PubMed

Metabolomics. 2024 Mar 6;20(2):36. doi: 10.1007/s11306-024-02089-z.ABSTRACTINTRODUCTION: Sepsis is a highly morbid condition characterized by multi-organ dysfunction resulting from dysregulated inflammation in response to acute infection. Mitochondrial dysfunction may contribute to sepsis pathogenesis, but quantifying mitochondrial dysfunction remains challenging.OBJECTIVE: To assess the extent to which circulating markers of mitochondrial dysfunction are increased in septic shock, and their relationship to severity and mortality.METHODS: We performed both full-scan and targeted (known markers of genetic mitochondrial disease) metabolomics on plasma to determine markers of mitochondrial dysfunction which distinguish subjects with septic shock (n = 42) from cardiogenic shock without infection (n = 19), bacteremia without sepsis (n = 18), and ambulatory controls (n = 19) - the latter three being conditions in which mitochondrial function, proxied by peripheral oxygen consumption, is presumed intact.RESULTS: Nine metabolites were significantly increased in septic shock compared to all three comparator groups. This list includes N-formyl-L-methionine (f-Met), a marker of dysregulated mitochondrial protein translation, and N-lactoyl-phenylalanine (lac-Phe), representative of the N-lactoyl-amino acids (lac-AAs), which are elevated in plasma of patients with monogenic mitochondrial disease. Compared to lactate, the clinical biomarker used to define septic shock, there was greater separation between survivors and non-survivors of septic shock for both f-Met and the lac-AAs measured within 24 h of ICU admission. Additionally, tryptophan was the one metabolite significantly decreased in septic shock compared to all other groups, while its breakdown product kynurenate was one of the 9 significantly increased.CONCLUSION: Future studies which validate the measurement of lac-AAs and f-Met in conjunction with lactate could define a sepsis subtype characterized by mitochondrial dysfunction.PMID:38446263 | DOI:10.1007/s11306-024-02089-z

Pest Manag Sci. 2024 Mar 6. doi: 10.1002/ps.8057. Online ahead of print.ABSTRACTBACKGROUND: Agaricus bisporus is a globally important edible fungus. The occurrence of ginger blotch caused by Pseudomonas 'gingeri' during A. bisporus growth and post-harvest stages results in significant economic losses. The biotoxin monoacetylphloroglucinol (MAPG) produced by P. 'gingeri' is responsible for inducing ginger blotch on A. bisporus. However, the understanding of the toxic mechanisms of MAPG on A. bisporus remains limited, which hinders the precise control of ginger blotch disease in A. bisporus and the breeding of disease-resistant varieties.RESULTS: Integrating transcriptomic, metabolomic, and physiological data revealed that MAPG led to an increase in intracellular superoxide anion (O2 - ) levels and lipid peroxidation in A. bisporus. MAPG changed the cellular membrane composition of A. bisporus, causing to damage membrane permeability. MAPG inhibited the expression of genes associated with the 19 s subunit of the proteasome, thereby impeding cellular waste degradation in A. bisporus. Unlike melanin, MAPG stimulated the synthesis of flavonoids in A. bisporus, which might explain the manifestation of ginger-colored symptoms rather than browning. Meanwhile, the glutathione metabolism pathway in A. bisporus played a pivotal role in counteracting the cytotoxic effects of MAPG. Additionally, enhanced catalase activity and upregulation of defense-related genes, including cytochrome P450s, Major Facilitator Superfamily (MFS), and ABC transporters, were observed.CONCLUSION: This study provides comprehensive insights into the MAPG toxicity in A. bisporus and uncovers the detoxification strategies of A. bisporus against MAPG. The findings offer valuable evidence for precise control and breeding of resistant varieties against ginger blotch in A. bisporus. This article is protected by copyright. All rights reserved.PMID:38446123 | DOI:10.1002/ps.8057

