probably, this stronger regression was mainly performed by the proteases of proteasome from the active translation by ribosomes. The suicide model and murder model coexisted in the tail resorption. Meanwhile, fatty acids, amino acids, pyrimidine, and purine which derived from the breakdown of tissues can be used as building blocks or energy source for successful metamorphosis. Our data improved a better comprehension of the tail resorption mechanisms underlying the metamorphism of N. pleskei tadpole through identifying important participating proteins and metabolites.PMID:39224435 | PMC:PMC11366584 | DOI:10.3389/fcell.2024.1431173

Heliyon. 2024 Aug 14;10(16):e36267. doi: 10.1016/j.heliyon.2024.e36267. eCollection 2024 Aug 30.ABSTRACTChronic hepatitis B infection (CHB) is a major risk factor for the development of hepatocellular carcinoma (HCC) globally and continues to pose a significant global health challenge. Jiawei Yinchenhao decoction (JWYCH) is a modified version of Yinchenhao decoction (YCHD), which is widely used to treat liver diseases including icteric hepatitis, cholelithiasis, and hepatic ascites. However, the effectiveness and underlying mechanism of JWYCH on CHB are still unclear. This study aimed to investigate the impact of JWYCH on CHB and explore the underlying mechanism via network pharmacology and metabolomics. C57BL/6 mice were administered rAAV-HBV1.3 via hydrodynamic injection (HDI) to establish the CHB model. The infected mice were orally administered JWYCH for 4 weeks. HBsAg, HBeAg, HBV DNA, the serum liver function index, and histopathology were detected. In addition, network pharmacology was used to investigate potential targets, whereas untargeted metabolomics analysis was employed to explore the hepatic metabolic changes in JWYCH in CHB mice and identify relevant biomarkers and metabolic pathways. JWYCH was able to reduce HBeAg levels and improve liver pathological changes in mice with CHB. Additionally, metabolomics analysis indicated that JWYCH can influence 105 metabolites, including pipecolic acid, alpha-terpinene, adenosine, and L-phenylalanine, among others. Bile acid metabolism, arachidonic acid metabolism, and retinol metabolism are suggested to be potential targets of JWYCH in CHB. In conclusion, JWYCH demonstrated a hepatoprotective effect on a mouse model of CHB, suggesting a potential alternative therapeutic strategy for CHB. The effect of JWYCH is associated mainly with regulating the metabolism of bile acid, arachidonic acid, and retinol. These differentially abundant metabolites may serve as potential biomarkers and therapeutic targets for CHB.PMID:39224343 | PMC:PMC11367511 | DOI:10.1016/j.heliyon.2024.e36267

Heliyon. 2024 Aug 8;10(16):e35966. doi: 10.1016/j.heliyon.2024.e35966. eCollection 2024 Aug 30.ABSTRACTPlant growth-promoting microorganisms (PGPMs), such as Pantoea sp. YSD J2, promote plant development and stress resistance, while their role in flavonoids accumulation still needs to be further understood. To investigate the complex flavonoid biosynthesis pathway of Cyperus esculentus L. var. sativus (tigernut), we compared Pantoea sp. YSD J2 inoculation (YSD J2) and water inoculation (CK) groups. YSD J2 significantly elevated the content of indole-3-acetic acid (IAA) and orientin. Furthermore, when analyzing flavonoid metabolome, YSD J2 caused increased levels of uralenol, petunidin-3-O-glucoside-5-O-arabinoside, luteolin-7-O-glucuronide-(2 → 1)-glucuronide, kaempferol-3-O-neohesperidoside, cyanidin-3-O-(2″-O-glucosyl)glucoside, kaempferol-3-O-glucuronide-7-O-glucoside, quercetin-3-O-glucoside, luteolin-7-O-glucuronide-(2 → 1)-(2″-sinapoyl)glucuronide, and quercetin-4'-O-glucoside, which further enhanced antioxidant activity. We then performed RNA-seq and LC-MS/MS, aiming to validate key genes and related flavonoid metabolites under YSD J2 inoculation, and rebuild the gene-metabolites regulatory subnetworks. Furthermore, the expression patterns of the trans cinnamate 4-monooxygenase (CYP73A), flavonol-3-O-L-rhamnoside-7-O-glucosyltransferase (UGT73C6), shikimate O-hydroxycinnamoyltransferase (HCT), chalcone isomerase (CHI), flavonol synthase (FLS), and anthocyanidin synthase (ANS) genes were confirmed by qRT-PCR. Additionally, 4 transcription factors (TF) (especially bHLH34, Cluster-37505.3) under YSD J2 inoculation are also engaged in regulating flavonoid accumulation. Moreover, the current work sheds new light on studying the regulatory effect of Pantoea sp. YSD J2 on tigernut development and flavonoid biosynthesis.PMID:39224290 | PMC:PMC11367128 | DOI:10.1016/j.heliyon.2024.e35966

