PubMed

Microb Cell Fact. 2024 Feb 21;23(1):58. doi: 10.1186/s12934-024-02334-z.ABSTRACTAcetoin, a versatile platform chemical and popular food additive, poses a challenge to the biosafety strain Bacillus subtilis when produced in high concentrations due to its intrinsic toxicity. Incorporating the PHB synthesis pathway into Bacillus subtilis 168 has been shown to significantly enhance the strain's acetoin tolerance. This study aims to elucidate the molecular mechanisms underlying the response of B. subtilis 168-phaCBA to acetoin stress, employing transcriptomic and metabolomic analyses. Acetoin stress induces fatty acid degradation and disrupts amino acid synthesis. In response, B. subtilis 168-phaCBA down-regulates genes associated with flagellum assembly and bacterial chemotaxis, while up-regulating genes related to the ABC transport system encoding amino acid transport proteins. Notably, genes coding for cysteine and D-methionine transport proteins (tcyB, tcyC and metQ) and the biotin transporter protein bioY, are up-regulated, enhancing cellular tolerance. Our findings highlight that the expression of phaCBA significantly increases the ratio of long-chain unsaturated fatty acids and modulates intracellular concentrations of amino acids, including L-tryptophan, L-tyrosine, L-leucine, L-threonine, L-methionine, L-glutamic acid, L-proline, D-phenylalanine, L-arginine, and membrane fatty acids, thereby imparting acetoin tolerance. Furthermore, the supplementation with specific exogenous amino acids (L-alanine, L-proline, L-cysteine, L-arginine, L-glutamic acid, and L-isoleucine) alleviates acetoin's detrimental effects on the bacterium. Simultaneously, the introduction of phaCBA into the acetoin-producing strain BS03 addressed the issue of insufficient intracellular cofactors in the fermentation strain, resulting in the successful production of 70.14 g/L of acetoin through fed-batch fermentation. This study enhances our understanding of Bacillus's cellular response to acetoin-induced stress and provides valuable insights for the development of acetoin-resistant Bacillus strains.PMID:38383407 | DOI:10.1186/s12934-024-02334-z

BMC Plant Biol. 2024 Feb 21;24(1):132. doi: 10.1186/s12870-024-04804-3.ABSTRACTSeed propagation is the main method of mulberry expansion in China, an important economic forest species. However, seed germination is the most sensitive stage to various abiotic stresses, especially salinity stress. To reveal the molecular regulatory mechanism of mulberry seed germination under salt stress, flavonoid metabolomics and transcriptomics analyses were performed on mulberry seeds germinated under 50 and 100 mmol/L NaCl stress. Analysis of the flavonoid metabolome revealed that a total of 145 differential flavonoid metabolites (DFMs) were classified into 9 groups, 40 flavonols, 32 flavones, 16 chalcones and 14 flavanones. Among them, 61.4% (89) of the DFMs accumulated continuously with increasing salt concentration, reaching the highest level at a 100 mmol/L salt concentration; these DFMs included quercetin-3-O-glucoside (isoquercitrin), kaempferol (3,5,7,4'-tetrahydroxyflavone), quercetin-7-O-glucoside, taxifolin (dihydroquercetin) and apigenin (4',5,7-trihydroxyflavone), indicating that these flavonoids may be key metabolites involved in the response to salt stress. Transcriptional analysis identified a total of 3055 differentially expressed genes (DEGs), most of which were enriched in flavonoid biosynthesis (ko00941), phenylpropanoid biosynthesis (ko00940) and biosynthesis of secondary metabolites (ko01110). Combined analysis of flavonoid metabolomic and transcriptomic data indicated that phenylalanine ammonia-lyase (PAL), 4-coumarate-CoA ligase (4CL), chalcone synthase (CHS), flavonol synthase (FLS), bifunctional dihydroflavonol 4-reductase/flavanone 4-reductase (DFR) and anthocyanidin reductase (ANR) were the key genes involved in flavonoid accumulation during mulberry seed germination under 50 and 100 mmol/L NaCl stress. In addition, three transcription factors, MYB, bHLH and NAC, were involved in the regulation of flavonoid accumulation under salt stress. The results of quantitative real-time PCR (qRT‒PCR) validation showed that the expression levels of 11 DEGs, including 7 genes involved in flavonoid biosynthesis, under different salt concentrations were consistent with the transcriptomic data, and parallel reaction monitoring (PRM) results showed that the expression levels of 6 key enzymes (proteins) involved in flavonoid synthesis were consistent with the accumulation of flavonoids. This study provides a new perspective for investigating the regulatory role of flavonoid biosynthesis in the regulation of mulberry seed germination under salt stress at different concentrations.PMID:38383312 | DOI:10.1186/s12870-024-04804-3

