PubMed

J Antibiot (Tokyo). 2024 Dec 6. doi: 10.1038/s41429-024-00792-6. Online ahead of print.ABSTRACTChemical and biological stimulus screening in a hypogean actinomycete was used to elicit secondary metabolism. Optimal biosynthesis of bioactive natural products was identified using Multiplexed Activity Profiling for determining dose-dependent activity via six single-cell biological readouts. Bioactive extracts were fractioned to establish candidate compounds for isolation using Multiplexed Activity Metabolomics by correlating microtiter well-isolated phenotypes and extracted ion current peaks. This guided the isolation of four filipin polyene macrolides including a new metabolite filipin XV, an alkyl side-chain hydroxylated congener of the filipin chainin, with substantially attenuated cytotoxicity. Filipin-specific cytotoxicity was confirmed using flow cytometry and fluorescence microscopy.PMID:39643649 | DOI:10.1038/s41429-024-00792-6

J Expo Sci Environ Epidemiol. 2024 Dec 6. doi: 10.1038/s41370-024-00736-0. Online ahead of print.ABSTRACTBACKGROUND: The chemical exposome includes exposure to numerous environmental and endogenous molecules, many of which have been linked to reproductive outcomes due to their endocrine-disrupting properties. As several breast cancer risk factors, including age and parity, are related to reproduction, it is imperative to investigate the interplay between such factors and the chemical exposome prior to conducting large scale exposome-based breast cancer studies.OBJECTIVE: This pilot study aimed to provide an overview of the chemical exposome in plasma samples from healthy women and identify associations between environmental exposures and three risk factors for breast cancer: age, parity, and age at menarche.MATERIAL AND METHODS: Plasma samples (n = 161), were selected based on reproductive history from 100 women participating in the Northern Sweden Health and Disease Study, between 1987 and 2006. Samples were analyzed by liquid chromatography high-resolution mass spectrometry (LC-HRMS) for 77 priority target analytes including contaminants and hormones, with simultaneous untargeted profiling of the chemical exposome and metabolome. Linear mixed effects models were applied to test associations between risk factors and chemical levels.RESULTS: Fifty-five target analytes were detected in at least one individual and over 94,000 untargeted features were detected across all samples. Among untargeted features, 430 could be annotated and were broadly classified as environmental (246), endogenous (167) or ambiguous (17). Applying mixed effect models to features detected in at least 70% of the samples (16,778), we found seven targeted analytes (including caffeine and various per- and poly-fluoroalkyl substances) and 38 untargeted features, positively associated with age. The directionality of these associations reversed for parity, decreasing with increasing births. Seven separate targeted analytes were associated with age at menarche.SIGNIFICANCE: This study demonstrates how a comprehensive chemical exposome approach can be used to inform future research prioritization regarding associations between known and unknown substances, reproduction, and breast cancer risk.IMPACT STATEMENT: This study illustrates how chemical exposomics of long-term stored blood samples offers valuable insights to discover chemical exposures and their potential links to disease in humans, particularly those related to reproduction and breast cancer risk factors.PMID:39643621 | DOI:10.1038/s41370-024-00736-0

J Biosci Bioeng. 2024 Dec 5:S1389-1723(24)00310-4. doi: 10.1016/j.jbiosc.2024.10.010. Online ahead of print.ABSTRACTBreeding sake yeast typically involves generating several gene mutants through UV irradiation or mutagen treatment and selecting those with desired traits based on indicators such as analog resistance. However, this approach often alters traits beyond the target trait due to the random and numerous mutations introduced. To address this issue, we used a previously established metabolome analysis, a sake metabolome analysis, to evaluate the selected yeast strain. After screening for target traits, 110 sake yeast candidates were cultured in yeastnitrogen-based liquid medium using test tubes. The contents were extracted and subjected to comprehensive metabolite analysis through sake metabolome analysis. A phylogenetic tree was then constructed using the metabolome analysis data, enabling the selection of candidate yeasts with only the target traits modified and other traits similar to the parental strain. Selected 21 candidate strains underwent fermentation tests, and the resulting sakes were analyzed using liquid chromatography quadrupole/time-of-flight mass spectrometry (LC-Q/TOF-MS). The findings suggested that the metabolomic data of yeast extracts obtained by simple small-scale culture was similar to the data of resulting sake in the larger-scale fermentation tests. This underscores the utility of metabolome analysis data of yeast extracts in the yeast breeding process, marking the first report proposing the use of the sake metabolome analysis method for yeast breeding.PMID:39643497 | DOI:10.1016/j.jbiosc.2024.10.010

