PubMed

CNS Neurosci Ther. 2024 Nov;30(11):e70060. doi: 10.1111/cns.70060.ABSTRACTDiagnosis and prediction of Alzheimer's disease (AD) are increasingly pressing in the early stage of the disease because the biomarker-targeted therapies may be most effective. Diagnosis of AD largely depends on the clinical symptoms of AD. Currently, cerebrospinal fluid biomarkers and neuroimaging techniques are considered for clinical detection and diagnosis. However, these clinical diagnosis results could provide indications of the middle and/or late stages of AD rather than the early stage, and another limitation is the complexity attached to limited access, cost, and perceived invasiveness. Therefore, the prediction of AD still poses immense challenges, and the development of novel biomarkers is needed for early diagnosis and urgent intervention before the onset of obvious phenotypes of AD. Blood-based biomarkers may enable earlier diagnose and aid detection and prognosis for AD because various substances in the blood are vulnerable to AD pathophysiology. The application of a systematic biological paradigm based on high-throughput techniques has demonstrated accurate alterations of molecular levels during AD onset processes, such as protein levels and metabolite levels, which may facilitate the identification of AD at an early stage. Notably, proteomics and metabolomics have been used to identify candidate biomarkers in blood for AD diagnosis. This review summarizes data on potential blood-based biomarkers identified by proteomics and metabolomics that are closest to clinical implementation and discusses the current challenges and the future work of blood-based candidates to achieve the aim of early screening for AD. We also provide an overview of early diagnosis, drug target discovery and even promising therapeutic approaches for AD.PMID:39572036 | DOI:10.1111/cns.70060

J Adv Res. 2024 Nov 19:S2090-1232(24)00543-5. doi: 10.1016/j.jare.2024.11.024. Online ahead of print.ABSTRACTINTRODUCTION: The intricate interplay of interleukin-10 (IL-10) and gut microbiota influences tumor development and progression, yet the impacts on colorectal cancer (CRC) metastasis remain incompletely understood.METHODS: The impact of Il10 deficiency on CRC metastasis was first evaluated in CRC metastasis tumor samples and mouse model. Antibiotic sterilization and fecal microbiota transplantation (FMT) experiment were used to assess the role of gut microbiota in IL-10 mediated CRC metastasis, and full-length 16S rDNA sequencing analysis further identified the potential target bacteria influencing CRC metastasis. The inhibitory effect of Parabacteroides distasonis (P. distasonis) on CRC metastasis was evaluated by oral administration in mice. Key metabolites involved in P. distasonis inhibition of CRC metastasis was identified by widely-targeted metabolome analysis and validated both in vivo and in vitro. The underlying mechanisms of P-hydroxyphenyl acetic acid (4-HPAA) inhibiting CRC metastasis was investigated via RNA-sequencing and validated in cellular experiments.RESULTS: We revealed that serum IL-10 levels were markedly elevated in metastatic CRC patients compared to non-metastatic cases. In parallel, Il10-deficiency (Il10-/) in mice resulted in decreased CRC metastasis in a gut microbiota-dependent manner. Mechanistically, Il10-/- mice reshaped gut microbiota composition, notably enriching P. distasonis. The enriched P. distasonis produced 4-HPAA, which activated the aryl hydrocarbon receptor (AHR) and subsequently inhibited the expression of VEGFA, a typical oncogene, thereby sequentially suppressing CRC metastasis. Importantly, engineered bacteria capable of producing 4-HPAA effectively hindered CRC metastasis. Furthermore, AHR depletion significantly disrupted the 4-HPAA-induced reduction in CRC cell migration and the inhibition of metastasis in both in vitro and in vivo lung metastasis mouse models.CONCLUSIONS: These findings demonstrate the significance of IL-10 deficiency in suppressing CRC metastasis through the 4-HPPA-AHR-VEGFA axis mediated by gut P. distasonis, suggesting that P. distasonis or 4-HPAA supplementation could offer a promising therapeutic strategy for CRC metastasis prevention.PMID:39571733 | DOI:10.1016/j.jare.2024.11.024