BMC Genomics. 2024 Feb 21;25(1):201. doi: 10.1186/s12864-024-10079-7.ABSTRACTTo gain a deeper understanding of the metabolic differences within and outside the body, as well as changes in transcription levels following estrus in yaks, we conducted transcriptome and metabolome analyses on female yaks in both estrus and non-estrus states. The metabolome analysis identified 114, 13, and 91 distinct metabolites in urine, blood, and follicular fluid, respectively. The Kyoto Encyclopedia of Genes and Genomes (KEGG) analysis highlighted an enrichment of pathways related to amino acid and lipid metabolism across all three body fluids. Our transcriptome analysis revealed 122 differentially expressed genes within microRNA (miRNA) and 640 within long non-coding RNA (lncRNA). Functional enrichment analysis of lncRNA and miRNA indicated their involvement in cell signaling, disease resistance, and immunity pathways. We constructed a regulatory network composed of 10 lncRNAs, 4 miRNAs, and 30 mRNAs, based on the targeted regulation relationships of the differentially expressed genes. In conclusion, the accumulation of metabolites such as amino acids, steroids, and organic acids, along with the expression changes of key genes like miR-129 during yak estrus, provide initial insights into the estrus mechanism in yaks.PMID:38383305 | DOI:10.1186/s12864-024-10079-7

J Agric Food Chem. 2024 Feb 21. doi: 10.1021/acs.jafc.3c08582. Online ahead of print.ABSTRACTVerticillium dahliae, a notorious phytopathogenic fungus, is responsible for vascular wilt diseases in numerous crops. Uncovering the molecular mechanisms underlying pathogenicity is crucial for controlling V. dahliae. Herein, we characterized a putative oxidoreductase-like protein (VdOrlp) from V. dahliae that contains a functional signal peptide. While the expression of VdOrlp was low in artificial media, it significantly increased during host infection. Deletion of VdOrlp had minimal effects on the growth and development of V. dahliae but severely impaired its pathogenicity. Metabolomic analysis revealed significant changes in organic heterocyclic compounds and phenylpropane compounds in cotton plants infected with ΔVdOrlp and V991. Furthermore, VdOrlp expression was induced by lignin, and its deletion affected the metabolism of host lignin and phenolic acids. In conclusion, our results demonstrated that VdOrlp plays an important role in the metabolism of plant phenylpropyl lignin and organic heterocyclic compounds and is required for fungal pathogenicity in V. dahliae.PMID:38383289 | DOI:10.1021/acs.jafc.3c08582

Biol Pharm Bull. 2024;47(2):499-508. doi: 10.1248/bpb.b23-00835.ABSTRACTTo reveal the mechanism of Shenkang injection (SKI) in the treatment of chronic renal failure, and verify the key pathway. In this work, an untargeted metabolomics approach was performed by LC-MS coupled with multivariate statistical analysis to provide new insights into therapeutic mechanism of SKI. Hematoxylin-eosin (H&E) Staining and Immunohistochemistry were used to evaluate the effects of drug treatment, Western blot was used to verify the critical pathway. Then, a total of 44 potential biomarkers of chronic renal failure (CRF) were identified and reversed regulation, including 2,8-dihydroxypurine, 5-methoxytryptophan, uric acid, acetylcarnitine, taurine, etc. Mainly concerned with arginine and proline metabolism, purine metabolism, histidine metabolism, etc. Pathological examination showed that the renal interstitium of SKI group was significantly improved, with fewer inflammatory cells and thinner vascular walls compared with the model group. Immunohistochemical results showed that the expression of α-smooth muscle actin (α-SMA) was decreased, and the expression of E-cadherin was increased in CRF model group, and the two indicators were reversed regulation in SKI injection, indicating that the degree of fibrosis was relieved. Critical signaling pathway phosphatidylinositol 3-kinase (PI3K)/protein kinase B (Akt) and nuclear factor-kappaB (NF-κB) protein expressions were significantly inhibited. This study was the first to employ metabolomics to elucidate the underlying mechanisms of SKI in chronic renal failure. The results would provide some support for clinical application of traditional Chinese medicines in clinic.PMID:38382928 | DOI:10.1248/bpb.b23-00835