Food Res Int. 2024 Dec;198:115395. doi: 10.1016/j.foodres.2024.115395. Epub 2024 Nov 16.ABSTRACTThe alteration in the taste of tomatoes after storage significantly influences consumer demand. Identification of the key compounds and related metabolic pathways involved in the taste changes of tomatoes during storage is very important for the tomato industry. This study examined the alterations in the taste of tomatoes stored at 4 °C under vacuum packaging, focusing on changes in metabolites and identifying specific metabolites that serve as markers for different taste attributes. The results showed that the decrease in sourness after storage at low temperatures was strongly associated with the decline in the function of the metabolic pathways of acetyl phosphate, pyrrole-2-carboxylic acid, and hydroxypyruvate. The increase in umami was closely related to the enrichment of amino acid-related metabolites such as tryptophan and proline. Furthermore, the utilization of vacuum packaging exerted an influence on the bitterness and astringency of tomatoes through altering the production of metabolites such as dimethylglycine, betaine, and flavonoids. These findings are essential for comprehending the variability in tomato taste and directing future quality control.PMID:39643376 | DOI:10.1016/j.foodres.2024.115395

Food Res Int. 2024 Dec;198:115334. doi: 10.1016/j.foodres.2024.115334. Epub 2024 Nov 9.ABSTRACTWhile tropical fruit seeds are considered potential sources of functional or edible vegetable oils, their lipid profiles are poorly documented. Herein, the lipid profiles of nine tropical fruit seed oils were systematically evaluated and compared using lipidomics and chemometrics techniques. Cherimoya exhibited the highest total lipid content, while avocado had the lowest. Canistel, cherimoya, and durian displayed a 9cC18:1 predominance. The remaining six seed oils were dominated by 9c12cC18:2n-6. In total, 1370 lipid molecules were identified, with triacylglycerol being the predominant subclass. Passion fruit, cherimoya, and durian had the highest glycerolipid, sphingolipid, and fatty acyl contents, respectively. Litchi exhibited the highest levels of glycerophospholipid and saccharolipid. Chemometric modeling screened 134 differential lipid molecules as markers for distinguishing between various tropical fruit seed oils. Positive correlations were primarily observed among the differential lipid molecules. Overall, these findings provide valuable insights into the integrated utilization of tropical fruit seed oils.PMID:39643370 | DOI:10.1016/j.foodres.2024.115334

Food Res Int. 2024 Dec;198:115333. doi: 10.1016/j.foodres.2024.115333. Epub 2024 Nov 10.ABSTRACTThis study investigated the effects of pineapple peel powder with varied chemical profiles and sonication-assisted polyphenol biotransformation during fermentation on the quality characteristics of yogurt products. It aimed at exploring the feasibility of sonication-assisted fermentation to enhance the physicochemical properties, control post-acidification, and improve antioxidant activities in yogurts fortified with polyphenol-rich pineapple peel powder. Targeted analysis showed that polyphenol-rich pineapple dietary fiber obtained by ultrasonication-assisted extraction (NPFU) exhibited the slowest rates of acidification, highest antioxidant capacity, and lowest degree of whey separation at 21.67 %. Sonication pretreatments significantly increased transformation of free phenolic acids derived from pineapple peel fiber during fermentation, particularly increasing the accumulation of ferulic acid, caffeic acid and 5-hydroxyflavone, revealing the positive effects of sonication-mediated fermentation in promoting the hydrolysis of conjugated phenolics into free fractions. Yogurts fortified with pineapple peel fiber displayed significantly higher antioxidant activities (p < 0.05) compared to those with pineapple peel whole powder, corresponding with the increased free phenolics. Non-targeted metabolomics analysis was employed to explore the mechanisms underlying the alleviated post-acidification by sonication-assisted fermentation during storage. Metabolomic profiling revealed that the bioactive components from pineapple peel extract significantly influenced the metabolism pathways of lactic acid bacteria particularly involving galactose metabolism, glycerophospholipid metabolism, closely associated with the acid production of the strains and the regulation of the post-acidification rates of yogurt during storage. These results confirmed the potential of ultrasound-assisted fermentation combined with the addition of pineapple dietary fiber to enhance yogurt quality, providing an innovative tool to develop future yogurt products with high marketability.PMID:39643368 | DOI:10.1016/j.foodres.2024.115333