J Ethnopharmacol. 2024 Nov 19:119129. doi: 10.1016/j.jep.2024.119129. Online ahead of print.ABSTRACTETHNOPHARMACOLOGICAL RELEVANCE: Type 2 diabetes mellitus (T2DM) poses significant threats to public health. In Traditional Chinese Medicine (TCM), the Phellodendri Chinensis Cortex-Anemarrhenae Rhizoma (PCC/AR) herb pair has long been used for T2DM treatment, although its specific anti-diabetic mechanisms remain unclear.AIM OF THE STUDY: This study aimed to elucidate the relationship between metabolomics of T2DM patients and the anti-diabetic effects of PCC/AR herb pair in mice through clinical metabolomics and both in vitro and in vivo experiments.MATERIALS AND METHODS: In this study, a T2DM mouse model was established via high-fat feeding (HFD) and streptozotocin (STZ) injection. The effects of PCC/AR on blood glucose, lipid metabolism, and inflammatory markers were evaluated. High-performance liquid chromatography-mass spectrometry (HPLC-MS) was performed for metabolomics analysis of T2DM patients.RESULTS: Serum metabolomics analysis identified significant alterations in metabolites linked to the biosynthesis of unsaturated fatty acids and purine metabolism in T2DM patients, with elevated 2-hydroxyvaleric acid (2HB) levels. In T2DM mice, PCC/AR intervention normalized FBG, GHbA1c, TC, TG, LDL-C, HDL-C, TNF-α and IL-1β levels, while improving insulin sensitivity and pancreatic β-cell function in T2DM mice. Notably, PCC/AR reduced key enzymes in gluconeogenesis and fatty acid synthesis, PEPCK and ACC1.CONCLUSION: PCC/AR herb pair exerts an anti-diabetes effect in T2DM mice by regulating 2HB through ACC1 inhibition, thereby reducing FFA and TG synthesis. Additionally, PCC/AR may also exert its effects by modulating glucose and lipid metabolism and reducing inflammation. These results support further investigation into the PCC/AR herb pair as a complementary therapy for T2DM.PMID:39571697 | DOI:10.1016/j.jep.2024.119129

Toxicol Appl Pharmacol. 2024 Nov 19:117161. doi: 10.1016/j.taap.2024.117161. Online ahead of print.ABSTRACTBrain injury following acute diquat poisoning has become increasingly common in moderate to severe cases, with unclear pathogenesis and high mortality. To investigate this, we conducted metabolomics on brain tissue from poisoned rats, combined with clinical biochemical and pathological analyses. In the high-dose group, 24 metabolites showed significant differences compared to the control group: 18 were upregulated, including cytosine, sedoheptulose-7-phosphate, indole, 3-dehydroshikimate, etc.; 6 were downregulated, including 6-phosphogluconic acid, 3-hydroxybenzoic acid, dAMP, etc. In the low-dose group, 10 metabolites showed significant differences: 4 were upregulated, including pentamidine, γ-tocotrienol, benzoylecgonine, etc.; and 6 were downregulated, including dAMP, glutathione, 3-hydroxybenzoic acid, etc. Enrichment analysis identified two key pathways-phenylalanine, tyrosine, and tryptophan biosynthesis, and the pentose phosphate pathway-as involved in brain injury. ROC analysis of six differential metabolites showed that sedoheptulose-7-phosphate, (2R)-2-hydroxy-3-(phosphonatooxy)propanoate, and 3-hydroxybenzoic acid had AUC values above 0.8. These findings suggest that these three metabolites demonstrate strong diagnostic potential for brain injury induced by diquat poisoning. Correlation analysis linked these biomarkers to clinical indicators such as neutrophil count and the eutrophil to lymphocyte ratio, supporting their relevance. This study provides insights into the mechanisms and biomarkers of diquat-induced brain injury, offering a foundation for future treatment and rapid detection.PMID:39571689 | DOI:10.1016/j.taap.2024.117161

Immunity. 2024 Nov 15:S1074-7613(24)00492-8. doi: 10.1016/j.immuni.2024.10.012. Online ahead of print.ABSTRACTHow mitochondria reconcile roles in functionally divergent cell death pathways of apoptosis and NLRP3 inflammasome-mediated pyroptosis remains elusive, as is their precise role in NLRP3 activation and the evolutionarily conserved physiological function of NLRP3. Here, we have shown that when cells were challenged simultaneously, apoptosis was inhibited and NLRP3 activation prevailed. Apoptosis inhibition by structurally diverse NLRP3 activators, including nigericin, imiquimod, extracellular ATP, particles, and viruses, was not a consequence of inflammasome activation but rather of their effects on mitochondria. NLRP3 activators turned out as oxidative phosphorylation (OXPHOS) inhibitors, which we found to disrupt mitochondrial cristae architecture, leading to trapping of cytochrome c. Although this effect was alone not sufficient for NLRP3 activation, OXPHOS inhibitors became triggers of NLRP3 when combined with resiquimod or Yoda-1, suggesting that NLRP3 activation requires two simultaneous cellular signals, one of mitochondrial origin. Therefore, OXPHOS and apoptosis inhibition by NLRP3 activators provide stringency in cell death decisions.PMID:39571574 | DOI:10.1016/j.immuni.2024.10.012

