PubMed

J Food Sci. 2024 Oct 22. doi: 10.1111/1750-3841.17476. Online ahead of print.ABSTRACTDiabetes is marked by postprandial hyperglycemia (PHG), an abnormal rise in blood glucose after meals. A key therapeutic goal to reduce PHG is the inhibition of α-amylase (αAM) and α-glucosidase (αGL), enzymes that break down carbohydrates into sugars. Cucurbita moschata has been shown to inhibit both enzymes. However, its inhibition mechanism has not been explored. This study investigated the in vitro inhibition mechanisms of αAM and αGL and conducted a metabolomic analysis of C. moschata (edible part) water-extract (CME), aiming to preliminarily identify its bioactive compounds (BCs). The inhibitory mechanisms were determined using Lineweaver-Burk plots. The BCs were identified and quantified using HPLC-QTOF-MS, employing both targeted and untargeted metabolomic approaches. CME had a significant higher effect (p < 0.05) on αAM activity than against αGL with IC50 of 28.99 and 698.42 mg/mL, respectively. The extract showed mixed and uncompetitive type inhibitions on αAM and αGL, respectively. The lowest inhibition constant (Ki) was 47.68 mg/mL on αAM activity at 20 mg/mL. Untargeted metabolic profiling by UPLC-MS-ESI-QTOF putatively identified 30 compounds in CME, such as amino acids, vitamins, phytohormones, fatty acids, cucurbitacins and phenolic acids, and flavonoids. Functional analysis of CME identified significant pathways, including pantothenate and CoA biosynthesis and phenylpropanoids, among others. The targeted analysis by UPLC-MS-ESI-QqQ allowed us to identify 12 compounds, with l-phenylalanine, p-hydroxybenzoic, and p-coumaric acid as majors. This study demonstrated the inhibitory potential of CME on αAM and αGL activities, which may be attributed to its metabolites. Thus, this plant represents a valuable source of BC against PHG. Practical Application: The research highlights that Cucurbita moschata has significant potential in managing postprandial hyperglycemia in diabetic patients by inhibiting enzymes like α-amylase and α-glucosidase. In addition, the identification of its compounds emphasizes its importance as a source of bioactive compounds. Therefore, C. moschata could be effectively utilized in the development of nutraceuticals or as an ingredient in functional foods specifically designed for postprandial hyperglycemia management. Thus, integrating C. moschata as part of the daily diet could offer patients with diabetes a natural alternative to control their blood glucose levels after eating.PMID:39437304 | DOI:10.1111/1750-3841.17476

J Agric Food Chem. 2024 Oct 22. doi: 10.1021/acs.jafc.4c05325. Online ahead of print.ABSTRACTLippia citriodora and Olea europaea are known for their shared common bioactivities. Although both matrices are rich in similar families of bioactive compounds, their specific phytochemical compounds are mostly different. Since these compounds can be metabolized in the organism, this study hypothesized that common bioavailable metabolites may contribute to their similar bioactive effects. To test this, an acute double-blind intervention study in humans was conducted with blood samples collected at multiple time points. Using an untargeted metabolomic approach based on HPLC-ESI-QTOF-MS, 66 circulating metabolites were detected, including 9 common to both extracts, such as homovanillic acid sulfate and glucuronide derivates, hydroxytyrosol sulfate, etc. These common metabolites displayed significantly different Tmax values depending on the source, suggesting distinct metabolization pathways for each extract. The study highlights how shared bioavailable metabolites may underlie similar bioactivities observed between these two plant sources.PMID:39437164 | DOI:10.1021/acs.jafc.4c05325