Food Res Int. 2024 Dec;198:115306. doi: 10.1016/j.foodres.2024.115306. Epub 2024 Nov 3.ABSTRACTTheacrine and theaflavins are known for their potential to mitigate depression and cognitive impairment. Jianghua Kucha black tea (JH) contains both compounds, yet its antidepressant properties are seldom documented. This study evaluated the effects of JH on depression in chronic unpredictable mild stress (CUMS) mice and explored the underlying mechanisms through integrative analyses of gut microbiota and fecal metabolomics. JH was found to significantly alleviate CUMS-induced depression-like behavior by improving body weight, food intake, 1% sucrose preference, immobility time, and numbers of crossings and standings compared to Zhuyeqi black tea (ZYQ), which contains theaflavins. JH notably altered the gut microbiota composition, enriching genera such as Turicibacter, Faecalibaculum, Akkermansia, and Desulfovibrio, while inhibiting genera norank_f__Muribaculaceae and Lactobacillus. Additionally, JH modified the fecal metabolite profile, characterized by increased levels of several secondary bile acids (BAs) and decreased levels of several purine intermediate metabolites. Furthermore, JH upregulated levels of monoamine neurotransmitters (5-HT and DA) and brain-derived neurotrophic factor (BDNF), while downregulating pro-inflammatory cytokines IL-6 and TNF-α in brain tissue. These findings suggested that JH could mitigate CUMS-induced depression-like behavior, potentially by modulating gut microbiota composition and function, as well as brain neurochemicals and cytokines.PMID:39643357 | DOI:10.1016/j.foodres.2024.115306

Food Res Int. 2024 Dec;198:115289. doi: 10.1016/j.foodres.2024.115289. Epub 2024 Nov 7.ABSTRACTEdible bird's nest (EBN) is a functional food renowned for its numerous health benefits. While its nutritional and therapeutic value is well-documented, the metabolites contributing to the bioactivities of EBN remain poorly understood. This study aimed to identify the metabolites present in EBN subjected to different treatments, including double-boiled EBN (EBNdb), EBN hydrolysate (EBNhydro), EBN fermented with Lactobacillus helveticus (EBNLH), Latilactobacillus curvatus (EBNLC), and Latilactobacillus sakei (EBNLS) using liquid chromatography-mass spectrometry (LC-MS) and correlate the identified bioactive metabolites with the bioactivities of EBN. It was found that the fermented EBNs exhibited the highest number of metabolites, with 76 tentatively identified, followed by EBNhydro (45) and EBNdb (37). Citric acid (1.97-4.48 g/kg) was present in all treated EBN samples, while L(+)-lactic acid (3.03-8.07 g/kg) and adipic acid (2.33-3.18 g/kg) were only found in fermented EBNs. Among the treated EBN samples, EBNLC demonstrated the significantly highest (p ≤ 0.05) antioxidative (22.34 ± 0.41 % 1,1-diphenyl-2-picrylhydrazil radical scavenging activity), antihypertensive (5.46 ± 0.26 % angiotensin-converting enzyme inhibitory activity), and antihyperglycemic activities (6.48 ± 0.34 % α-amylase inhibitory activity). A total of 18 metabolites, including citric acid, 4-sphingenin, N-acetylcitrulline, 4-aminophenol, L(+)-lactic acid, 2-oxoadipate, sildenafil, formylglycinamidin-RP, 11β,17α,21-α-5β-pregnane-3,20-dione, 2-ketobutyric acid, homoserine, benzaldehyde, 1-pyrroline4-hydroxy-2-carboxylate, nortriptyline, 1-methylguanine, 3-hydroxy-trimethyllysine, 3-phenylpropionate, and reserphine were predicted as bioactive metabolites using the partial least squares discriminant analysis (PLS-DA). This study provides valuable insights into the metabolites present in EBN and serves as fundamental data for future investigations into the bioactive compounds responsible for its specific health benefits, potentially leading to the development of enhanced EBN-based functional foods.PMID:39643356 | DOI:10.1016/j.foodres.2024.115289