Ann Allergy Asthma Immunol. 2024 Feb 19:S1081-1206(24)00084-X. doi: 10.1016/j.anai.2024.02.008. Online ahead of print.ABSTRACTBACKGROUND: Pathogenesis of chronic rhinosinusitis with nasal polyps (CRSwNP) with comorbid asthma remains unclear.OBJECTIVE: In order to assess upper and lower airway unity and identify a possible common pathogenesis in CRSwNP with asthma.METHODS: This study analyzed the expression of proteins and metabolites in nasal lavage fluid cells (NLFCs) and induced sputum cells (ISCs). Differentially expressed proteins and their function-related metabolites in the upper and lower airways of CRSwNP patients with or without asthma were identified, relevant signaling pathways were analyzed, and key pathway-related proteins were identified. Parallel reaction monitoring (PRM) was used to verify these target proteins.RESULTS: Protein or metabolite expression between NLFCs and ISCs was highly correlated and conservative based on expression profiles and weighted gene co-expression network analysis. Seventeen differentially co-expressed proteins and their function-related 13 metabolites were identified in the NLFCs and ISCs of CRSwNP, while 11 proteins and 11 metabolites were identified in CRSwNP with asthma. An asthma pathway was involved in the co-pathogenesis of upper and lower airways in whether CRSwNP or CRSwNP with asthma. The asthma pathway-related proteins proteoglycan 2 (PRG2) and eosinophil peroxidase (EPX), as the core of the protein-metabolism interaction networks between the upper and lower airways, were both highly co-expressed in NLFCs and ISCs in patients with either CRSwNP or CRSwNP with asthma by PRM validation.CONCLUSION: Proteomics and metabolomics reveal upper and lower airway unity. Asthma pathway-related proteins PRG2 and EPX from the upper airway could be used to assess the potential risk of lower airway dysfunction in CRSwNP.PMID:38382675 | DOI:10.1016/j.anai.2024.02.008

J Ethnopharmacol. 2024 Feb 19:117939. doi: 10.1016/j.jep.2024.117939. Online ahead of print.ABSTRACTETHNOPHARMACOLOGICAL RELEVANCE: Tripterygium wilfordii polyglycosides (TWP) tablet is the most widely used traditional Chinese medicine preparation for the treatment of rheumatoid arthritis (RA), but the hepatotoxicity often limits its widespread application. In traditional use, Salvia miltiorrhiza has cardioprotective and hepatoprotective effects. Salvianolic acid extract (SA) is a hydrophilic component of Salvia miltiorrhiza and has significant antioxidant and hepatoprotective effects.AIM OF THE STUDY: To investigate the protective effects of SA on the TWP-induced acute liver injury in rats and to explore the related mechanisms by integration of metabolomics and transcriptomics.MATERIALS AND METHODS: SA and TWP extracts were identified by UPLC-Q/TOF-MS. SA (200 mg/kg) was administered for consecutive 7 days. On day 7, TWP (360 mg/kg) was administered by gavage to induce the acute liver injury in rats. Serum biochemical assay and H&E staining were used to evaluate liver damage. Liver metabolomics and transcriptomics were used to explore the potential mechanisms, and further molecular biological experiments such as qPCR and IHC were utilized to validate the relevant signaling pathways.RESULTS: SA can prevent liver injury symptoms caused by TWP, such as elevated liver index, elevated ALT and AST, and pathological changes in liver tissue. Liver metabolomics studies showed that TWP can significantly alter the content of individual bile acid in the liver and SA had the most significant impact on the biosynthetic pathway of bile acids. The transcriptomics results of the liver indicated that the genes changed in the SA + TWP group were mainly involved in sterol metabolism, lipid regulation and bile acid homeostasis pathways. The gene expression of Nr1h4, which encodes farnesoid X receptor (FXR), an important regulator of bile acid homeostasis, was significantly changed. Further studies confirmed that SA can prevent the downregulation of FXR and its downstream signaling induced by TWP, thereby regulating bile acid metabolism, ultimately preventing acute liver injury caused by TWP.CONCLUSION: Our results demonstrated that SA could protect the liver from TWP-induced hepatic injury by modulation of the bile acid metabolic pathway. SA may provide a new strategy for the protection against TWP-induced acute liver injury.PMID:38382651 | DOI:10.1016/j.jep.2024.117939