Plant Biotechnol J. 2024 Oct 22. doi: 10.1111/pbi.14487. Online ahead of print.ABSTRACTWood of broad-leaf tree species is a valued source of renewable biomass for biorefinery and a target for genetic improvement efforts to reduce its recalcitrance. Glucuronoxylan (GX) plays a key role in recalcitrance through its interactions with cellulose and lignin. To reduce recalcitrance, we modified wood GX by expressing GH10 and GH11 endoxylanases from Aspergillus nidulans in hybrid aspen (Populus tremula L. × tremuloides Michx.) and targeting the enzymes to cell wall. The xylanases reduced tree height, modified cambial activity by increasing phloem and reducing xylem production, and reduced secondary wall deposition. Xylan molecular weight was decreased, and the spacing between acetyl and MeGlcA side chains was reduced in transgenic lines. The transgenic trees produced hypolignified xylem having thin secondary walls and deformed vessels. Glucose yields of enzymatic saccharification without pretreatment almost doubled indicating decreased recalcitrance. The transcriptomics, hormonomics and metabolomics data provided evidence for activation of cytokinin and ethylene signalling pathways, decrease in ABA levels, transcriptional suppression of lignification and a subset of secondary wall biosynthetic program, including xylan glucuronidation and acetylation machinery. Several candidate genes for perception of impairment in xylan integrity were detected. These candidates could provide a new target for uncoupling negative growth effects from reduced recalcitrance. In conclusion, our study supports the hypothesis that xylan modification generates intrinsic signals and evokes novel pathways regulating tree growth and secondary wall biosynthesis.PMID:39436777 | DOI:10.1111/pbi.14487

J Clin Invest. 2024 Oct 22:e183984. doi: 10.1172/JCI183984. Online ahead of print.ABSTRACTBACKGROUND: In type 1 diabetes (T1D), impaired insulin sensitivity may contribute to the development of diabetic kidney disease (DKD) through alterations in kidney oxidative metabolism.METHODS: Young adults with T1D (n = 30) and healthy controls (HC, n = 20) underwent hyperinsulinemic-euglycemic clamp studies, MRI, 11C-acetate PET, kidney biopsies, single-cell RNA sequencing, and spatial metabolomics to assess this relationship.RESULTS: Participants with T1D had significantly higher glomerular basement membrane thickness compared to HC. T1D participants exhibited lower insulin sensitivity and cortical oxidative metabolism, correlating with higher insulin sensitivity. Proximal tubular transcripts of TCA cycle and oxidative phosphorylation enzymes were lower in T1D. Spatial metabolomics showed reductions in tubular TCA cycle intermediates, indicating mitochondrial dysfunction. The Slingshot algorithm identified a lineage of proximal tubular cells progressing from stable to adaptive/maladaptive subtypes, using pseudotime trajectory analysis, which computationally orders cells along a continuum of states. This analysis revealed distinct distribution patterns between T1D and HC, with attenuated oxidative metabolism in T1D attributed to a greater proportion of adaptive/maladaptive subtypes with low expression of TCA cycle and oxidative phosphorylation transcripts. Pseudotime progression associated with higher HbA1c, BMI, GBM, and lower insulin sensitivity and cortical oxidative metabolism.CONCLUSION: These early structural and metabolic changes in T1D kidneys may precede clinical DKD.CLINICALTRIALS: gov NCT04074668.PMID:39436695 | DOI:10.1172/JCI183984

Geroscience. 2024 Oct 22. doi: 10.1007/s11357-024-01391-x. Online ahead of print.ABSTRACTThe 1-HMR metabolomics-based MetaboHealth score, comprised of 14 serum metabolic markers, associates with disease-specific mortality, but it is unclear whether the score also reflects cognitive changes and functional impairment. We aimed to assess the associations between the MetaboHealth score with cognitive function and functional decline in older adults at increased cardiovascular risk. A total of 5292 older adults free of dementia at baseline with mean age 75.3 years (SD = 3.4) from the Prospective Study of Pravastatin in the Elderly (PROSPER). MetaboHealth score were measured at baseline, and cognitive function and functional independence were measured at baseline and every 3 months during up to 2.5 years follow-up. Cognitive function was assessed using the Stroop test (selective attention), the Letter Digit Coding test (LDCT) (processing speed), and the two versions of the Picture Learning test (delayed and immediate; memory). Two tests of functional independence were used: Barthel Index (BI) and instrumental activities at daily living (IADL). A higher MetaboHealth score was associated with worse cognitive function (in all domains) and with worse functional independence. For example, after full adjustments, a 1-SD higher MetaboHealth score was associated with 9.02 s (95%CI 7.29, 10.75) slower performance on the Stroop test and 2.79 (2.21, 3.26) less digits coded on the LDCT. During follow-up, 1-SD higher MetaboHealth score was associated with an additional decline of 0.53 s (0.23, 0.83) on the Stroop test and - 0.08 (- 0.11, - 0.06) points on the IADL. Metabolic disturbance, as reflected by an increased metabolomics-based health score, may mark future cognitive and functional decline.PMID:39436550 | DOI:10.1007/s11357-024-01391-x