Proteomics. 2024 Mar 6:e2300312. doi: 10.1002/pmic.202300312. Online ahead of print.ABSTRACTThe ectoparasitic mite Varroa destructor transmits and triggers viral infections that have deleterious effects on honey bee colonies worldwide. We performed a manipulative experiment in which worker bees collected at emergence were exposed to Varroa for 72 h, and their proteomes were compared with those of untreated control bees. Label-free quantitative proteomics identified 77 differentially expressed A. mellifera proteins (DEPs). In addition, viral proteins were identified by orthogonal analysis, and most importantly, Deformed wing virus (DWV) was found at high levels/intensity in Varroa-exposed bees. Pathway enrichment analysis suggested that the main pathways affected included peroxisomal metabolism, cyto-/exoskeleton reorganization, and cuticular proteins. Detailed examination of individual DEPs revealed that additional changes in DEPs were associated with peroxisomal function. In addition, the proteome data support the importance of TGF-β signaling in Varroa-DWV interaction and the involvement of the mTORC1 and Hippo pathways. These results suggest that the effect of DWV on bees associated with Varroa feeding results in aberrant autophagy. In particular, autophagy is selectively modulated by peroxisomes, to which the observed proteome changes strongly corresponded. This study complements previous research with different study designs and suggests the importance of the peroxisome, which plays a key role in viral infections.PMID:38446070 | DOI:10.1002/pmic.202300312

J Bacteriol. 2024 Mar 6:e0037123. doi: 10.1128/jb.00371-23. Online ahead of print.ABSTRACTChlamydia trachomatis is an intracellular bacterial pathogen that undergoes a biphasic developmental cycle, consisting of intracellular reticulate bodies and extracellular infectious elementary bodies. A conserved bacterial protease, HtrA, was shown previously to be essential for Chlamydia during the reticulate body phase, using a novel inhibitor (JO146). In this study, isolates selected for the survival of JO146 treatment were found to have polymorphisms in the acyl-acyl carrier protein synthetase gene (aasC). AasC encodes the enzyme responsible for activating fatty acids from the host cell or synthesis to be incorporated into lipid bilayers. The isolates had distinct lipidomes with varied fatty acid compositions. A reduction in the lipid compositions that HtrA prefers to bind to was detected, yet HtrA and MOMP (a key outer membrane protein) were present at higher levels in the variants. Reduced progeny production and an earlier cellular exit were observed. Transcriptome analysis identified that multiple genes were downregulated in the variants especially stress and DNA processing factors. Here, we have shown that the fatty acid composition of chlamydial lipids, HtrA, and membrane proteins interplay and, when disrupted, impact chlamydial stress response that could trigger early cellular exit.IMPORTANCE: Chlamydia trachomatis is an important obligate intracellular pathogen that has a unique biphasic developmental cycle. HtrA is an essential stress or virulence protease in many bacteria, with many different functions. Previously, we demonstrated that HtrA is critical for Chlamydia using a novel inhibitor. In the present study, we characterized genetic variants of Chlamydia trachomatis with reduced susceptibility to the HtrA inhibitor. The variants were changed in membrane fatty acid composition, outer membrane proteins, and transcription of stress genes. Earlier and more synchronous cellular exit was observed. Combined, this links stress response to fatty acids, membrane proteins, and HtrA interplay with the outcome of disrupted timing of chlamydial cellular exit.PMID:38445896 | DOI:10.1128/jb.00371-23