Food Chem. 2024 Nov 16;465(Pt 2):142089. doi: 10.1016/j.foodchem.2024.142089. Online ahead of print.ABSTRACTAll-aqueous (water-in-water) emulsions are increasingly used as droplets reactors. The present communication reports that precursors of a reaction segregated by partitioning between emulsion phases can undergo reaction at the interface, i.e., on droplet surface, while the interface remains liquid. Na2SO4-in-polyethylene glycol (PEG) emulsions were prepared, and precursors (glucose, asparagine, and tryptophan) of the Maillard reaction were partitioned either inside the droplets (co-encapsulation) or segregated between the emulsion interior and exterior phases. It was found that following the interfacial (i.e., on-droplet) reaction of the segregated precursors, ∼99 % of the Amadori product N-(1-deoxy-D-fructos-1-yl)-L-tryptophan (Fru-Trp) partitioned into the PEG phase. Also, hydrophobic advanced reaction products including β-carboline derivatives and Strecker aldehyde, alongside melanoidins, showed a clear affinity towards the PEG phase. Once the precursors were co-encapsulated within Na2SO4 droplets, following their generation succinimide and pyridine derivatives remained partitioned within the droplets, whereas N-hydroxysuccinimide, pyrrole derivatives, and melanoidins predominantly partitioned into the PEG phase.PMID:39571442 | DOI:10.1016/j.foodchem.2024.142089

Food Chem. 2024 Nov 16;465(Pt 2):142064. doi: 10.1016/j.foodchem.2024.142064. Online ahead of print.ABSTRACTDeoxynivalenol and Alternaria toxins are common food contaminants posing significant threats to human and animal health. Although their individual toxicities have been extensively studied, the combined effects of co-exposure remain largely unexplored. Our findings revealed combined toxins displayed concentration-dependent synergistic and antagonistic interactions on human hepatocellular carcinoma cells. Co-exposure significantly reduced mitochondrial activity, increased intracellular ROS levels, and activated the mitochondrial-dependent caspase signaling pathway, ultimately leading to enhanced apoptosis. Metabolomics analysis revealed that combined exposure severely disrupted multiple key metabolic processes, including those related to energy (NAD+, adenosine, AMP, and ADP), amino acids (l-aspartate, l-glutamate), and carbohydrate (Glucose-6-phosphate) metabolisms. These findings highlight that co-occurrence exacerbates the disruption of overall metabolic balance, potentially impairing the normal function of cells by affecting energy production, protein synthesis, and cell proliferation. This study underscores the importance of considering combined mycotoxin exposure and provided possible ideas for inhibiting or mitigating toxicity to ensure food safety.PMID:39571435 | DOI:10.1016/j.foodchem.2024.142064

Clin Nutr. 2024 Nov 14;43(12):344-358. doi: 10.1016/j.clnu.2024.11.023. Online ahead of print.ABSTRACTBACKGROUND & AIMS: Long-term effects of coronavirus disease 2019 (long COVID) develop in a substantial number of people following an acute COVID-19 episode. Red beetroot juice may have positive effects on multiple pathways involved in long COVID. The aim of this pilot study was to explore the impact of beetroot juice supplementation on physical function, gut microbiota, and systemic inflammation in adults with long COVID.METHODS: A single-center, double-blind, placebo-controlled randomized trial was conducted to test the effects of 14 days of beetroot juice supplementation, rich in nitrates and betalains, on functional and biological outcomes in adults aged between 20 and 60 years with long COVID. Participants were randomized 1:1 to receive either daily oral supplementation with 200 mL beetroot juice (∼600 mg nitrate) or placebo (∼60 mg nitrate) for 14 days. The primary endpoint was the change from baseline to day 14 in a fatigue resistance test. Secondary outcomes included the distance walked on the 6-min walk test, handgrip strength, and flow-mediated dilation. Secondary endpoints also included changes from baseline in circulating inflammatory mediators and metagenomic and fecal water metabolomic profiles. Partial least squares discriminant analysis (PLS-DA) models were built to evaluate the differences in biological variables associated with the interventions.RESULTS: Thirty-one participants were randomized in the study. Twenty-five of them (median (interquartile range) age 40 (10), 14 [56 %] women), received either beetroot juice (15) or placebo (10) and completed the study. At 14 days, fatigue resistance significantly improved from baseline (mean difference [standard error]: +21.8 [3.7] s; p < 0.001) with no significant differences between intervention groups. A significant increase from baseline in the distance walked on the 6-min walk test was observed (mean difference [standard error]: +30.0 [9.4] m; p = 0.03), which was not different between groups. Flow-mediated dilation did not differ between participants who received beetroot juice and those on placebo. PLS-DA models allowed correct classification of participants with 92.2 ± 4.4 % accuracy. Those who ingested red beetroot juice had a greater abundance of bacteria with well-known beneficial effects, including Akkermansia, Oscillospira, Prevotella, Roseburia, Ruminococcaceae, and Turicibacter, compared with placebo. Participants allocated to beetroot juice supplementation were also characterized by significantly higher levels of fecal nicotinate, trimethylamine, and markers of beetroot juice intake (e.g., 5,6-dihydroxyindole). Finally, higher levels of interferon gamma and macrophage inflammatory protein-1β were found in participants who consumed beetroot juice.CONCLUSION: Beetroot juice supplementation for two weeks did not to induce significant improvements in functional outcomes in adults with long COVID compared with placebo. Beneficial effects were observed in both gut microbiota composition (i.e., increase in probiotic species) and inflammatory mediators.TRIAL REGISTRATION: Trial was registered under ClinicalTrials.gov. Identifier no. NCT06535165.PMID:39571342 | DOI:10.1016/j.clnu.2024.11.023