J Gen Physiol. 2024 Nov 4;156(11):e202313530. doi: 10.1085/jgp.202313530. Epub 2024 Oct 22.ABSTRACTThe phototransduction cascade enables the photoreceptor to detect light over a wide range of intensities without saturation. The main second messenger of the cascade is cGMP and the primary regulatory mechanism is calcium feedback. However, some experimental data suggest that cAMP may also play a role in regulating the phototransduction cascade, but this would require changes in cAMP on a time scale of seconds. Currently, there is a lack of data on the dynamics of changes in intracellular cAMP levels on this timescale. This is largely due to the specificity of the sensory modality of photoreceptors, which makes it practically impossible to use conventional experimental approaches based on fluorescence methods. In this study, we employed the method of rapid cryofixation of retinal samples after light stimulation and subsequent isolation of outer segment preparations. The study employed highly sensitive metabolomics approaches to measure levels of cAMP. Additionally, PKA activity was measured in the samples using a western blot. The results indicate that when exposed to near-saturating but still moderate light, cAMP levels increase transiently within the first second and then return to pre-stimulus levels. The increase in cAMP activates PKA, resulting in the phosphorylation of PKA-specific substrates in frog retinal outer segments.PMID:39436404 | DOI:10.1085/jgp.202313530

mSystems. 2024 Oct 22:e0081224. doi: 10.1128/msystems.00812-24. Online ahead of print.ABSTRACTIndividuals with latent tuberculosis infection (LTBI) account for almost 30% of the population worldwide and have the potential to develop active tuberculosis (ATB). Despite this, the current understanding of the pathogenesis of LTBI is limited. The gut microbiome can be altered in tuberculosis patients, and an understanding of the changes associated with the progression from good health to LTBI to ATB can provide novel perspectives for understanding the pathogenesis of LTBI by identifying microbial and molecular biomarkers associated therewith. In this study, fecal samples from healthy controls (HC), individuals with LTBI and ATB patients were collected for gut microbiome and metabolomics analyses. Compared to HC and LTBI subjects, participants with ATB showed a significant decrease in gut bacterial α-diversity. Additionally, there were significant differences in gut microbial communities and metabolism among the HC, LTBI, and ATB groups. PICRUSt2 analysis revealed that microbiota metabolic pathways involving the degradation of purine and pyrimidine metabolites were upregulated in LTBI and ATB individuals relative to HCs. Metabolomic profiling similarly revealed that purine and pyrimidine metabolite levels were decreased in LTBI and ATB samples relative to those from HCs. Further correlation analyses revealed that the levels of purine and pyrimidine metabolites were negatively correlated with those of gut microbial genera represented by Ruminococcus_gnavus_group (R. gnavus), and the levels of R. gnavus were also positively correlated with adenosine nucleotide degradation II, which is a purine degradation pathway. Moreover, a combined signature including hypoxanthine and xanthine was found to effectively distinguish between LTBI and HC samples (area under the curve [AUC] of training set = 0.796; AUC of testing set = 0.924). Therefore, through gut microbiome and metabolomic analyses, these findings provide valuable clues regarding how alterations in gut purine and pyrimidine metabolism are linked to the pathogenesis of LTBI.IMPORTANCEThis study provides valuable insight into alterations in the gut microbiome and metabolomic profiles in a cohort of adults with LTBI and ATB. Perturbed gut purine and pyrimidine metabolism in LTBI was associated with the compositional alterations of gut microbiota, which may be an impetus for developing novel diagnostic strategies and interventions targeting LTBI.PMID:39436103 | DOI:10.1128/msystems.00812-24

Expert Rev Neurother. 2024 Oct 22:1-14. doi: 10.1080/14737175.2024.2415985. Online ahead of print.ABSTRACTINTRODUCTION: Alzheimer's disease (AD) is the most common neurodegenerative disorder, which is characterized by a progressive loss of cognitive functions. The high prevalence, chronicity, and multimorbidity are very common in AD, which significantly impair the quality of life and functioning of patients. Early detection and accurate diagnosis of Alzheimer's disease (AD) can stop the illness from progressing thereby postponing its symptoms. Therefore, for the early diagnosis and monitoring of AD, more sensitive, noninvasive, straightforward, and affordable screening tools are needed.AREAS COVERED: This review summarizes the importance of early detection methods and novel techniques for Alzheimer's disease diagnosis that can be used by healthcare professionals.EXPERT OPINION: Early diagnosis assists the patient and caregivers to understand the problem establishing reasonable goals and making future plans together. Early diagnosis techniques not only help in monitoring disease progression but also provide crucial information for the development of novel therapeutic targets. Researchers can plan to potentially alleviate symptoms or slow down the progression of Alzheimer's disease by identifying early molecular changes and targeting altered pathways.PMID:39435792 | DOI:10.1080/14737175.2024.2415985