Microbiol Spectr. 2024 Mar 6:e0523022. doi: 10.1128/spectrum.05230-22. Online ahead of print.ABSTRACTAltered gut microbiota and metabolites are important for non-alcoholic fatty liver disease (NAFLD) in children. We aimed to comprehensively examine the effects of gut metabolites on NAFLD progression. We performed integrative metabolomics (untargeted discovery and targeted validation) analysis of non-alcoholic fatty liver (NAFL), non-alcoholic steatohepatitis (NASH), and obesity in children. Fecal samples were collected from 75 subjects in the discovery cohort (25 NAFL, 25 NASH, and 25 obese control children) and 145 subjects in an independent validation cohort (53 NAFL, 39 NASH, and 53 obese control children). Among 2,491 metabolites, untargeted metabolomics revealed a complete NAFLD metabolic map containing 318 increased and 123 decreased metabolites. Then, machine learning selected 65 important metabolites that can distinguish the severity of the NAFLD. Furthermore, precision-targeted metabolomics selected 5 novel gut metabolites from 20 typical metabolites. The functionality of candidate metabolites was validated in hepatocyte cell lines. In the end, this study annotated two novel elevated pathogenic metabolites (dodecanoic acid and creatinine) and a relationship between depleted protective gut microbiota (Butyricicoccus and Alistipes), increased inflammation (IL-1β), lipid metabolism (TG), and liver function (ALT and AST). This study demonstrates the role of novel gut metabolites (dodecanoic acid and creatinine), as the fatty acid metabolism regulator contributing to NAFLD development through its influence on inflammation and liver function.IMPORTANCE: Altered gut microbiota and metabolites are a major cause of non-alcoholic fatty liver disease (NAFLD) in children. This study demonstrated a complete gut metabolic map of children with NAFLD, containing 318 increased and 123 decreased metabolites by untargeted metabolomic. Multiple validation approaches (machine learning and targeted metabolomic) selected five novel gut metabolites for targeted metabolomics, which can distinguish NAFLD status and severity. The gut microbiota (Butyricicoccus and Alistipes) and metabolites (creatinine and dodecanoic acid) were novel biomarkers associated with impaired liver function and inflammation and validated by experiments of hepatocyte cell lines. The data provide a better understanding of the importance of gut microbiota and metabolite alterations in NAFLD, which implies that the altered gut microbiota and metabolites may represent a potential target to prevent NAFLD development.PMID:38445874 | DOI:10.1128/spectrum.05230-22

Bioinformatics. 2024 Mar 5:btae132. doi: 10.1093/bioinformatics/btae132. Online ahead of print.ABSTRACTMOTIVATION: Identification of genomic, molecular and clinical markers prognostic of patient survival is important for developing personalized disease prevention, diagnostic and treatment approaches. Modern omics technologies have made it possible to investigate the prognostic impact of markers at multiple molecular levels, including genomics, epigenomics, transcriptomics, proteomics and metabolomics, and how these potential risk factors complement clinical characterization of patient outcomes for survival prognosis. However, the massive sizes of the omics data sets, along with their correlation structures, pose challenges for studying relationships between the molecular information and patients' survival outcomes.RESULTS: We present a general workflow for survival analysis that is applicable to high-dimensional omics data as inputs when identifying survival-associated features and validating survival models. In particular, we focus on the commonly used Cox-type penalized regressions and hierarchical Bayesian models for feature selection in survival analysis, which are are especially useful for high-dimensional data, but the framework is applicable more generally.AVAILABILITY AND IMPLEMENTATION: A step-by-step R tutorial using The Cancer Genome Atlas survival and omics data for the execution and evaluation of survival models has been made available at https://ocbe-uio.github.io/survomics/survomics.html.PMID:38445722 | DOI:10.1093/bioinformatics/btae132

Gut Microbes. 2024 Jan-Dec;16(1):2325067. doi: 10.1080/19490976.2024.2325067. Epub 2024 Mar 6.ABSTRACTThe gut-to-lung axis is critical during respiratory infections, including influenza A virus (IAV) infection. In the present study, we used high-resolution shotgun metagenomics and targeted metabolomic analysis to characterize influenza-associated changes in the composition and metabolism of the mouse gut microbiota. We observed several taxonomic-level changes on day (D)7 post-infection, including a marked reduction in the abundance of members of the Lactobacillaceae and Bifidobacteriaceae families, and an increase in the abundance of Akkermansia muciniphila. On D14, perturbation persisted in some species. Functional scale analysis of metagenomic data revealed transient changes in several metabolic pathways, particularly those leading to the production of short-chain fatty acids (SCFAs), polyamines, and tryptophan metabolites. Quantitative targeted metabolomics analysis of the serum revealed changes in specific classes of gut microbiota metabolites, including SCFAs, trimethylamine, polyamines, and indole-containing tryptophan metabolites. A marked decrease in indole-3-propionic acid (IPA) blood level was observed on D7. Changes in microbiota-associated metabolites correlated with changes in taxon abundance and disease marker levels. In particular, IPA was positively correlated with some Lactobacillaceae and Bifidobacteriaceae species (Limosilactobacillus reuteri, Lactobacillus animalis) and negatively correlated with Bacteroidales bacterium M7, viral load, and inflammation markers. IPA supplementation in diseased animals reduced viral load and lowered local (lung) and systemic inflammation. Treatment of mice with antibiotics targeting IPA-producing bacteria before infection enhanced viral load and lung inflammation, an effect inhibited by IPA supplementation. The results of this integrated metagenomic-metabolomic analysis highlighted IPA as an important contributor to influenza outcomes and a potential biomarker of disease severity.PMID:38445660 | DOI:10.1080/19490976.2024.2325067