Food Res Int. 2024 Dec;198:115386. doi: 10.1016/j.foodres.2024.115386. Epub 2024 Nov 16.ABSTRACTThis study comprehensively investigated the impact of different storage times on the quality and metabolomic profiles of Liupao tea (LPT). The sensory evaluations revealed that both Maosheng (MS) and Tianyu (TY) teas exhibited a browning of tea appearance and brightening of tea infusion during storage. The taste evolved from bitterness and astringency to purity and briskness, while the aroma shifted from stuffy to woody and aged aromas. Notably, MS teas exhibited superior sensory quality after 10 years, while TY teas reached optimal quality in the 8th year of storage. Correlation analysis of metabolites and sensory attributes has underscored the integral influence of metabolites throughout the storage process, which significantly directed the development of tea quality. The non-volatile metabolites exerted significant influence on tea flavor by modulating key biochemical pathways, including the oxidation of catechins, the formation of alkaloids as well as the glycosylation and/or methylation of flavonoids. However, TY teas experienced both glycosylation and methylation, which promoted the transformation of bitterness and astringency, achieving a mellow and brisk taste more quickly than MS teas. The transformation pathways of volatile metabolites potentially involved the hydrolysis of linalool glycosides and phenylethanol glycosides, the synthesis of sesquiterpenes, the methylation of gallic acid and the degradation of carotenoids. However, the divergent trends observed in ketones and aldehydes between the two types of tea could culminate in distinct aromatic profiles, which might be due to different metabolic pathways or differences in the rates of metabolite formation and degradation during storage. Additionally, the antioxidant analysis revealed that both MS and TY teas exhibited a parabolic trend in comprehensive antioxidant capacity during storage, which primarily influenced by the oxidative polymerization of phenolic compounds and the glycosylation of flavonoids. In summary, this study emphasized the multifaceted attributes of tea quality and the importance of metabolites in shaping sensory quality and health properties. It was found that the optimal storage time of 8 to 10 years for LPT was conducive to attaining a desirable balance of flavor and health benefits.PMID:39643349 | DOI:10.1016/j.foodres.2024.115386

Food Res Int. 2024 Dec;198:115374. doi: 10.1016/j.foodres.2024.115374. Epub 2024 Nov 17.ABSTRACTTorreya grandis is a medicinally and nutritionally rich tree nut with high flavonoid content. However, a thorough evaluation of the variation in flavonoids among T. grandis cultivars remains to explore. In this study, we conducted a widely-targeted metabolomic analysis of five T. grandis cultivars, identifying 64 distinct flavonoids. Key subclasses of flavonoids, including flavan-3-ols, anthocyanidins, procyanidins, and flavonols, were characterized for their abundance and related to their potential health benefits. Our analysis revealed that T. grandis 'Shishengfei' exhibited the highest flavonoid diversity and content, while other cultivars showed relatively lower levels. By integrating transcriptome data, we identified genes and metabolic pathways associated with flavonoid biosynthesis, which could offer potential targets for metabolic engineering to enhance the flavonoid content in T. grandis. This research not only establishes a database of flavonoid components in T. grandis but also offers insights for selecting and breeding cultivars with enhanced health-promoting properties, contributing to the fields of food chemistry and nutrition.PMID:39643346 | DOI:10.1016/j.foodres.2024.115374