Neural Regen Res. 2024 Oct 22. doi: 10.4103/NRR.NRR-D-24-00531. Online ahead of print.ABSTRACTAge-related macular degeneration Is a serious neurodegenerativo disease of the retina that significantly impacts vision. Unfortunately, the specific pathogenesis remains unclear, and effective early treatment options are consequently lacking. The microbiome is defined as a large ecosystem of microorganisms living within and coexisting with a host. The intestinal microbiome undergoes dynamic changes owing to age, diet, genetics, and other factors. Such dysregulation of the intestinal flora can disrupt the microecological balance, resulting in immunological and metabolic dysfunction in the host, and affecting the development of many diseases. In recent decades, significant evidence has indicated that the intestinal flora also influences systems outside of the digestive tract, including the brain. Indeed, several studies have demonstrated the critical role of the gut-brain axis in the development of brain neurodegenerative diseases, including Alzheimer's disease and Parkinson's disease. Similarly, the role of the "gut-eye axis" has been confirmed to play a role in the pathogenesis of many ocular disorders. Moreover, age-related macular degeneration and many brain neurodegenerative diseases have been shown to share several risk factors and to exhibit comparable etiologies. As such, the intestinal flora may play an important role in age-related macular degeneration. Given the above context, the present review aims to clarify the gut-brain and gut-eye connections, assess the effect of intestinal flora and metabolites on age-related macular degeneration, and identify potential diagnostic markers and therapeutic strategies. Currently, direct research on the role of intestinal flora in age-related macular degeneration is still relatively limited, while studies focusing solely on intestinal flora are insufficient to fully elucidate its functional role in age-related macular degeneration. Organ-on-a-chip technology has shown promise in clarifying the gut-eye interactions, while integrating analysis of the intestinal flora with research on metabolites through metabolomics and other techniques is crucial for understanding their potential mechanisms.PMID:39435619 | DOI:10.4103/NRR.NRR-D-24-00531

Adv Sci (Weinh). 2024 Oct 22:e2309331. doi: 10.1002/advs.202309331. Online ahead of print.ABSTRACTCD169+ macrophages are a newly defined macrophage subpopulation that can recognize and bind with other cells through related ligands, playing an essential role in antigen presentation and immune tolerance. However, its role in Allergic Rhinitis (AR) is still unclear. To investigate the characteristics of CD169+ macrophages in AR, this work first detects their expression patterns in the nasal mucosa of clinical patients. These results show a significant increase in CD169+ macrophages in the nasal mucosa of patients with AR. Subsequently, this work establishes an animal AR model using CD169 transgenic mice and compared the advantages of the two models. Moreover, this work also demonstrates the effects of CD169 knockout on eosinophils, Th cells, Treg cells, and the migration of dendritic cells (DCs). In addition, this metabolomic data shows that CD169+ macrophages can upregulate alanine production and increase reactive oxygen species (ROS) levels. This process may be mediated through the Keap1/Nrf2/HO-1 signaling pathway. In addition, this work also finds that SLC38A2 plays an essential role in the process of CD169+ macrophages promoting alanine uptake by DCs. This study confirms that CD169+ macrophages can upregulate their internal alanine production and increase ROS levels through the Keap1/Nrf2/HO-1 axis, playing an irreplaceable role in AR.PMID:39435598 | DOI:10.1002/advs.202309331