Hypertension. 2024 Mar 6. doi: 10.1161/HYPERTENSIONAHA.123.22614. Online ahead of print.ABSTRACTBACKGROUND: Hypertension, a complex condition, is primarily defined based on blood pressure readings without involving its pathophysiological mechanisms. We aimed to identify biomarkers through a proteomic approach, thereby enhancing the future definition of hypertension with insights into its molecular mechanisms.METHODS: The discovery analysis included 1560 participants, aged 55 to 74 years at baseline, from the KORA (Cooperative Health Research in the Region of Augsburg) S4/F4/FF4 cohort study, with 3332 observations over a median of 13.4 years of follow-up. Generalized estimating equations were used to estimate the associations of 233 plasma proteins with hypertension and systolic blood pressure (SBP). For validation, proteins significantly associated with hypertension or SBP in discovery analysis were validated in the KORA-Age1/Age2 cohort study (1024 participants, 1810 observations). A 2-sample Mendelian randomization analysis was conducted to infer causalities of validated proteins with SBP.RESULTS: Discovery analysis identified 49 proteins associated with hypertension and 99 associated with SBP. Validation in the KORA-Age1/Age2 study replicated 7 proteins associated with hypertension and 23 associated with SBP. Three proteins, NT-proBNP (N-terminal pro-B-type natriuretic peptide), KIM1 (kidney injury molecule 1), and OPG (osteoprotegerin), consistently showed positive associations with both outcomes. Five proteins demonstrated potential causal associations with SBP in Mendelian randomization analysis, including NT-proBNP and OPG.CONCLUSIONS: We identified and validated 7 hypertension-associated and 23 SBP-associated proteins across 2 cohort studies. KIM1, NT-proBNP, and OPG demonstrated robust associations, and OPG was identified for the first time as associated with blood pressure. For NT-proBNP (protective) and OPG, causal associations with SBP were suggested.PMID:38445514 | DOI:10.1161/HYPERTENSIONAHA.123.22614

Eco Environ Health. 2024 Jan 24;3(1):107-115. doi: 10.1016/j.eehl.2024.01.003. eCollection 2024 Mar.ABSTRACTChemical exposure and local hypoxia caused by mask-wearing may result in skin physiology changes. The effects of methylparaben (MeP), a commonly used preservative in personal care products, and hypoxia on skin health were investigated by HaCaT cell and ICR mouse experiments. MeP exposure resulted in lipid peroxidation and interfered with cellular glutathione metabolism, while hypoxia treatment disturbed phenylalanine, tyrosine, and tryptophan biosynthesis pathways and energy metabolism to respond to oxidative stress. A hypoxic environment increased the perturbation of MeP on the purine metabolism in HaCaT cells, resulting in increased expression of proinflammatory cytokines. The synergistic effects were further validated in a mouse model with MeP dermal exposure and "mask-wearing" treatment. CAT, PPARG, and MMP2 were identified as possible key gene targets associated with skin health risks posed by MeP and hypoxia. Network toxicity analysis suggested a synergistic effect, indicating the risk of skin inflammation and skin barrier aging.PMID:38445214 | PMC:PMC10912353 | DOI:10.1016/j.eehl.2024.01.003