Food Res Int. 2024 Dec;198:115361. doi: 10.1016/j.foodres.2024.115361. Epub 2024 Nov 17.ABSTRACTMicrobial metabolism plays a critical role in the flavor development of Guangxi fermented bamboo shoots (GFBS). To clarify the role of microorganisms in flavor formation and predict the metabolic pathways of key characteristic flavor compounds, this study employed metabolomics, Odor Activity Value (OAV), and Taste Activity Value (TAV) calculations, integrated with Partial Least Squares Discriminant Analysis (PLS-DA), to investigate changes in GFBS flavors-represented by volatile flavor compounds, organic acids, and free amino acids-across a 30-day fermentation period. Metagenomic datasets were used to identify taxonomic and functional changes in the microbial community. As a result, 26 characteristic flavor compounds (OAV or TAV > 1) were identified in mature GFBS, and 23 differential flavor compounds were identified at different fermentation stages using PLS-DA (VIP > 1.2). The top 10 microbial genera associated with these characteristic flavor compounds were identified, including Acinetobacter, Enterobacter, Raoultella, Enterococcus, Klebsiella, Lactococcus, Leuconostoc, Weissella, Lactiplantibacillus and Limosilactobacillus. Based on these findings, a predictive metabolic network of key flavor compounds in GFBS was constructed, providing a comprehensive understanding of the diverse metabolic roles of microorganisms during fermentation. This work lays a theoretical foundation for the standardized production and quality control of GFBS flavor.PMID:39643345 | DOI:10.1016/j.foodres.2024.115361

Neuropharmacology. 2024 Dec 4:110246. doi: 10.1016/j.neuropharm.2024.110246. Online ahead of print.ABSTRACTParkinson's disease (PD) is a highly heterogeneous and therefore a possible cause of translation failure of drugs from animal testing to human treatments can be because existing models cannot replicate the entire spectrum of PD features. One of the theories of the origin of neurodegenerative diseases assumes metabolic dysfunction as a common fundamental thread of disease development. Intracerebroventricular administration of streptozotocin induces insulin resistance in the brain (Alzheimer's disease animal model). The aim of this project is to examine whether metabolic dysfunction caused by direct application of streptozotocin to brain region affected in PD (striatum) can induce characteristic PD symptoms. Adult male Wistar rats were given streptozotocin bilaterally or unilaterally in striatum. PET scan, cognitive, behavioural and motoric functions were tested one month after administration. Metabolite and protein analysis was done by untargeted metabolomics, ELISA and Western blot. Rats administered bilaterally showed motoric deficit, cognitive deficit of spatial learning and memory, fear conditioned and recognition memory, and anxiety-like behaviour, accompanied by impaired brain glucose uptake and metabolism. The results provide first evidence that bilateral intrastriatal administration of streptozotocin (particularly lower dose) can cause development of the hallmark PD symptoms. As metabolic dysfunction is increasingly associated with PD, an animal model with hypermetabolism in the early-on could be a better PD model for testing diverse therapeutics and the results could be better translated to humans. Further characterization is needed for understanding possible underlying mechanism and development of a new animal model for unique PD endophenotype expressing motoric, cognitive and metabolic symptomatology.PMID:39643239 | DOI:10.1016/j.neuropharm.2024.110246

Biochim Biophys Acta Mol Basis Dis. 2024 Dec 4:167613. doi: 10.1016/j.bbadis.2024.167613. Online ahead of print.ABSTRACTAcute pancreatitis (AP) is a severe inflammatory disorder associated with metabolic reprogramming and mitochondrial dysfunction. This study investigated central carbon metabolism alterations in pancreatic acinar cells during AP, elucidated the molecular mechanisms of tricarboxylic acid (TCA) cycle disorders, and explored the role of protein hypersuccinylation in AP pathogenesis. Using in vitro and in vivo AP models, targeted metabolomics and bioinformatics analyses revealed TCA cycle dysregulation characterized by elevated succinyl-CoA and decreased succinate levels. Colorimetric assays, mass spectrometry, and site-directed mutagenesis demonstrated that SIRT5 downregulation led to SUCLA2 hypersuccinylation at K118, inhibiting succinyl-CoA synthetase activity and triggering a vicious cycle of succinyl-CoA accumulation and SUCLA2 succinylation. Adenovirus-mediated SIRT5 overexpression and SUCLA2 knockdown clarified the SIRT5-SUCLA2 pathway's role in regulating TCA cycle disorders. Protein succinylation levels positively correlated with pancreatic tissue damage and mitochondrial injury severity. Succinylome analysis identified cytochrome c1 (CYC1) as a key hypersuccinylated protein, and the SIRT5-SUCLA2 pathway regulated its succinylation level and electron transport chain complex III activity. Hypersuccinylation induced mitochondrial DNA release, activating the cGAS-STING pathway, contributing to multiple organ dysfunction syndrome. Modulating the SIRT5-SUCLA2 axis attenuated TCA cycle dysregulation, protein hypersuccinylation, mitochondrial damage, and inflammatory responses in AP. These findings reveal novel mechanisms linking the SIRT5-SUCLA2 axis, TCA cycle dysfunction, and protein hypersuccinylation in AP pathogenesis, providing potential therapeutic targets for AP treatment.PMID:39643219 | DOI:10.1016/j.bbadis.2024.167613