Mol Genet Metab Rep. 2024 Oct 5;41:101145. doi: 10.1016/j.ymgmr.2024.101145. eCollection 2024 Dec.ABSTRACTAutosomal dominant congenital disorder of glycosylation (CDG) type Iw (OMIM# 619714) is caused by a heterozygous mutation in the STT3A gene. Most CDGs have an autosomal recessive (AR) mode of inheritance, but several cases with an autosomal dominant (AD) form of an AR CDG have been recently identified. This report describes a 17-year-old male who was referred to the Undiagnosed Diseases Network (UDN) with a history of macrocephaly, failure to thrive, short stature, epilepsy, autism, attention-deficit/hyperactivity disorder, mild developmental delay, intermittent hypotonia, dysmorphic features, and mildly enlarged aortic root. Trio exome sequencing was negative. His biochemical workup included normal plasma amino acids, ammonia, acylcarnitine profile and urine organic and amino acids. His UDN genome sequencing (GS) identified a previously unreported de novo STT3A variant (c.1631A > G: p.Asn544Ser). This variant removes a glycosylation site and was predicted to be destabilizing by structural biology modeling. The patient was formally diagnosed by the UDN Metabolomics Core as having an abnormal transferrin profile indicative of CDG type Iw through metabolomic profiling. We report here an affected male with phenotypic, molecular, and metabolic findings consistent with CDG type Iw due to a heterozygous STT3A variant. This case highlights the importance of further testing of individuals with the phenotypic and metabolic findings of an AR disorder who are heterozygous for a single disease-causing allele and can be shown to have a new AD form of the disorder that represents clinical heterogeneity.PMID:39435313 | PMC:PMC11491968 | DOI:10.1016/j.ymgmr.2024.101145

Front Plant Sci. 2024 Oct 7;15:1468858. doi: 10.3389/fpls.2024.1468858. eCollection 2024.ABSTRACTCoconut meat and coconut water have garnered significant attention for their richness in healthful flavonoids. However, the dynamics of flavonoid metabolites in coconut water during different developmental stages remain poorly understood. This study employed the metabolomics approach using liquid chromatography-tandem mass spectrometry (LC-MS/MS) to investigate the changes in flavonoid metabolite profiles in coconut water from two varieties, 'Wenye No.5'(W5) and Hainan local coconut (CK), across six developmental stages. The results showed that a total of 123 flavonoid metabolites including chalcones, dihydroflavonoids, dihydroflavonols, flavonoids, flavonols, flavonoid carboglycosides, and flavanols were identified in the coconut water as compared to the control. The total flavonoid content in both types of coconut water exhibited a decreasing trend with developmental progression, but the total flavonoid content in CK was significantly higher than that in W5. The number of flavonoid metabolites that differed significantly between the W5 and CK groups at different developmental stages were 74, 74, 60, 92, 40 and 54, respectively. KEGG pathway analysis revealed 38 differential metabolites involved in key pathways for flavonoid biosynthesis and secondary metabolite biosynthesis. This study provides new insights into the dynamics of flavonoid metabolites in coconut water and highlights the potential for selecting and breeding high-quality coconuts with enhanced flavonoid content. The findings have implications for the development of coconut-based products with improved nutritional and functional properties.PMID:39435019 | PMC:PMC11491327 | DOI:10.3389/fpls.2024.1468858

RSC Adv. 2024 Oct 21;14(45):33034-33047. doi: 10.1039/d4ra05758a. eCollection 2024 Oct 17.ABSTRACTEndophytes acquire flavonoid biosynthetic genes from the host medicinal plants. Despite tea (Camellia sinensis (L.) Kuntze) being the major source of bioactive catechins, catechin-producing endophytic fungi have never been reported from the tea plant. Here, we report the isolation and characterization of catechin-producing endophytic fungi isolated from tea leaves, their chemical characterization, and associated bioactivities. Among the nine isolated endophytes, two (CSPL6 and CSPL5b) produced catechin (381.48 and 166.40 μg per mg extract) and epigallocatechin-o-gallate (EGCG; 484.41 and 281.99 μg per mg extract) as quantified by high-performance liquid chromatography (HPLC). The isolates were identified as Pseudopestalotiopsis camelliae-sinensis and Didymella sinensis based on molecular and morphological characterization. Untargeted metabolomics using gas-chromatography mass spectroscopy (GCMS) revealed the presence of several bioactive phytochemicals mostly belonging to tyrosols, pyridoxines, fatty acids, aminopyrimidine, and benzenetriol classes. Metabolic pathways pertaining to the biosynthesis of unsaturated fatty acids (UFAs), butanoate metabolism, and linoleic acid metabolism were highly enriched in both catechin-producing isolates. The isolates were able to differentially scavenge intracellular O2 and N2 free-radicals, but CSPL5b demonstrated relatively superior bioactivities compared to CSPL6. Both isolates stimulated the growth of various probiotic strains, indicating prebiotic effects that are otherwise known to be associated with catechins. Collectively, the current study demonstrated that fungal endophytes CSPL6 and CSPL5b, isolated from tea leaves, could be used as alternative sources of catechins, and hold promising potential in evidence-based therapeutics.PMID:39434990 | PMC:PMC11492194 | DOI:10.1039/d4ra05758a