Front Psychiatry. 2024 Feb 20;15:1261617. doi: 10.3389/fpsyt.2024.1261617. eCollection 2024.ABSTRACTBACKGROUND: Complementary to traditional biostatistics, the integration of untargeted urine metabolomic profiling with Machine Learning (ML) has the potential to unveil metabolic profiles crucial for understanding diseases. However, the application of this approach in autism remains underexplored. Our objective was to delve into the metabolic profiles of autism utilizing a comprehensive untargeted metabolomics platform coupled with ML.METHODS: Untargeted metabolomics quantification (UHPLC/Q-TOF-MS) was performed for urine analysis. Feature selection was conducted using Lasso regression, and logistic regression, support vector machine, random forest, and extreme gradient boosting were utilized for significance stratification. Pathway enrichment analysis was performed to identify metabolic pathways associated with autism.RESULTS: A total of 52 autistic children and 40 typically developing children were enrolled. Lasso regression identified ninety-two urinary metabolites that significantly differed between the two groups. Distinct metabolites, such as prostaglandin E2, phosphonic acid, lysine, threonine, and phenylalanine, were revealed to be associated with autism through the application of four different ML methods (p<0.05). The alterations observed in the phosphatidylinositol and inositol phosphate metabolism pathways were linked to the pathophysiology of autism (p<0.05).CONCLUSION: Significant urinary metabolites, including prostaglandin E2, phosphonic acid, lysine, threonine, and phenylalanine, exhibit associations with autism. Additionally, the involvement of the phosphatidylinositol and inositol phosphate pathways suggests their potential role in the pathophysiology of autism.PMID:38445087 | PMC:PMC10912307 | DOI:10.3389/fpsyt.2024.1261617

Front Microbiol. 2024 Feb 20;15:1349367. doi: 10.3389/fmicb.2024.1349367. eCollection 2024.ABSTRACTThe human gut microbiota is a complex microbial community with critical functions for the host, including the transformation of various chemicals. While effects on microorganisms has been evaluated using single-species models, their functional effects within more complex microbial communities remain unclear. In this study, we investigated the response of a simplified human gut microbiota model (SIHUMIx) cultivated in an in vitro bioreactor system in combination with 96 deep-well plates after exposure to 90 different xenobiotics, comprising 54 plant protection products and 36 food additives and dyes, at environmentally relevant concentrations. We employed metaproteomics and metabolomics to evaluate changes in bacterial abundances, the production of Short Chain Fatty Acids (SCFAs), and the regulation of metabolic pathways. Our findings unveiled significant changes induced by 23 out of 54 plant protection products and 28 out of 36 food additives across all three categories assessed. Notable highlights include azoxystrobin, fluroxypyr, and ethoxyquin causing a substantial reduction (log2FC < -0.5) in the concentrations of the primary SCFAs: acetate, butyrate, and propionate. Several food additives had significant effects on the relative abundances of bacterial species; for example, acid orange 7 and saccharin led to a 75% decrease in Clostridium butyricum, with saccharin causing an additional 2.5-fold increase in E. coli compared to the control. Furthermore, both groups exhibited up- and down-regulation of various pathways, including those related to the metabolism of amino acids such as histidine, valine, leucine, and isoleucine, as well as bacterial secretion systems and energy pathways like starch, sucrose, butanoate, and pyruvate metabolism. This research introduces an efficient in vitro technique that enables high-throughput screening of the structure and function of a simplified and well-defined human gut microbiota model against 90 chemicals using metaproteomics and metabolomics. We believe this approach will be instrumental in characterizing chemical-microbiota interactions especially important for regulatory chemical risk assessments.PMID:38444810 | PMC:PMC10912515 | DOI:10.3389/fmicb.2024.1349367