J Affect Disord. 2024 Dec 4:S0165-0327(24)02008-1. doi: 10.1016/j.jad.2024.12.029. Online ahead of print.ABSTRACTBACKGROUND: Post-traumatic stress disorder (PTSD) is a debilitating chronic mental disorder that leads to reduced quality of life and increased economic burden. Observational studies have found an association between human blood metabolites and PTSD. Nonetheless, these studies have limitations and are subject to confounding factors as well as reverse causation. Herein, we employed a two-sample Mendelian randomization (MR) approach for the systematic analysis of the blood metabolites and PTSD causal link.METHODS: Data for the human blood metabolome, cerebrospinal fluid (CSF) metabolome, and PTSD were obtained from publicly available summary-level genome-wide association studies (GWAS), respectively. The inverse variance weighted (IVW) approach represented the main analytic method for assessing exposure-outcome causal associations, employing multiple sensitivity analyses to verify the results' stability. In addition, replication and meta-analysis, steiger test and reverse MR analysis methods were performed to clarify further that these metabolites have independent causal effects on PTSD. Finally, the results of blood and CSF metabolomics analyses were synthesized to obtain biological markers with a causal link to PTSD.RESULTS: Conclusively, we identified potential causal associations between six blood metabolites and PTSD. The sensitivity analyses elucidated the absence of pleiotropy or heterogeneity in the MR results. The Steiger test and reverse MR analysis did not reveal reverse causal associations, proving the robustness of our results. Combined blood and CSF metabolome analyses showed the same trend for theophylline.CONCLUSION: This study reveals a strong causal link between metabolites and PTSD, which can be used as a biomarker for clinical PTSD disease screening and prevention. This study also provides a new perspective on the mechanism of metabolite-mediated PTSD development by combining genomics and metabolomics.PMID:39643216 | DOI:10.1016/j.jad.2024.12.029

Int J Biol Macromol. 2024 Dec 4:138388. doi: 10.1016/j.ijbiomac.2024.138388. Online ahead of print.ABSTRACTTea leaf spot, caused by the fungus Didymella segeticola, occurs in the high-mountain tea plantations of Southwest China. Due to a limited understanding of the disease's epidemiology and the lack of comprehensive control measures, it has a significant negative impact on tea yield and quality. In this study, we revealed that D. segeticola infection begins when conidia germinate to form a germ tube on the leaf surface. The fungus then grows in the intercellular spaces of the leaf epidermal cells, invading tea tissue and causing necrotic lesions. This infection leads to significant alterations in the cell walls of spongy and palisade mesophyll cells, severely damaging chloroplasts. We employed transcriptomic and metabolomic analyses based on an in vitro infection model using matcha powder to uncover two key genes of D. segeticola: DsHAD (encoding holoacid dehydrogenase) and DsADH (encoding alcohol dehydrogenase). These genes are the first to be associated with conidiation, virulence, and sensitivity to oxidative stress. DsHAD regulates the virulence of D. segeticola by modulating glutamate homeostasis. Our results elucidate the infection strategy of D. segeticola on tea leaves and provide valuable data for future research on control measures for tea leaf spot.PMID:39643170 | DOI:10.1016/j.ijbiomac.2024.138388