Environ Int. 2024 Nov 16;194:109151. doi: 10.1016/j.envint.2024.109151. Online ahead of print.ABSTRACTPathogenic variants in the Leucine-rich repeat kinase 2 (LRRK2) gene are a primary monogenic cause of Parkinson's disease (PD). However, the likelihood of developing PD with inherited LRRK2 pathogenic variants differs (a phenomenon known as "reduced penetrance"), with factors including age and geographic region, highlighting a potential role for lifestyle and environmental factors in disease onset. To investigate this, household dust samples from four different groups of individuals were analyzed using metabolomics/exposomics and metagenomics approaches: PD+/LRRK2+ (PD patients with pathogenic LRRK2 variants; n = 11), PD-/LRRK2+ (individuals with pathogenic LRRK2 variants but without PD diagnosis; n = 8), iPD (PD of unknown cause; n = 11), and a matched, healthy control group (n = 11). The dust was complemented with metabolomics and lipidomics of matched serum samples, where available. A total of 1,003 chemicals and 163 metagenomic operational taxonomic units (mOTUs) were identified in the dust samples, of which ninety chemicals and ten mOTUs were statistically significant (ANOVA p-value < 0.05). Reduced levels of 2-benzothiazolesulfonic acid (BThSO3) were found in the PD-/LRRK2+ group compared to the PD+/LRRK2+ . Among the significant chemicals tentatively identified in dust, two are hazardous chemical replacements: Bisphenol S (BPS), and perfluorobutane sulfonic acid (PFBuS). Furthermore, various lipids were found altered in serum including different lysophosphatidylethanolamines (LPEs), and lysophosphatidylcholines (LPCs), some with higher levels in the PD+/LRRK2+ group compared to the control group. A cellular study on isogenic neurons generated from a PD+/LRRK2+ patient demonstrated that BPS negatively impacts mitochondrial function, which is implicated in PD pathogenesis. This pilot study demonstrates how non-target metabolomics/exposomics analysis of indoor dust samples complemented with metagenomics can prioritize relevant chemicals that may be potential modifiers of LRRK2 penetrance.PMID:39571299 | DOI:10.1016/j.envint.2024.109151

Int Immunopharmacol. 2024 Nov 20;144:113607. doi: 10.1016/j.intimp.2024.113607. Online ahead of print.ABSTRACTBACKGROUND AND AIM: The acute pulmonary infectious disease caused by influenza viruses is known as influenza virus pneumonia (IVP). In recent years, Gegen Qinlian Decoction (GQD) has been widely used to treat pulmonary inflammation; however, the underlying mechanism of action of GQD in IVP remains unclear. This study aimed to elucidate the molecular mechanism through which GQD improved IVP.MATERIALS AND METHODS: The efficacy of GQD was evaluated using classical pharmacodynamic indicators in a murine model of H1N1-induced IVP. Network pharmacology predicted the material basis of GQD in improving IVP, while metabonomics and 16 s rDNA sequencing assessed its regulation on small molecule metabolites and intestinal flora. Additionally, molecular biology techniques were used to investigate the molecular mechanism underlying the improvement of IVP by GQD.RESULTS: The study results demonstrated that GQD exhibited a significant ameliorative effect on the inflammatory response in lung tissue of IVP mice. The potential pharmacological substances of GQD for improving IVP were identified by network pharmacology combined with ultra-high performance liquid chromatography/high-resolution time-of-flight mass spectrometry (UHPLC-HR-TOFMS) analysis, including puerarin, baicalin, berberine, and glycyrrhizin. Further analysis of biological processes and mechanisms of action predicted that GQD could improve IVP by inhibiting activation of inflammasomes, regulating the body's immune system, and intestinal microecology. Metabolomics and microbiomics findings revealed that GQD could bi-directionally regulate lipid and amino acid metabolites by increasing the abundance of beneficial bacteria like Akkermansia and Acetobacter, thereby maintaining host metabolic balance and immune homeostasis. RT-qPCR and immunohistochemistry results indicated that GQD improved IVP by inhibiting the complement C3/NLRP3 inflammasome pathway.CONCLUSION: The findings of this study confirmed that GQD effectively inhibited IVP by modulating the "gut microbiota-metabolomics-immune/inflammation" axis in the host, thereby establishing a solid immunological foundation for the clinical application of GQD.PMID:39571267 | DOI:10.1016/j.intimp.2024.113607