ERJ Open Res. 2024 Mar 4;10(2):00805-2023. doi: 10.1183/23120541.00805-2023. eCollection 2024 Mar.ABSTRACTMetabolic signatures are lacking for heated tobacco products, making it crucial to identify new biosignatures of lung damage. This will enable the establishment of product-specific guidelines and an understanding of associated toxicity. https://bit.ly/3TkhBox.PMID:38444658 | PMC:PMC10910264 | DOI:10.1183/23120541.00805-2023

Front Plant Sci. 2024 Feb 20;15:1334996. doi: 10.3389/fpls.2024.1334996. eCollection 2024.ABSTRACTSoft rot of konjac (Amorphophallus spp.) is a devastating disease caused by the bacterium Pectobacterium carotovorum subsp. carotovorum (Pcc) with serious adverse effects on plantation development, corm quality and crop yield due to the current lack of effective control measures. The main objective of the present study was to elucidate the mechanisms underlying plant resistance to soft rot disease. A combination of transcriptomic and metabolomic analyses demonstrated significant enrichment of differentially expressed genes (DEG) and differentially accumulated metabolites (DAM) associated with plant hormones, phenylpropanoid biosynthesis and, in particular, alkaloid metabolism, in Amorphophallus muelleri following Pcc infection compared with A. konjac, these data implicate alkaloid metabolism as the dominant mechanism underlying disease resistance of A. muelleri. Quantitative real-time polymerase chain reaction analysis further revealed involvement of PAL, CYP73A16, CCOAOMT1, RBOHD and CDPK20 genes in the response of konjac to Pcc. Analysis of the bacteriostatic activities of total alkaloid from A. muelleri validated the assumption that alkaloid metabolism positively regulates disease resistance of konjac. Our collective results provide a foundation for further research on the resistance mechanisms of konjac against soft rot disease.PMID:38444534 | PMC:PMC10912172 | DOI:10.3389/fpls.2024.1334996

Front Plant Sci. 2024 Feb 20;15:1375876. doi: 10.3389/fpls.2024.1375876. eCollection 2024.NO ABSTRACTPMID:38444532 | PMC:PMC10913081 | DOI:10.3389/fpls.2024.1375876

Front Plant Sci. 2024 Feb 20;15:1319680. doi: 10.3389/fpls.2024.1319680. eCollection 2024.ABSTRACTPigments derived from red pepper fruits are widely used in food and cosmetics as natural colorants. Nitrogen (N) is a key nutrient affecting plant growth and metabolism; however, its regulation of color-related metabolites in pepper fruit has not been fully elucidated. This study analyzed the effects of N supply (0, 250, and 400 kg N ha-1) on the growth, fruit skin color, and targeted and non-target secondary metabolites of field-grown pepper fruits at the mature red stage. Overall, 16 carotenoids were detected, of which capsanthin, zeaxanthin, and capsorubin were the dominant ones. N application at 250 kg ha-1 dramatically increased contents of red pigment capsanthin, yellow-orange zeaxanthin and β-carotene, with optimum fruit yield. A total of 290 secondary metabolites were detected and identified. The relative content of most flavonoids and phenolic acids was decreased with increasing N supply. Correlation analysis showed that color parameters were highly correlated with N application rates, carotenoids, flavonoids, phenolic acids, lignans, and coumarins. Collectively, N promoted carotenoid biosynthesis but downregulated phenylpropanoid and flavonoid biosynthesis, which together determined the spectrum of red color expression in pepper fruit. Our results provide a better understanding of the impact of N nutrition on pepper fruit color formation and related physiology, and identification of target metabolites for enhancement of nutritional quality and consumer appeal.PMID:38444531 | PMC:PMC10912300 | DOI:10.3389/fpls.2024.1319680