J Mol Biol. 2024 Dec 4:168888. doi: 10.1016/j.jmb.2024.168888. Online ahead of print.ABSTRACTOsteoarthritis (OA) is the most common degenerative joint disease and the second leading cause of disability worldwide. Single-omics analyses are far from elucidating the complex mechanisms of lipid metabolic dysfunction in OA. This study identified a shared lipid metabolic signature of OA by integrating metabolomics, single-cell and bulk RNA-seq, as well as metagenomics. Compared to the normal counterparts, cartilagesin OA patients exhibited significant depletion of homeostatic chondrocytes (HomCs) (P=0.03) and showed lipid metabolic disorders in linoleic acid metabolism and glycerophospholipid metabolism which was consistent with our findings obtained from plasma metabolomics. Through high-dimensional weighted gene co-expression network analysis (hdWGCNA), weidentified PLA2G2A as a hub gene associated with lipid metabolic disorders in HomCs. And an OA-associated subtype of HomCs, namely HomC1 (marked by PLA2G2A, MT-CO1, MT-CO2, and MT-CO3) was identified, which also exhibited abnormal activation of lipid metabolic pathways. This suggests the involvement of HomC1 in OA progression through the shared lipid metabolism aberrancies, which were further validated via bulk RNA-Seq analysis. Metagenomic profiling identified specific gut microbial species significantly associated with the key lipid metabolism disorders, including Bacteroides uniformis (P<0.001, R=-0.52), Klebsiella pneumonia (P=0.003, R=0.42), Intestinibacter_bartlettii (P=0.009, R=0.38), and Streptococcus anginosus (P=0.009, R=0.38). By integrating the multi-omics features, a random forest diagnostic model with outstanding performance was developed (AUC=0.97). In summary, this study deciphered the crucial role of a integrated lipid metabolic signature in OA pathogenesis, and established a regulatory axis of gut microbiota-metabolites-cell-gene, providing new insights into the gut-joint axis and precision therapy for OA.PMID:39643156 | DOI:10.1016/j.jmb.2024.168888

Metab Eng. 2024 Dec 4:S1096-7176(24)00164-2. doi: 10.1016/j.ymben.2024.12.001. Online ahead of print.ABSTRACTLactate metabolism plays a critical role in mammalian cell bioprocessing, influencing cellular performance and productivity. The transition from lactate production to consumption, known as lactate metabolic shift, is highly beneficial and has been shown to extend culture lifespan and enhance productivity, yet its molecular drivers remain poorly understood. Here, we have explored the mechanisms that underpin this metabolic shift through two case studies, illustrating environmental- and genetic-driven factors. We characterised these study cases at process, metabolic and transcriptomic levels. Our findings indicate that glutamine depletion coincided with the timing of the lactate metabolic shift, significantly affecting cell growth, productivity and overall metabolism. Transcriptome analysis revealed dynamic regulation the ATF4 pathway, involved in the amino acid (starvation) response, where glutamine depletion activates ATF4 gene and its targets. Manipulating ATF4 expression through overexpression and knockdown experiments showed significant changes in metabolism of glutamine and lactate, impacting cellular performance. Overexpression of ATF4 increased cell growth and glutamine consumption, promoting a lactate metabolic shift. In contrast, ATF4 downregulation decreased cell proliferation and glutamine uptake, leading to production of lactate without any signs of lactate shift. These findings underscore a critical role for ATF4 in regulation of glutamine and lactate metabolism, related to phasic patterns of growth during CHO cell culture. This study offers unique insight into metabolic reprogramming during the lactate metabolic shift and the molecular drivers that determine cell status during culture.PMID:39643154 | DOI:10.1016/j.ymben.2024.12.001

Eur J Pharm Sci. 2024 Dec 4:106979. doi: 10.1016/j.ejps.2024.106979. Online ahead of print.ABSTRACTIn 2018 Amsterdam UMC decided to prepare chenodeoxycholic acid (CDCA) capsules (also known as pharmacy compounding) for patients with the genetic metabolic disease cerebrotendinous xanthomatosis (CTX) when the product with a marketing authorization was commercially unavailable for patients. However after reanalysis, unknown impurities were identified in the CDCA active pharmaceutical ingredient (API) using thin-layer chromatography from the European Pharmacopoeia (Ph.Eur.) monograph. Therefore the API did not comply with the Ph.Eur. specifications for related substances. As a result pharmacy compounding was halted and an investigation was initiated to identify and quantify the unknown impurities. Meanwhile, a second CDCA API was sourced from another manufacturer. However, this API also appeared to contain an unknown impurity. This impurity could be identified as a dimer of CDCA using reversed phase liquid chromatography mass spectrometry. Since the Ph.Eur. at the time did not describe a suitable analytical method for the quantification of this new impurity, a high pressure liquid chromatography with differential refractometer (HPLC-RI) method was developed to quantify the dimer. Subsequently, in 2019, a new draft version of the CDCA Ph.Eur. monograph was published, including the dimer as an additional impurity together with a HPLC-RI method for its identification and quantification. The CDCA-dimer is classified as non-toxic and permitted in the CDCA API up to a maximum of 0.5%. Because the API complied with the updated Ph.Eur. specifications, pharmacy compounding of CDCA capsules could be resumed.PMID:39643128 | DOI:10.1016/j.ejps.2024.106979