Microb Pathog. 2024 Feb 19:106586. doi: 10.1016/j.micpath.2024.106586. Online ahead of print.ABSTRACTAvian colibacillosis is a bacterial disease caused by avian pathogenic Escherichia coli (APEC) that results in great losses in the poultry industry every year. Individual Silkie chickens of the same breed that are given the same feed in the same feeding conditions have different levels of resistance or susceptibility to APEC. Differences in gut microbes, gut metabolites, and gene expression in the spleen of APEC-resistant and APEC-susceptible chickens were compared, and multiple omics associations were analyzed to explore the mechanism of resistance to APEC in Silkie chickens. Compared with those in the APEC-susceptible group, the APEC-resistant group showed significantly increased abundances of many gut microorganisms, including Bacillus, Thermoactinomyces, Arthrobacter, and Ureibacillus, which were positively correlated with norvaline, l-arginine, and valyl-glycine levels. Intestinal tryptophan, indole, and indole derivative-related differentially abundant metabolites played an active role in combatting APEC infection. In the spleen, "response to stimulus" was the most significantly enriched GO term, and "cytokine‒cytokine receptor interaction" was the most significantly enriched KEGG pathway. The arginine biosynthesis and PPAR signaling pathways were the KEGG pathways that were significantly enriched with differentially abundant metabolites and differentially expressed genes. This study provides new insight into the prevention and treatment of APEC infection in Silkie chickens and lays a foundation to study the mechanism of APEC infection in poultry.PMID:38382628 | DOI:10.1016/j.micpath.2024.106586

J Adv Res. 2024 Feb 19:S2090-1232(24)00077-8. doi: 10.1016/j.jare.2024.02.015. Online ahead of print.ABSTRACTINTRODUCTION: Obesity and imbalance in lipid homeostasis contribute greatly to heart failure with preserved ejection fraction (HFpEF), the dominant form of heart failure. Few effective therapies exist to control metabolic alterations and lipid homeostasis.OBJECTIVES: We aimed to investigate the cardioprotective roles of AdipoRon, the adiponectin receptor agonist, in regulating lipid accumulation in the two-hit HFpEF model.METHODS: HFpEF mouse model was induced using 60 % high-fat diet plus L-NAME drinking water. Then, AdipoRon (50 mg/kg) or vehicle were administered by gavage to the two-hit HFpEF mouse model once daily for 4 weeks. Cardiac function was evaluated using echocardiography, and Postmortem analysis included RNA-sequencing, untargeted metabolomics, transmission electron microscopy and molecular biology methods.RESULTS: Our study presents the pioneering evidence that AdipoR was downregulated and impaired fatty acid oxidation in the myocardia of HFpEF mice, which was associated with lipid metabolism as indicated by untargeted metabolomics. AdipoRon, orally active synthetic adiponectin receptor agonist, could upregulate AdipoR1/2 (independently of adiponectin) and reduce lipid droplet accumulation, and alleviate fibrosis to restore HFpEF phenotypes. Finally, AdipoRon primarily exerted its effects through restoring the balance of myocardial fatty acid intake, transport, and oxidation via the downstream AMPKα or PPARα signaling pathways. The protective effects of AdipoRon in HFpEF mice were reversed by compound C and GW6471, inhibitors of AMPKα and PPARα, respectively.CONCLUSIONS: AdipoRon ameliorated the HFpEF phenotype by promoting myocardial fatty acid oxidation, decreasing fatty acid transport, and inhibiting fibrosis via the upregulation of AdipoR and the activation of AdipoR1/AMPKα and AdipoR2/PPARα-related downstream pathways. These findings underscore the therapeutic potential of AdipoRon in HFpEF. Importantly, all these parameters get restored in the context of continued mechanical and metabolic stressors associated with HFpEF.PMID:38382593 | DOI:10.1016/j.jare.2024.02.015