Plant Physiol Biochem. 2024 Oct 31;217:109231. doi: 10.1016/j.plaphy.2024.109231. Online ahead of print.ABSTRACTRoot exudates are the most direct performance for plants responding to adverse environments, and are also important media for materials exchange, energy transmission and information communication between the roots and rhizosphere. However, how plant roots and exudates respond to aluminum (Al) stress under elevated CO2 concentration (eCO2) is still unclear. Ricinus communis is a famous oilseed crop throughout the world, which has strong tolerance to metal contaminated soil. In the present study, root physiological changes and the exudates of this species under aluminum stress and eCO2 based on metabolomic were investigated. The results showed that high Al concentration stress significantly increased aluminum, MDA, proline, and soluble sugar contents, and decreased the dry weights and soluble protein concentration. Furthermore, eCO2 alleviated the inhibition of root growth under high Al stress by increasing the dry weights, antioxidant enzyme activities and decreasing the MDA content. Collectively, a total of 511 metabolites were detected in the castor exudates of which lipids, organic acids, and organic oxygen compounds occupied 40.82%, 17.78% and 12.54%, respectively. There were 83, 15, and 100 differential metabolites for high Al stress, eCO2 and the interaction of the two factors compared with the control. 12 differential metabolites were found under eCO2 and Al stress compared with Al stress alone. Under Al stress, TCA cycle, organic acids, and lipids metabolisms were inhibited; coumarins and carbohydrates conjugates were significantly up-regulated, which may help castor adapt to aluminum-contaminated conditions. Moreover, eCO2 increased the secretion of organic acids, fatty acyls, and carbohydrates to enhance the antioxidant capacity and root growth of castor under Al stress; eCO2 enhanced the TCA cycle, organic acids accumulation, lipids metabolism, biosynthesis of amino acids, pentose and glucuronate interconversions, and inhibited DNA oxidative stress of castor roots under Al stress. The present study provides new insights into the crucial role of root exudates in improving Al-tolerance of castor under eCO2.PMID:39571237 | DOI:10.1016/j.plaphy.2024.109231

J Chromatogr B Analyt Technol Biomed Life Sci. 2024 Nov 8;1250:124352. doi: 10.1016/j.jchromb.2024.124352. Online ahead of print.ABSTRACTUlcerative colitis (UC) is a common disease of the digestive system that is challenging to treat. Gegen Qinlian Decoction (GQD), which is an ancient classic formula in Chinese medicine, is effective at alleviating the symptoms of UC, but comprehensive research on its mechanism of action has not been performed. Here, we explored the material basis and potential molecular mechanism underlying GQD-mediated protection against UC by integrated metabolomics and network pharmacology. First, differentially expressed metabolites were screened and identified via a metabolomics approach, and the metabolic pathway was analyzed via MetaboAnalyst. Second, a protein-protein interaction (PPI) network was constructed to identify hub genes that encode metabolic enzymes. Third, the differentially expressed metabolites were used to construct a compound-reaction-enzyme-gene network. Finally, the metabolites were compared with relevant active components for molecular docking, molecular dynamics (MD) simulation, and verification experiment. GQD intervention alleviated UC in mice and significantly inhibited metabolic dysfunction in mice with UC; specifically, GQD reversed the abnormal changes in metabolites in the colon and serum, and regulated the arachidonic acid metabolism, tryptophan metabolism, glycerophospholipid metabolism, and purine metabolism pathways. Further literature review and molecular docking analysis with targeted MD simulation and Poisson-Boltzmann surface area (MM-PBSA) analysis were performed, revealing that GQD may inhibit the disruption of arachidonic acid metabolism and tryptophan metabolism by suppressing PTGS2 and CYP450 protein expression; these results were verified by qRT-PCR, WB, and surface plasmon resonance (SPR) assays. Our experiments indicated that GQD alleviated UC in mice by systematically regulating arachidonic acid metabolism and tryptophan metabolism, supporting further research and the development of GQD as a novel drug for ameliorating UC.PMID:39571215 | DOI:10.1016/j.jchromb.2024.124352