J Alzheimers Dis Rep. 2024 Jul 23;8(1):1093-1104. doi: 10.3233/ADR-230154. eCollection 2024.ABSTRACTBACKGROUND: Previous studies found that visual impairment (VI) is associated with higher risk of cognitive impairment, but the molecular basis of these conditions is unknown.OBJECTIVE: We aim to compare the metabolite associations of VI and cognitive impairment.METHODS: The study population with comprehensive measurements was derived from the UK Biobank study. Visual acuity worse than 0.3 logMAR units were defined as VI. Failure in one or more of the four cognitive tests was defined as cognitive impairment. A panel of 249 metabolites was measured using a nuclear magnetic resonance metabolites profiling platform. Logistic regression models were applied to compare metabolite associations with VI and cognitive impairment.RESULTS: 23,775 participants with complete data on visual acuity, cognitive tests and metabolomics, and without a history of neurological disorders at baseline were included. After adjusting for confounding factors, VI was significantly associated with cognitive impairment (odds ratio[OR] = 1.49, 95% confidence interval [CI]: 1.27-1.74, p < 0.001). After multiple testing correction (p < 9×10-4), five metabolites including the ratio of omega-6 to omega-3 fatty acids (FAs) (OR = 1.18[1.10-1.27]), ratio of omega-3 to total FAs (OR = 0.84[0.77-0.91]), ratio of docosahexaenoic acid (DHA) to total FAs (OR = 0.86[0.80-0.94]), DHA (OR = 0.85[0.78-0.92]), and omega-3 FAs (OR = 0.84[0.77-0.91]) were uniquely associated with VI. Glycoprotein acetyls (OR = 1.06[1.03-1.10]) and alanine (OR = 0.95[0.92-0.98]) were exclusively associated with cognitive impairment. Albumin was identified as the common metabolite shared by the two phenotypes (OR = 0.90[0.85-0.95] for VI, and 0.95[0.92-0.98]) for cognitive impairment).CONCLUSIONS: We identified distinct and overlapping metabolites associated with VI and cognitive impairment, unveiling their distinct metabolic profiles and potential common pathophysiology.PMID:39434817 | PMC:PMC11491940 | DOI:10.3233/ADR-230154

Korean J Intern Med. 2024 Oct 22. doi: 10.3904/kjim.2024.111. Online ahead of print.ABSTRACTDiabetic nephropathy (DN), a leading cause of chronic kidney disease and end-stage kidney disease (ESKD), poses global health challenges given its increasing prevalence. DN increases the risk of mortality and cardiovascular events. Early identification and appropriate DN management are crucial. However, current diagnostic methods rely on general traditional markers, highlighting the need for DN-specific diagnostics. Metabolomics, the study of small molecules produced by metabolic activity, promises to identify specific biomarkers that distinguish DN from other kidney diseases, decode the underlying disease mechanisms, and predict the disease course. Profound changes in metabolic pathways are apparent in individuals with DN, alterations in the tricarboxylic acid cycle and amino acid and lipid metabolism, suggestive of mitochondrial dysfunction. Metabolomics aids prediction of chronic kidney disease progression; several metabolites serve as indicators of renal functional decline and the risk of ESKD. Integration of such information with other omics data will further enhance our understanding of DN, paving the way to personalized treatment. In summary, metabolomics and multi-omics offer valuable insights into DN and are promising diagnostic and prognostic tools.PMID:39434603 | DOI:10.3904/kjim.2024.111