Front Microbiol. 2024 Aug 19;15:1411645. doi: 10.3389/fmicb.2024.1411645. eCollection 2024.ABSTRACTINTRODUCTION: Parasites can facilitate their own spread and reproduction by manipulating insect hosts behavior, as seen in the interaction between Thitarodes xiaojinensis and Ophiocordyceps sinensis. Infection by O. sinensis leads to the mummification of T. xiaojinensis larvae, but the underlying mechanisms remain mysterious.METHODS: The morphology of O. sinensis infected larvae and fungal growth were first observed. Subsequently, the metabolite changes in the larvae before and after infection with the fungus were analyzed by LC/MS and targeted metabolomics. The expression of mannitol-related genes was detected using RT-qPCR, and morphological changes in larvae were observed after injection of different concentrations of mannitol into the O. sinensis-infected larvae.RESULTS: Significant changes were found in phenotype, fungal morphology in hemocoel, larval hardness, and mannitol metabolites in infected, mummified 0 h larvae and larvae 5 days after mummification behavior. Surprisingly, the occurrence of mummification behavior was accompanied by fungal dimorphism, as well as the absence of mannitol in both infected and non-infected larvae, until the initial accumulation of mannitol and the expression of mannitol-associated genes occurred at the time of mummification behavior. The presence of mannitol may promote fungal dimorphism to mediate changes in fungal toxicity or resistance, leading to the end of the fungus-insect coexistence period and the incidence of mummification behavior. Furthermore, mannitol injections increase the mummification rate of the infected larvae without significant difference from the normal mummification phenotype.DISCUSSION: This finding suggests the importance of mannitol in the mummification of host larvae infected with O. sinensis.PMID:39224221 | PMC:PMC11368059 | DOI:10.3389/fmicb.2024.1411645

Front Nutr. 2024 Aug 19;11:1461624. doi: 10.3389/fnut.2024.1461624. eCollection 2024.NO ABSTRACTPMID:39224186 | PMC:PMC11366702 | DOI:10.3389/fnut.2024.1461624

J Periodontal Res. 2024 Sep 3. doi: 10.1111/jre.13344. Online ahead of print.ABSTRACTAIM: Injectable platelet-rich fibrin (I-PRF), a second-generation platelet concentrate, is widely used to enhance soft and hard tissue healing alone or in combination with biomaterials, relying on its harboring of various pivotal growth/differentiation factors. This randomized trial assessed the effect of clindamycin (CLN) augmented injectable platelet-rich fibrin (I-PRF) with modified minimally invasive surgical technique (M-MIST) versus I-PRF alone with M-MIST on the clinical and radiographic parameters in the management of periodontal intra-bony defects in patients with stage-III grade B periodontitis.METHODS: This is a 9-month parallel-grouped, two arm, double-blinded, randomized controlled trial (RCT) that included 28 patients (n = 28) with stage-III grade B periodontitis, who were allocated randomly to test- (CLN/I-PRF + M-MIST, 50 μL of CLN per 1 mL of I-PRF; n = 14) or control-group (I-PRF + M-MIST; n = 14). Clinical attachment level (CAL; primary outcome), probing depth (PD), gingival margin level (GML), plaque index (PI), and gingival index (GI) were recorded at baseline, 3, 6, and 9 months, whereas radiographic parameters radiographic linear defect depth (RLDD), and radiographic defect area (RDA) were recorded at baseline, 6, and 9 months. The CLN release kinetics from the I-PRF were further characterized.RESULTS: Compared to baseline, both groups independently demonstrated significant improvements in CAL, PD, GML, GI, PI, RLDD and BDA at 3, 6 and 9 months (p < .05). A significant reduction in CAL measurements was noticeable in the CLN/I-PRF + M-MIST and I-PRF + M-MIST group independently over time (p < .05). CLN/I-PRF + M-MIST showed significantly lower CAL than PRF + M-MIST group at baseline, after three as well as 9 months (p < .05). Intergroup comparisons at 9 months demonstrated that CAL-gain was non-significant between groups (p > .05), GI significantly lower in CLN/I-PRF + M-MIST, whereas PD-reduction significantly higher I-PRF + M-MIST group (p < .05). CLN was steadily released for the I-PRF for up to 48 h, with a peak concentration at 24 h, which then gradually declined till the seventh day.CONCLUSIONS: I-PRF with M-MIST provided significant clinical and radiographic improvement up to 9 months postoperatively in stage-III grade B periodontitis. CLN, at the applied concentration and release duration, does not appear to further positively impact these observed I-PRF effects.PMID:39224058 | DOI:10.1111/jre.13344