PLoS One. 2024 Nov 21;19(11):e0310689. doi: 10.1371/journal.pone.0310689. eCollection 2024.ABSTRACTYiyi decoction is a Chinese herbal formula for the treatment of acute pancreatitis that has been used in clinical practice for decades. A previous study has suggested that resveratrol, emodin, rhein and their derivatives might be the potential pharmacodynamic components in Yiyi decoction, and researchers have proposed that resveratrol, emodin and rhein are candidate markers for quality control. The present study investigated the intervention effect of Yiyi decoction and its effective components on murine acute pancreatitis using metabolomic approach that integrated global and unique metabolic characteristics. First, serum metabolomics based on the platform of ultra-high performance liquid chromatography coupled with quadrupole time-of-flight mass spectrometry was performed to assess metabolic changes in experimental acute pancreatitis. Second, an in-depth analysis of bile acid metabolism was performed based on an in-house database. Finally, an integrated analysis of the intervention effect of Yiyi decoction and its effective components in response to these metabolic perturbations was performed. As a result, 39 potential biomarkers for the pathogenesis of acute pancreatitis, mainly phospholipids, fatty acids, bile acids and lipoylcarnitines, were screened and annotated. Integrated analysis revealed that the metabolic disorders in acute pancreatitis mice were reversed by Yiyi decoction primarily via regulating glycerophospholipid metabolism, bile acid biosynthesis, carnitine synthesis and fatty acid metabolism. Yiyi decoction components may effectively target the migratory metabolome. Histopathological and biochemical analyses suggested that Yiyi decoction maintained the gut barrier function and inhibited inflammatory cytokines, thus exert anti-acute pancreatitis effects. The present study utilized an approach that integrated global and unique metabolic characteristics to elucidate the underlying mechanisms of Chinese herbal formulas from a metabolomics perspective.PMID:39570855 | DOI:10.1371/journal.pone.0310689

PLoS One. 2024 Nov 21;19(11):e0313915. doi: 10.1371/journal.pone.0313915. eCollection 2024.ABSTRACTBlack Sigatoka is the most widespread banana disease worldwide. It is caused by Pseudocercospora fijiensis, a fungal pathogen known for developing resistance to fungicides such as thiabendazole. Despite the increasing costs associated with the use of chemicals to control this disease, the pathogen's mechanisms for fungicide resistance are not fully understood. The metabolite profiles of P. fijiensis isolates with different levels of resistance to thiabendazole were characterized by GC-MS. A total of 33 isolates were obtained from symptomatic banana plants and the sensitivity of each isolate to thiabendazole was assessed at 0, 1, 10, 100, 1000, and 10000 μg.mL-1. Then, the metabolite profile of each isolate was assessed using GC-MS. Metabolites such as hexadecanoic acid, tetradecanoic acid, octadecadienoic acid and octadecanoic acid were significantly over-accumulated in the presence of thiabendazole at 10 μg.mL-1. Phosphoric acid, L-proline, and D-allose increased in concentration with time in the presence of 100 μg.mL-1 of thiabendazole, and mannonic acid, 1-hexadecanol, D-sorbitol and tetracosanoic acid were only detected in the presence of the fungicide. Metabolic pathways including that of fructose, mannose metabolism, the biosynthesis of unsaturated fatty acids, and ABC transporters were upregulated in resistant isolates. Our findings show an increment of tetracosanoic (myristic) acid suggesting a possible β-tubulin-compensation mechanism in resistant isolates. The presence of myristic acid promoted the generation of diacylglycerol kinase δ which facilitated the production of β-tubulin in other studies. Additionally, important changes in the metabolite profiles were observed as soon as six hours after exposure to the fungicide showing an early response of the pathogen. To the best of our knowledge, this is the first report that describes the changes in the metabolite profile of P. fijiensis resistant to thiabendazole when exposed to the fungicide.PMID:39570826 | DOI:10.1371/journal.pone.0313915