Biomed Chromatogr. 2024 Oct 21:e6029. doi: 10.1002/bmc.6029. Online ahead of print.ABSTRACTGiven the genetic and clinical overlap observed between schizophrenia and depression, the present study was to identify the similarities and differences in serum metabolic profiles between patients with schizophrenia and depression. Global metabolomics research methods based on UHPLC-QTOF-MS/MS were performed. A total of 113 and 118 differential metabolites were screened and identified in depression and schizophrenia groups, respectively, as compared to health control; among those, 94 differential metabolites were shared by both. Pathway analysis indicated arginine and proline metabolism, alanine, aspartate, and glutamate metabolism were two significant metabolic pathways both in depression and schizophrenia groups as compared with health control groups, respectively. Similarly, 77 differential metabolites were identified between depression and schizophrenia groups, in which, serum N-acetylglutamine and isovalerylglycine levels showed significant differences between patients with depression and schizophrenia with p values less than 0.001 and without significant outliers. Sphingolipid metabolism was identified as a significant metabolic pathway distinguishing between depression and schizophrenia groups based on pathway analysis. Conclusively, common alterations in arginine and proline metabolism, alanine, aspartate, and glutamate metabolism were observed in patients with schizophrenia and depression; whereas differences in serum N-acetylglutamine and isovalerylglycine levels as well as sphingolipid metabolism were discovered between the two categories of patients.PMID:39434479 | DOI:10.1002/bmc.6029

Genome Med. 2024 Oct 21;16(1):120. doi: 10.1186/s13073-024-01395-4.ABSTRACTBACKGROUND: Altered metabolism plays a role in the pathophysiology of cardiac diseases, such as atrial fibrillation (AF) and heart failure (HF). We aimed to identify novel plasma metabolites and proteins associating with cardiac disease.METHODS: Mendelian randomisation (MR) was used to assess the association of 174 metabolites measured in up to 86,507 participants with AF, HF, dilated cardiomyopathy (DCM), and non-ischemic cardiomyopathy (NICM). Subsequently, we sourced data on 1567 plasma proteins and performed cis MR to identify proteins affecting the identified metabolites as well as the cardiac diseases. Proteins were prioritised on cardiac expression and druggability, and mapped to biological pathways.RESULTS: We identified 35 metabolites associating with cardiac disease. AF was affected by seventeen metabolites, HF by nineteen, DCM by four, and NCIM by taurine. HF was particularly enriched for phosphatidylcholines (p = 0.029) and DCM for acylcarnitines (p = 0.001). Metabolite involvement with AF was more uniform, spanning for example phosphatidylcholines, amino acids, and acylcarnitines. We identified 38 druggable proteins expressed in cardiac tissue, with a directionally concordant effect on metabolites and cardiac disease. We recapitulated known associations, for example between the drug target of digoxin (AT1B2), taurine and NICM risk. Additionally, we identified numerous novel findings, such as higher RET values associating with phosphatidylcholines and decreasing AF and HF. RET is targeted by drugs such as regorafenib which has known cardiotoxic side-effects. Pathway analysis implicated involvement of GDF15 signalling through RET, and ghrelin regulation of energy homeostasis in cardiac pathogenesis.CONCLUSIONS: This study identified 35 plasma metabolites involved with cardiac diseases and linked these to 38 druggable proteins, providing actionable leads for drug development.PMID:39434187 | DOI:10.1186/s13073-024-01395-4

Microbiome. 2024 Oct 21;12(1):208. doi: 10.1186/s40168-024-01932-8.ABSTRACTBACKGROUND: The disease resistance phenotype is closely related to immunomodulatory function and immune tolerance and has far-reaching implications in animal husbandry and human health. Microbes play an important role in the initiation, prevention, and treatment of diseases, but the mechanisms of host-microbiota interactions in disease-resistant phenotypes are poorly understood. In this study, we hope to uncover and explain the role of microbes in intestinal diseases and their mechanisms of action to identify new potential treatments.METHODS: First, we established the colitis model of DSS in two breeds of sheep and then collected the samples for multi-omics testing including metagenes, metabolome, and transcriptome. Next, we made the fecal bacteria liquid from the four groups of sheep feces collected from H-CON, H-DSS, E-CON, and E-DSS to transplant the fecal bacteria into mice. H-CON feces were transplanted into mice named HH group and H-DSS feces were transplanted into mice named HD group and Roseburia bacteria treatment named HDR groups. E-CON feces were transplanted into mice named EH group and E-DSS feces were transplanted into mice in the ED group and Roseburia bacteria treatment named EDR groups. After successful modeling, samples were taken for multi-omics testing. Finally, colitis mice in HD group and ED group were administrated with Roseburia bacteria, and the treatment effect was evaluated by H&E, PAS, immunohistochemistry, and other experimental methods.RESULTS: The difference in disease resistance of sheep to DSS-induced colitis disease is mainly due to the increase in the abundance of Roseburia bacteria and the increase of bile acid secretion in the intestinal tract of Hu sheep in addition to the accumulation of potentially harmful bacteria in the intestine when the disease occurs, which makes the disease resistance of Hu sheep stronger under the same disease conditions. However, the enrichment of harmful microorganisms in East Friesian sheep activated the TNFα signalling pathway, which aggravated the intestinal injury, and then the treatment of FMT mice by culturing Roseburia bacteria found that Roseburia bacteria had a good curative effect on colitis.CONCLUSION: Our study showed that in H-DSS-treated sheep, the intestinal barrier is stabilized with an increase in the abundance of beneficial microorganisms. Our data also suggest that Roseburia bacteria have a protective effect on the intestinal barrier of Hu sheep. Accumulating evidence suggests that host-microbiota interactions are associated with IBD disease progression. Video Abstract.PMID:39434180 | DOI:10.1186/s40168-024-01932-8