Environ Sci Technol. 2024 Feb 21. doi: 10.1021/acs.est.3c05741. Online ahead of print.ABSTRACTAntibiotic resistance genes (ARGs) are ancient but have become a modern critical threat to health. Gut microbiota, a dynamic reservoir for ARGs, transfer resistance between individuals. Surveillance of the antibiotic resistome in the gut during different host growth phases is critical to understanding the dynamics of the resistome in this ecosystem. Herein, we disentangled the ARG profiles and the dynamic mechanism of ARGs in the egg and adult phases of Tetramorium caespitum. Experimental results showed a remarkable difference in both gut microbiota and gut resistome with the development of T. caespitum. Meta-based metagenomic results of gut microbiota indicated the generalizability of gut antibiotic resistome dynamics during host development. By using Raman spectroscopy and metabolomics, the metabolic phenotype and metabolites indicated that the biotic phase significantly changed lipid metabolism as T. caespitum aged. Lipid metabolites were demonstrated as the main factor driving the enrichment of ARGs in T. caespitum. Cuminaldehyde, the antibacterial lipid metabolite that displayed a remarkable increase in the adult phase, was demonstrated to strongly induce ARG abundance. Our findings show that the gut resistome is host developmental stage-dependent and likely modulated by metabolites, offering novel insights into possible steps to reduce ARG dissemination in the soil food chain.PMID:38382547 | DOI:10.1021/acs.est.3c05741

Autophagy. 2024 Feb 21:1-3. doi: 10.1080/15548627.2024.2319022. Online ahead of print.ABSTRACTRibosomes are conserved macromolecular machines that are responsible for protein synthesis in all cells. While our knowledge of ribosome biogenesis and function has increased significantly in recent years, little is known about how ribosomes are degraded under specific cellular conditions. We recently uncovered that ribosomes are efficiently turned over by selective macroautophagy/autophagy during oncogene-induced senescence (OIS). By profiling the ribosome interactome in human fibroblasts undergoing OIS, we discovered a key role for the de-ubiquitinating enzyme USP10 in guiding this process. Release of USP10 from ribosomes during senescence leads to their enhanced ubiquitination and selective sequestering by autophagy through the SQSTM1/p62 receptor protein. This process is important for sustaining senescence-associated metabolome and secretome alterations.PMID:38382540 | DOI:10.1080/15548627.2024.2319022

Environ Int. 2024 Feb 17;185:108513. doi: 10.1016/j.envint.2024.108513. Online ahead of print.ABSTRACTCadmium (Cd) is a toxic heavy metal found in natural and industrial environments. Exposure to Cd can lead to various metabolic disturbances, notably disrupting glucose and lipid homeostasis. Despite this recognition, the direct impact of Cd exposure on lipid metabolism within adipose tissue, and the mechanisms underlying these effects, have not been fully elucidated. In this study, we found that Cd accumulates in adipose tissues of mice subjected to Cd exposure. Intriguingly, Cd exposure in itself did not induce significant alterations in the adipose tissue under normal conditions. However, when subjected to cold stimulation, several notable changes were observed in the mice exposed to Cd, including a reduction in the drop of body temperature, a decrease in the size of inguinal white adipose tissue (WAT), and an increase in the expression of thermogenic genes UCP1 and PRDM16. These results indicate that Cd exposure might enhance the responsiveness of adipose tissue to external stimuli and increase the energy expenditure of the tissue. RNA-seq analysis further revealed that Cd exposure altered gene expression profiles, particularly affecting peroxisome proliferator-activated receptor (PPAR)-mediated metabolic pathways, promoting metabolic remodeling in adipose tissue and resulting in the depletion of lipids stored in adipose tissue for energy. Non-targeted metabolomic analysis of mouse serum showed that Cd exposure significantly disrupted metabolites and significantly increased serum fatty acid and triglyceride levels. Correspondingly, population-level data confirmed an association between Cd exposure and elevated levels of serum total cholesterol, total triglycerides, and low-density lipoprotein cholesterol. In summary, we provide substantial evidence of the molecular events induced by Cd that are relevant to the regulation of lipid metabolism in adipose tissue. Our findings suggest that the toxic effects of Cd can impact adipocyte functionality, positioning adipose tissue as a critical target for metabolic diseases resulting from Cd exposure.PMID:38382403 | DOI:10.1016/j.envint.2024.108513