Metab Brain Dis. 2024 Nov 21;40(1):32. doi: 10.1007/s11011-024-01458-w.ABSTRACTPeople living with HIV (PLHIV) are known to be at a higher risk of developing an array of aging-related diseases despite well-adhered combined antiretroviral therapy (cART). The present study aimed to investigate the impact of chronic HIV infection on neurocognitive function in virally suppressed PLHIV. We enrolled HIV-positive individuals randomly from an ART Center in Chennai, South India. A similar number of HIV-uninfected individuals matched for age and gender with the HIV-infected individuals served as controls. All individuals provided a detailed clinical history and underwent neuropsychological assessment using the International HIV Dementia Scale (IHDS). Plasma proteome analysis was performed using the Proximity extension assay (PEA) with the Olink® neuroexploratory panel, and untargeted metabolomics was performed using Ultra-High-Performance Liquid Chromatography/Mass Spectrometry/Mass Spectrometry. Despite a median duration of 9 years on first-line cART and suppressed viremia, a significant proportion of PLHIV registered significant levels of asymptomatic neurocognitive impairment, with 71% of these individuals scoring ≤ 10 in the IHDS test. We also observed significant alterations in a number of proteins and metabolites that are known to be associated with neuroinflammation, neurodegeneration, cognitive impairment, and gastrointestinal cancers, in the PLHIV group. Thus the study provides clinical as well as laboratory evidence to substantiate the presence of asymptomatic neurocognitive impairment in a large proportion of PLHIV, despite adequate cART and undetectable viremia, thereby supporting the view that HIV infection potentiates the risk for accelerated and accentuated neurological aging. This observation highlights the need to devise and implement appropriate intervention strategies for better long term management of HIV-infected persons.PMID:39570517 | DOI:10.1007/s11011-024-01458-w

J Clin Lab Anal. 2024 Nov 21:e25124. doi: 10.1002/jcla.25124. Online ahead of print.ABSTRACTBACKGROUND: HER2-positive breast cancer (BC), a highly aggressive malignancy, has been treated with the targeted therapy inetetamab for metastatic cases. Inetetamab (Cipterbin) is a recently approved targeted therapy for HER2-positive metastatic BC, significantly prolonging patients' survival. Currently, there is no established biomarker to reliably predict or assess the therapeutic efficacy of inetetamab in BC patients.METHODS: This study harnesses the power of metabolomics and machine learning to uncover biomarkers for inetetamab in BC therapy. A total of 23 plasma samples from inetetamab-treated BC patients were collected and stratified into responders and nonresponders. Ultra-high-performance liquid chromatography-quadrupole time-of-flight mass spectrometry was utilized to analyze the metabolites in blood samples. A combination of univariate and multivariate statistical analyses was employed to identify these metabolites, and their biological functions were then ascertained by Gene Ontology (GO) and Kyoto Encyclopedia of Genes and Genomes (KEGG) enrichment analysis. Finally, machine learning algorithms were employed to screen responsive biomarkers from all differentially expressed metabolites.RESULTS: Our finding revealed 6889 unique metabolites that were detected. Pathways like retinol metabolism, fatty acid biosynthesis, and steroid hormone biosynthesis were enriched for differentially expressed metabolites. Notably, two key metabolites associated with inetetamab response in BC were identified: FAPy-adenine and 2-Pyrocatechuic acid. There was some negative correlation between progress-free survival (PFS) and their kurtosis content.CONCLUSIONS: In summary, the identification of these two significant differential metabolites holds promise as potential biomarkers for evaluating and predicting inetetamab treatment outcomes in BC, ultimately contributing to the diagnosis of the disease and the discovery of prognostic markers.PMID:39569974 | DOI:10.1002/jcla.25124

Plant J. 2024 Nov 21. doi: 10.1111/tpj.17145. Online ahead of print.ABSTRACTCytochrome P450 monooxygenases (CYPs) are well known for their ability to catalyze diverse oxidation reactions, playing a significant role in the biosynthesis of various natural products. In the realm of monoterpenoid indole alkaloids (MIAs), one of the largest groups of alkaloids in nature, CYPs are integral to reactions such as hydroxylation, epoxidation, ring opening, ring rearrangement, and aromatization, contributing to the extensive diversification of these compounds. In this study, we investigate the transcriptome, metabolome, and MIA biosynthesis in Tabernaemontana litoralis (milky way tree), a prolific producer of rare pseudoaspidosperma-type MIAs. Alongside known pseudoaspidosperma biosynthetic genes, we identify and characterize three new CYPs that facilitate regio- and stereospecific oxidation of four MIA skeletons: iboga, aspidosperma, pseudoaspidosperma, and quebrachamine. Notably, the tabersonine 14,15-β-epoxidase catalyzes the formation of pachysiphine, the stereoisomer of 14,15-α-epoxytabersonine (lochnericine) found in Catharanthus roseus (Madagascar periwinkle) roots. The pseudovincadifformine 18-hydroxylase is the first CYP identified to modify a pseudoaspidosperma skeleton. Additionally, we demonstrate that the enzyme responsible for C10-hydroxylation of the iboga MIA coronaridine also catalyzes C10-hydroxylation of voaphylline, which bears a quebrachamine skeleton. With the discovery of a new MIA, 11-hydroxypseudovincadifformine, this study provides a comprehensive understanding of MIA biosynthesis and diversification in T. litoralis, highlighting its potential for further exploration.PMID:39569755 | DOI:10.1111/tpj.17145