BMC Genomics. 2024 Oct 21;25(1):984. doi: 10.1186/s12864-024-10903-0.ABSTRACTBACKGROUND: Hydrogen peroxide (H2O2), a novel water treatment agent, can be used for disinfection, water quality adjustment, and disease prevention, while excessive H2O2 can injure farm animals, even leading to death. Hydrogen peroxide is a recommended disinfectant and bactericide for treating gill diseases and vibriosis in the greenfin horse-faced filefish Thamnaconus septentrionalis. However, its cumulative effect, toxic molecular mechanism and relevant signal transduction/metabolic networks in marine fishes are largely unknown.RESULTS: We employed a multi-omics approach to investigate the detrimental effects of 50 mg/L H2O2 exposure (2 h/d) on filefish for 2 d, 4 d, and 6 d. Transcriptome sequencing showed that differentially expressed genes (DEGs) were mainly classified into functions such as signal transduction, nervous system, liver and bile acid metabolism, energy metabolism, cell adhesion and communication, inflammation and immune response. Metabolomic analysis found that the significantly changed metabolites (SCMs) were involved in phenylalanine metabolism, inflammatory mediator regulation, linoleic acid metabolism, and necroptosis. The main SCMs were cholic acid, carnitine C12:1, dimethylmalonic acid, glutamic acid, L-lactic acid, shikimic acid, 2-methylsuccinic acid, and others. Moreover, H2O2-induced oxidative stress also disturbs the balance of the gut microbiota, altering the microbial composition and affecting digestive processes.CONCLUSIONS: Integrated multiomics analysis revealed that H2O2-induced detrimental impacts include mucosal damage, inflammatory and immune responses, altered energy metabolism, and gut microbiota disorders. These findings offer novel insights into the harmful effects and signal transduction/metabolic pathways triggered by H2O2 exposure in marine fishes.PMID:39434036 | DOI:10.1186/s12864-024-10903-0

EMBO J. 2024 Oct 21. doi: 10.1038/s44318-024-00269-0. Online ahead of print.ABSTRACTThe mevalonate pathway produces essential lipid metabolites such as cholesterol. Although this pathway is negatively regulated by metabolic intermediates, little is known of the metabolites that positively regulate its activity. We found that the amino acid glutamine is required to activate the mevalonate pathway. Glutamine starvation inhibited cholesterol synthesis and blocked transcription of the mevalonate pathway-even in the presence of glutamine derivatives such as ammonia and α-ketoglutarate. We pinpointed this glutamine-dependent effect to a loss in the ER-to-Golgi trafficking of SCAP that licenses the activation of SREBP2, the major transcriptional regulator of cholesterol synthesis. Both enforced Golgi-to-ER retro-translocation and the expression of a nuclear SREBP2 rescued mevalonate pathway activity during glutamine starvation. In a cell model of impaired mitochondrial respiration in which glutamine uptake is enhanced, SREBP2 activation and cellular cholesterol were increased. Thus, the mevalonate pathway senses and is activated by glutamine at a previously uncharacterized step, and the modulation of glutamine synthesis may be a strategy to regulate cholesterol levels in pathophysiological conditions.PMID:39433901 | DOI:10.1038/s44318-024-00269-0