J Hazard Mater. 2024 Feb 15;468:133784. doi: 10.1016/j.jhazmat.2024.133784. Online ahead of print.ABSTRACTThe relationship between PM2.5 and metabolic diseases, including type 2 diabetes (T2D), has become increasingly prominent, but the molecular mechanism needs to be further clarified. To help understand the mechanistic association between PM2.5 exposure and human health, we investigated short-term PM2.5 exposure trajectory-related multi-omics characteristics from stool metagenome and metabolome and serum proteome and metabolome in a cohort of 3267 participants (age: 64.4 ± 5.8 years) living in Southern China. And then integrate these features to examine their relationship with T2D. We observed significant differences in overall structure in each omics and 193 individual biomarkers between the high- and low-PM2.5 groups. PM2.5-related features included the disturbance of microbes (carbohydrate metabolism-associated Bacteroides thetaiotaomicron), gut metabolites of amino acids and carbohydrates, serum biomarkers related to lipid metabolism and reducing n-3 fatty acids. The patterns of overall network relationships among the biomarkers differed between T2D and normal participants. The subnetwork membership centered on the hub nodes (fecal rhamnose and glycylproline, serum hippuric acid, and protein TB182) related to high-PM2.5, which well predicted higher T2D prevalence and incidence and a higher level of fasting blood glucose, HbA1C, insulin, and HOMA-IR. Our findings underline crucial PM2.5-related multi-omics biomarkers linking PM2.5 exposure and T2D in humans.PMID:38382338 | DOI:10.1016/j.jhazmat.2024.133784

Curr Opin Biotechnol. 2024 Feb 20;86:103081. doi: 10.1016/j.copbio.2024.103081. Online ahead of print.ABSTRACTBelgium is known for its traditional lambic beer productions, obtained through spontaneous fermentation and maturation in wooden barrels. Lambic beer is also used to make fruit lambic beers, such as Kriek beer. Despite fruit beer being an old beer type, dating back to the second half of the seventeenth century, no research has been performed on lambic beer-fruit co-fermentation processes. Further, these beers get competition from market-driven, sweet, (fruit-)flavored ones without the co-fermentation step. This paper will first discuss a new, general fruit beer classification, going from sour fruit beers produced through co-fermentation to sweet ones without a co-fermentation step. Second, a state-of-the-art of the scarce literature on the microbiology and metabolomics of lambic beer-fruit co-fermentation processes will be given.PMID:38382326 | DOI:10.1016/j.copbio.2024.103081

J Pharm Biomed Anal. 2024 Feb 10;242:116030. doi: 10.1016/j.jpba.2024.116030. Online ahead of print.ABSTRACTLiver's distinctive function renders it highly susceptible to diverse damage sources. Characterizing the metabolic profiles and spatial signatures in different liver injuries is imperative for early diagnosis and etiology-oriented treatment. In this comparative study, we conducted whole-body spatial metabolomics on zebrafish with liver injury induced by ethanol (EtOH), acetaminophen (APAP), and thioacetamide (TAA). The two specific levels, the whole-body and liver-specific metabolic profiles, as well as their regional distributions, were systematically mapped in situ by mass spectrometry imaging, which is distinct from conventional LC-MS and GC-MS methods. We found that liver injury regions exhibited more pronounced metabolic reprogramming than the entire organism, leading to significant alterations in eight fatty acids, three phospholipids, and four low-molecular-weight metabolites. More importantly, fatty acids as well as small molecule metabolites including glutamine, glutamate, taurine and malic acid displayed contrasting changes between alcoholic liver disease (ALD) and non-alcoholic fatty liver disease (NAFLD). In addition, phospholipids, including Lyso PC (16:0) and Lyso PE (18:0), demonstrated notable down-regulation in all damaged liver, whereas PC (34:1) underwent upregulation. This study not only deepens insights into distinct potential biomarkers for liver injuries, but also underscores spatial metabolomics as a powerful tool to elucidate possible pathogenic mechanisms in other metabolic diseases.PMID:38382318 | DOI:10.1016/j.jpba.2024.116030