Adv Sci (Weinh). 2024 Nov 21:e2411015. doi: 10.1002/advs.202411015. Online ahead of print.ABSTRACTMuscular atrophy is among the systematic decline in organ functions in aging, while defective thermogenic fat functionality precedes these anomalies. The potential crosstalk between adipose tissue and muscle during aging is poorly understood. In this study, it is showed that UCP1 knockout (KO) mice characterized deteriorated brown adipose tissue (BAT) function in aging, yet their glucose homeostasis is sustained and energy expenditure is increased, possibly compensated by improved inguinal adipose tissue (iWAT) and muscle functionality compared to age-matched WT mice. To understand the potential crosstalk, RNA-seq and metabolomic analysis were performed on adipose tissue and muscle in aging mice and revealed that creatine levels are increased both in iWAT and muscle of UCP1 KO mice. Interestingly, molecular analysis and metabolite tracing revealed that creatine biosynthesis is increased in iWAT while creatine uptake is increased in muscle in UCP1 KO mice, suggesting creatine transportation from iWAT to muscle. Importantly, creatine analog β-GPA abolished the differences in muscle functions between aging WT and UCP1 KO mice, while UCP1 inhibitor α-CD improved muscle glycolytic function and glucose metabolism in aging mice. Overall, these results suggested that iWAT and skeletal muscle compensate for declined BAT function during aging via creatine metabolism to sustain metabolic homeostasis.PMID:39569747 | DOI:10.1002/advs.202411015

Curr Opin Lipidol. 2024 Nov 22. doi: 10.1097/MOL.0000000000000964. Online ahead of print.ABSTRACTPURPOSE OF REVIEW: Cardiometabolic diseases are a major global health concern, with diet playing a crucial role in their prevention and management. Recent advancements in the identification of metabolic signatures related to dietary patterns offer a more objective assessment of individualized dietary exposure and provide deeper insights into diet-disease associations.RECENT FINDINGS: Recent studies have shown that distinct metabolic signatures are associated with the adherence to various dietary patterns. These signatures show even stronger associations with cardiometabolic disease incidence, independent of traditional risk factors and self-reported adherence to such dietary patterns. Emerging dietary approaches, such as sustainable diets, health outcome-focused diets, and population data-driven dietary patterns, also hold promise for improving cardiometabolic health. Additionally, metabolic signatures could offer insights into diet-disease associations in underrepresented populations, addressing genetic and lifestyle differences.SUMMARY: Application of metabolomics provides a more precise understanding of how dietary patterns influence cardiometabolic health. Although the number of studies remains limited, and current evidence is inconsistent, the approach has significant potential for improving clinical and public health strategies. Future research should prioritize prospective studies and address population- and outcome-specific dietary needs to enable targeted interventions that optimize cardiometabolic health.PMID:39569665 | DOI:10.1097/MOL.0000000000000964

Biomol Biomed. 2024 Nov 20. doi: 10.17305/bb.2024.11218. Online ahead of print.ABSTRACTAmyotrophic lateral sclerosis (ALS) is a neurodegenerative disease characterized by the selective death of motor neurons in the spinal cord, brainstem, and motor cortex. This study investigates the effects of simvastatin on the G93A-copper/zinc superoxide dismutase (G93ASOD1) transgenic mouse model of ALS. The experiment included three groups: C57BL/6 wild-type (WT) mice, C57BL/6J SOD1G93A mice treated with PBS (SOD1G93A + PBS), and C57BL/6J SOD1G93A mice treated with simvastatin (SOD1G93A + simvastatin). The primary endpoints were survival rates, body weight changes, performance in pole climbing and suspension tests, and neurological deficit scores. Pathological changes were assessed using H&E staining, transmission electron microscopy, Nissl staining, and Masson staining. Proteomic and metabolomic analyses were performed to identify differentially expressed proteins (DEPs) and metabolites. Quantitative real-time polymerase chain reaction (qRT-PCR) and western blotting were used to measure gene expression. Although there were no significant differences in survival rates, body weight, pole climbing, and suspension test performance, or neurological deficit scores between the SOD1G93A + simvastatin and SOD1G93A + PBS groups, simvastatin treatment improved axonal organization within the spinal cord, increased the number of neurons, and reduced cytoplasmic swelling and gastrocnemius fibrosis. A total of 47 DEPs and 13 differential metabolites were identified between the SOD1G93A + PBS and SOD1G93A + simvastatin groups. Notably, the expression levels of Apoa4 and Alb were elevated in the SOD1G93A + simvastatin group compared to the SOD1G93A + PBS group. Our results suggest that simvastatin may have potential therapeutic effects in ALS, likely involving the modulation of Apoa4 and Alb expression.PMID:39569650 | DOI:10.17305/bb.2024.11218