Heliyon. 2024 Feb 24;10(5):e27075. doi: 10.1016/j.heliyon.2024.e27075. eCollection 2024 Mar 15.ABSTRACTNonalcoholic fatty liver disease (NAFLD) has emerged as a prominent global health concern, representing a substantial burden within the spectrum of chronic liver diseases. Despite its escalating prevalence, a definitive therapeutic strategy or efficacious pharmacological intervention for NAFLD has yet to receive official approval to date. While Fu Fang Qiyin granules have exhibited efficacy in addressing NAFLD, the intricacies of their underlying mechanism of action remain inadequately elucidated. In this study, we substantiated the ameliorative impact of Qiyin on highfat diet (HFD)induced NAFLD in rat models. The results of metabonomics showed that 108 potential biomarkers in serum and urine related to amino acid metabolism, energy metabolism, and pyrimidine metabolism, have returned to normal levels compared to the model group. Hepatic transcriptomics further indicated that Qiyin potentially confers protective effects against NAFLD by mediating liver inflammation and fibrosis through lumican (LUM) and decorin (DCN). In summation, our investigation provides compelling evidence affirming the therapeutic promise of Qiyin for NAFLD. It elucidates the underlying mechanistic pathways, furnishing a compelling rationale for its prospective clinical application.PMID:38444462 | PMC:PMC10912341 | DOI:10.1016/j.heliyon.2024.e27075

Gut Microbes. 2024 Jan-Dec;16(1):2323752. doi: 10.1080/19490976.2024.2323752. Epub 2024 Mar 6.ABSTRACTAlzheimer's disease (AD) is a debilitating brain disorder with rapidly mounting prevalence worldwide, yet no proven AD cure has been discovered. Using a multi-omics approach in a transgenic AD mouse model, the current study demonstrated the efficacy of a modified Mediterranean-ketogenic diet (MkD) on AD-related neurocognitive pathophysiology and underlying mechanisms related to the gut-microbiome-brain axis. The findings revealed that MkD induces profound shifts in the gut microbiome community and microbial metabolites. Most notably, MkD promoted growth of the Lactobacillus population, resulting in increased bacteria-derived lactate production. We discovered elevated levels of microbiome- and diet-derived metabolites in the serum as well, signaling their influence on the brain. Importantly, these changes in serum metabolites upregulated specific receptors that have neuroprotective effects and induced alternations in neuroinflammatory-associated pathway profiles in hippocampus. Additionally, these metabolites displayed strong favorable co-regulation relationship with gut-brain integrity and inflammatory markers, as well as neurobehavioral outcomes. The findings underscore the ameliorative effects of MkD on AD-related neurological function and the underlying gut-brain communication via modulation of the gut microbiome-metabolome arrays.PMID:38444392 | DOI:10.1080/19490976.2024.2323752

Brain Behav. 2024 Mar;14(3):e3448. doi: 10.1002/brb3.3448.ABSTRACTINTRODUCTION: Treatment strategies for depression based on interventions for glucose and lipid metabolism disorders are receiving increasing attention. Investigating the mechanism of their antidepressant effect and exploring new diagnostic and therapeutic biomarkers have attracted increasing attention. Dulaglutide, a long-acting GLP-1 receptor agonist, has been reported to alleviate cognitive deficits and neuronal damage. However, the antidepressant effect of dulaglutide and, especially, the underlying mechanism are still poorly understood. In this study, we aimed to explore the underlying biomarkers of depression and potential modulatory targets of dulaglutide in chronic mild stress (CMS) mice.METHODS: Sixty mice were randomly divided into a control group (CON group), a CMS+Vehicle group (CMS+Veh group), a CMS+0.3 mg/kg dulaglutide group (Low Dula group), and a CMS+0.6 mg/kg dulaglutide group (High Dula group). Numerous behavioral tests, mainly the open field test, forced swimming test, and tail suspension test, were applied to evaluate the potential effect of dulaglutide treatment on anxiety- and depression-like behaviors in mice exposed to chronic stress. Furthermore, a liquid chromatography-tandem mass spectrometry-based metabolomics approach was utilized to investigate the associated mechanisms of dulaglutide treatment.RESULTS: Three weeks of dulaglutide treatment significantly reversed depressive-like but not anxiety-like behaviors in mice exposed to chronic stress for 4 weeks. The results from the metabolomics analysis showed that a total of 20 differentially expressed metabolites were identified between the CON and CMS+Veh groups, and 46 metabolites were selected between the CMS+Veh and High Dula groups in the hippocampus of the mice. Comprehensive analysis indicated that lipid metabolism, amino acid metabolism, energy metabolism, and tryptophan metabolism were disrupted in model mice that experienced depression and underwent dulaglutide therapy.CONCLUSION: The antidepressant effects of dulaglutide in a CMS depression model were confirmed. We identified 64 different metabolites and four major pathways associated with metabolic pathophysiological processes. These primary data provide a new perspective for understanding the antidepressant-like effects of dulaglutide and may facilitate the use of dulaglutide as a potential therapeutic strategy for depression.PMID:38444330 | DOI:10.1002/brb3.3448