Gut Microbes. 2024 Jan-Dec;16(1):2393272. doi: 10.1080/19490976.2024.2393272. Epub 2024 Sep 3.ABSTRACTThe intestine is the largest organ in terms of surface area in the human body. It is responsible not only for absorbing nutrients but also for protection against the external world. The gut microbiota is essential in maintaining a properly functioning intestinal barrier, primarily through producing its metabolites: short-chain fatty acids, bile acids, and tryptophan derivatives. Ethanol overconsumption poses a significant threat to intestinal health. Not only does it damage the intestinal epithelium, but, maybe foremostly, it changes the gut microbiome. Those ethanol-driven changes shift its metabolome, depriving the host of the protective effect the physiological gut microbiota has. This literature review discusses the impact of ethanol consumption on the gut, the gut microbiota, and its metabolome, providing a comprehensive overview of the mechanisms through which ethanol disrupts intestinal homeostasis and discussing potential avenues for new therapeutic intervention.PMID:39224006 | DOI:10.1080/19490976.2024.2393272

CNS Neurosci Ther. 2024 Sep;30(9):e70026. doi: 10.1111/cns.70026.ABSTRACTAIMS: Incidence of acute mountain sickness (AMS) ranges from 40%-90%, with high-altitude cerebral edema (HACE) representing a life-threatening end stage of severe AMS. However, practical and convenient preventive strategies for HACE are lacking. Remote ischemic preconditioning (RIPC) has demonstrated preventive effects on ischemia- or hypoxia-induced cardiovascular and cerebrovascular diseases. This study aimed to investigate the potential molecular mechanism of HACE and the application of RIPC in preventing HACE onset.METHODS: A hypobaric hypoxia chamber was used to simulate a high-altitude environment of 7000 meters. Metabolomics and metabolic flux analysis were employed to assay metabolite levels. Transcriptomics and quantitative real-time PCR (q-PCR) were used to investigate gene expression levels. Immunofluorescence staining was performed on neurons to label cellular proteins. The fluorescent probes Mito-Dendra2, iATPSnFR1.0, and CMTMRos were used to observe mitochondria, ATP, and membrane potential in cultured neurons, respectively. TUNEL staining was performed to detect and quantify apoptotic cell death. Hematoxylin and eosin (H&E) staining was utilized to analyze pathological changes, such as tissue swelling in cerebral cortex samples. The Rotarod test was performed to assess motor coordination and balance in rats. Oxygen-glucose deprivation (OGD) of cultured cells was employed as an in vitro model to simulate the hypoxia and hypoglycemia induced by RIPC in animal experiments.RESULTS: We revealed a causative perturbation of glucose metabolism in the brain preceding cerebral edema. Ischemic preconditioning treatment significantly reprograms glucose metabolism, ameliorating cell apoptosis and hypoxia-induced energy deprivation. Notably, ischemic preconditioning improves mitochondrial membrane potential and ATP production through enhanced glucose-coupled mitochondrial metabolism. In vivo studies confirm that RIPC alleviates cerebral edema, reduces cell apoptosis induced by high-altitude hypoxia, and improves motor dysfunction resulting from cerebral edema.CONCLUSIONS: Our study elucidates the metabolic basis of HACE pathogenesis. This study provides a new strategy for preventing HACE that RIPC reduces brain edema through reprogramming metabolism, highlighting the potential of targeting metabolic reprogramming for neuroprotective interventions in neurological diseases caused by ischemia or hypoxia.PMID:39223758 | DOI:10.1111/cns.70026