Bioresour Technol. 2024 Dec 4:131949. doi: 10.1016/j.biortech.2024.131949. Online ahead of print.ABSTRACTPolyhydroxyalkanoate (PHA) is considered a sustainable alternative to traditional petroleum-based plastics due to its biodegradability and biocompatibility. In this study, Acidovorax diaphorobacter ZCH-15, an efficient PHA-producing strain, was isolated from activated sludge. Using food waste-derived orange peel as a substrate, the strain initially achieved a PHA concentration of 0.39 g/L. Under optimal fermentation conditions (30℃, pH 8, 2 % inoculum concentration, and 30 g/L carbon source), the PHA concentration increased by 138 % to reach a maximum of 0.93 g/L. Proton nuclear magnetic resonance spectroscopy and gas chromatography analyses identified the PHA composition as poly(3-hydroxybutyrate-co-3-hydroxyvalerate), which exhibited high crystallinity and structural stability. Metabolomic analysis indicated that the tricarboxylic acid cycle and pentose phosphate pathway were involved in producing succinyl-CoA, a precursor required for PHA synthesis. This study demonstrates the potential for cost-effective industrial PHA production while enabling the high-value utilization of food waste.PMID:39643061 | DOI:10.1016/j.biortech.2024.131949

J Ethnopharmacol. 2024 Dec 4:119172. doi: 10.1016/j.jep.2024.119172. Online ahead of print.ABSTRACTETHNOPHARMACOLOGICAL RELEVANCE: Selaginella moellendorffii Hieron. has been used as ethnic drug for chronic inflammation treatment. Biflavonoids represent a crucial class of bioactive compounds recognized for their potent anti-inflammatory activity in S. moellendorffii (SM). However, the effective components, targets, and pathways that SM in anti-inflammasome remain unclear.AIM OF THE STUDY: Therefore, this study initially evaluated the effective components of SM and explored the underlying mechanisms.MATERIALS AND METHODS: Firstly, a series of biflavonoids were isolated from SM, and then all compounds were evaluated for their anti-inflammatory ability in the THP-macrophages co-stimulated with lipopolysaccharide (LPS) and NLRP3 inflammasome inducers. Secondly, transcriptomic analysis and metabolomics analysis revealed the differential genes and metabolites associated with effective components treatment. Finally, molecular docking of effective components with NLRP3 was performed and western blotting was performed in order to determine the expression of related proteins.RESULTS: Overall, eleven biflavonoids were successfully isolated from SM. Particularly, F7 exhibited the most potent inhibitory effect against NLRP3 inflammasome-mediated cytokines levels, cell membrane integrity and Ca2+ influx. Transcriptomic studies demonstrated that the differential genes (DEGs) were mainly enriched in NF-κB signaling pathway and NOD-like receptor signaling pathway. Metabolomics studies that the metabolites were mainly involved the pyrimidine metabolites. Further validation analysis manifested that F7's significant downregulation of NLRP3 inflammasome-related genes and proteins expression (P<0.05, P<0.01), encompassing both priming (NLRP3, TNF-α, p-p65/p65) and activation stages (IL-1β, IL-18, Caspase-1, GSDMD-N/GSDMD). Moreover, NLRP3 knockdown attenuated F7-mediated inhibition of pyroptosis. Finally, in silico results showed that F7 exhibited promising predicted binding affinity towards NLRP3.CONCLUSIONS: Collectively, these findings revealed an anti-inflammatory material basis for SM and confirmed F7 as a potent inhibitor of pyroptosis by suppressing NF-κB/NLRP3 Pathway.PMID:39643022 | DOI:10.1016/j.jep.2024.119172