Plant Cell Environ. 2024 Mar 5. doi: 10.1111/pce.14871. Online ahead of print.ABSTRACTDay respiration (Rd ) is the metabolic, nonphotorespiratory process by which illuminated leaves liberate CO2 during photosynthesis. Rd is used routinely in photosynthetic models and is thus critical for calculations. However, metabolic details associated with Rd are poorly known, and this can be problematic to predict how Rd changes with environmental conditions and relates to night respiration. It is often assumed that day respiratory CO2 release just reflects 'ordinary' catabolism (glycolysis and Krebs 'cycle'). Here, we carried out a pulse-chase experiment, whereby a 13 CO2 pulse in the light was followed by a chase period in darkness and then in the light. We took advantage of nontargeted, isotope-assisted metabolomics to determine non-'ordinary' metabolism, detect carbon remobilisation and compare light and dark 13 C utilisation. We found that several concurrent metabolic pathways ('ordinary' catabolism, oxidative pentose phosphates pathway, amino acid production, nucleotide biosynthesis and secondary metabolism) took place in the light and participated in net CO2 efflux associated with day respiration. Flux reconstruction from metabolomics leads to an underestimation of Rd , further suggesting the contribution of a variety of CO2 -evolving processes. Also, the cornerstone of the Krebs 'cycle', citrate, is synthetised de novo from photosynthates mostly in darkness, and remobilised or synthesised from stored material in the light. Collectively, our data provides direct evidence that leaf day respiration (i) involves several CO2 -producing reactions and (ii) is fed by different carbon sources, including stored carbon disconnected from current photosynthates.PMID:38444114 | DOI:10.1111/pce.14871

Scand J Immunol. 2024 Jan;99(1):e13328. doi: 10.1111/sji.13328. Epub 2023 Sep 11.ABSTRACTCalcineurin inhibitors have been found to exhibit a preventive role against neuroinflammation, which represents a crucial underlying mechanism in neurodegenerative diseases (ND). Additionally, they possess suppressive effects on the activation of apoptotic pathways, which constitute another mechanism underlying such diseases. Given that pimecrolimus, a calcineurin inhibitor, impedes the synthesis of pro-inflammatory cytokines, such as interleukin (IL)-2, IL-4, and IL-10, and influences apoptotic processes, it is noteworthy to test its potential neuroprotective properties. Thus, the objective of this investigation was to assess the potential protective effects of pimecrolimus against the degenerative consequences of both microglial secretomes and hydrogen peroxide (H2O2), an oxidant agent. The survival rates of HMC3 microglia cells, neuron-like differentiated SH-SY5Y (d-SH-SY5Y) cells, and their co-culture were determined using the 3-(4,5-Dimethylthiazol-2-yl)-2,5-Diphenyltetrazolium Bromide (MTT) method. Furthermore, the levels of pro-inflammatory cytokines IL-1β and IL-6, and anti-inflammatory cytokine IL-10 were measured using ELISA kits, besides total antioxidant and oxidant capacities in conditioned media of cells. Additionally, the effect of pimecrolimus on neurite length in these cell groups was evaluated through morphological observations. This study revealed, for the first time, that pimecrolimus exerts preventive effects on neurodegenerative processes by virtue of its anti-inflammatory and -antioxidant activities. It holds promise as a potential treatment option for ND.PMID:38441277 | DOI:10.1111/sji.13328