Eur J Clin Nutr. 2024 Sep 2. doi: 10.1038/s41430-024-01502-z. Online ahead of print.ABSTRACTBACKGROUND: The associations of gut microbial metabolites, such as trimethylamine N-oxide (TMAO), its precursors, and phenylacetylglutamine (PAGln), with the risk of gestational diabetes mellitus (GDM) remain unclear.METHODS: Serum samples of 201 women with GDM and 201 matched controls were collected and then targeted metabolomics was performed to examine the metabolites of interest. Multivariable conditional logistic regression was applied to investigate the relationship between metabolites and GDM. Meta-analysis was performed to combine our results and four similar articles searched from online databases, and Mendelian randomization (MR) analysis was eventually conducted to explore the causalities.RESULTS: In the case-control study, after dichotomization and comparing the higher versus the lower group, the adjusted odds ratio and 95% confidence interval of choline and L-carnitine with GDM were 2.124 (1.186-3.803) and 0.293 (0.134-0.638), respectively; but neutral relationships between TMAO, betaine, and PAGln with GDM were observed. The following meta-analysis consistently revealed that L-carnitine was negatively associated with GDM. However, MR analyses showed no evidence of causalities.CONCLUSIONS: Maternal levels of L-carnitine were related to the risk of GDM in both the original case-control study and meta-analysis. However, we did not observe any genetic evidence to establish a causal relationship between this metabolite and GDM.PMID:39223299 | DOI:10.1038/s41430-024-01502-z

Sci Rep. 2024 Sep 2;14(1):20385. doi: 10.1038/s41598-024-71516-x.ABSTRACTFermented traditional Chinese medicines (TCMs) have been identified as a low-cost and promising feed additive to to alleviate weaning stress in young livestock and poultry effectively. This study investigated the impact of probiotic fermentation on the metabolite content of BanQi (Radix Isatidis and Astragalus membranaceus) extract while also examined the effects of both fermented-BanQi (FBQ) and unfermented-BanQi (UBQ) on growth performance, serum biochemistry, intestinal villi, and gut microbiota in weaned lambs. This study demonstrated that compared with UBQ, FBQ contained significantly higher levels of free amino acids (e.g., phenylalanine and isoleucine), short peptides (e.g., Val-Leu-Pro-Val-Pro-Gln and Gly-Leu), and the active ingredients (e.g., vindesine and reserpine) (P < 0.05). The addition of FBQ to the diet significantly increased the final body weight and average daily gain of weaned lambs (P < 0.05). In addition, FBQ significantly increased the total protein level in the serum and the villus length of the jejunum and ileum in lambs, while significantly reduced the levels of aspartate aminotransferase (AST) and urea (P < 0.05). Sequencing of the intestinal flora showed that FBQ improved the diversity of intestinal flora and promoted the enrichment of beneficial bacteria in the lamb intestine, such as Mogibacterium and Butyrivibrio, compared to NC or UBQ groups (P < 0.05). Fermentation with Bacillus subtilis can enhance the content of free amino acids, peptides, and active ingredients in BanQi extract, making it an effective method to improve the efficacy of traditional Chinese medicine. Adding FBQ to the diet can improve the growth performance of weaned lambs, and its mechanism may be related to increasing the height of intestinal villi and increasing the diversity of intestinal flora.PMID:39223216 | DOI:10.1038/s41598-024-71516-x

Sci Rep. 2024 Sep 2;14(1):20386. doi: 10.1038/s41598-024-71416-0.ABSTRACTSodium-glucose cotransporter 2 (SGLT2) inhibitors have been shown to be renoprotective in ischemia-reperfusion (I/R) injury, with several proposed mechanisms, though additional mechanisms likely exist. This study investigated the impact of luseogliflozin on kidney fibrosis at 48 h and 1 week post I/R injury in C57BL/6 mice. Luseogliflozin attenuated kidney dysfunction and the acute tubular necrosis score on day 2 post I/R injury, and subsequent fibrosis at 1 week, as determined by Sirius red staining. Metabolomics enrichment analysis of I/R-injured kidneys revealed suppression of the glycolytic system and activation of mitochondrial function under treatment with luseogliflozin. Western blotting showed increased nutrient deprivation signaling with elevated phosphorylated AMP-activated protein kinase and Sirtuin-3 in luseogliflozin-treated kidneys. Luseogliflozin-treated kidneys displayed increased protein levels of carnitine palmitoyl transferase 1α and decreased triglyceride deposition, as determined by oil red O staining, suggesting activated fatty acid oxidation. Luseogliflozin prevented the I/R injury-induced reduction in nuclear factor erythroid 2-related factor 2 activity. Western blotting revealed increased glutathione peroxidase 4 and decreased transferrin receptor protein 1 expression. Immunostaining showed reduced 4-hydroxynonenal and malondialdehyde levels, especially in renal tubules, indicating suppressed ferroptosis. Luseogliflozin may protect the kidney from I/R injury by inhibiting ferroptosis through oxidative stress reduction.PMID:39223189 | DOI:10.1038/s41598-024-71416-0