J Pharm Biomed Anal. 2024 Feb 18;242:116060. doi: 10.1016/j.jpba.2024.116060. Online ahead of print.ABSTRACTGiant congenital melanocytic nevi (GCMN) is a congenital cutaneous developmental deformity tumor that usually occurs at birth or in the first few weeks after birth, but its pathogenesis is still unclear. In this study, nuclear magnetic resonance-based metabolomics strategy was employed to evaluate the metabolic variations in serum and urine of the GCMN patients in order to understand its underlying biochemical mechanism and provide a potential intervention idea. Twenty-nine metabolites were observed to change significantly in serum and urine metabolomes, which are mainly involved in a variety of metabolic pathways including glyoxylate and dicarboxylate metabolism, TCA cycle and metabolisms of amino acids. The substantial cores of all the disturbed metabolic pathways are related to amino acid metabolism and carbohydrate metabolism and regulate the physiological state of the GCMN patients. Our results provide the physiological basis and physiological responses of GCMN and will be helpful for better understanding the molecular mechanisms of GCMN in future research.PMID:38382316 | DOI:10.1016/j.jpba.2024.116060

J Pharm Biomed Anal. 2024 Feb 7;242:116019. doi: 10.1016/j.jpba.2024.116019. Online ahead of print.ABSTRACTGinseng is commonly used as a nutritional supplement and daily wellness product due to its ability to invigorate qi. As a result, individuals with Qi-deficiency often use ginseng as a health supplement. Ginsenosides and polysaccharides are the primary components of ginseng. However, the therapeutic effects and mechanisms of action of these components in Qi-deficiency remain unclear. This study aimed to determine the modulatory effects and mechanisms of ginseng water extract, ginsenosides, and ginseng polysaccharides in a rat model of Qi-deficiency using metabolomics and network analysis. The rat model of Qi-deficiency was established via swimming fatigue and a restricted diet. Oral administration of different ginseng water extracts for 30 days primarily alleviated oxidative stress and disrupted energy metabolism and immune response dysfunction caused by Qi-deficiency in rats. Ultra-high-performance liquid chromatography combined with quadrupole time-of-flight mass spectrometry (UPLC-QTOF-MS) was used for untargeted serum metabolomic analysis. Based on the analysis results, the active constituents of ginseng significantly reversed the changes in serum biomarkers related to Qi-deficiency in rats, particularly energy, amino acid, and unsaturated fatty acid metabolism. Furthermore, analysis of the metabolite-gene network suggested that the anti-Qi-deficiency effects of the ginseng components were mainly associated with toll-like receptor (TLR) signaling and inflammatory response. Additional verification revealed that treatment with the ginseng components effectively reduced the inflammatory response and activation of the myocardial TLR4/NF-κB pathway induced by Qi-deficiency, especially the ginseng water extracts. Therefore, ginseng could be an effective preventive measure against the progression of Qi-deficiency by regulating metabolic and inflammatory responses.PMID:38382315 | DOI:10.1016/j.jpba.2024.116019

Talanta. 2024 Feb 14;272:125788. doi: 10.1016/j.talanta.2024.125788. Online ahead of print.ABSTRACTGas chromatography-ion mobility spectrometry (GC-IMS) plays a significant role in both targeted and non-targeted analyses. However, the non-linear behavior of IMS and its complex ion chemistry pose challenges for finding optimal experimental conditions using existing methodologies. To address these issues, integrating machine learning (ML) strategies offers a promising approach. In this study, we propose a hybrid strategy, combining design of experiment (DOE) and machine learning (ML) for optimizing GC-IMS conditions in non-targeted volatilomic/flavoromic analysis, with saffron volatiles as a case study. To begin, a rotatable circumscribed central composite design (CCD) is used to define five influential GC-IMS factors of sample amount, headspace temperature, incubation time, injection volume, and split ratio. Subsequently, two ML models are utilized: multiple linear regression (MLR) as a linear model and Bayesian regularized-artificial neural network (BR-ANN) as a nonlinear model. These models are employed to predict the response variables of total peak areas (PAs) and the number of detected peaks (PNs) in GC-IMS. The findings show that there is a direct correlation between the factors in GC-IMS and the PNs, suggesting that MLR is a suitable approach for building a model in this scenario. However, the PAs exhibit nonlinear behavior, suggesting that BR-ANN is better suitable to capture this complexity. Notably, Derringer's desirability function is utilized to integrate the PAs and PNs, and in this scenario, MLR demonstrates satisfactory performance in modeling the GC-IMS factors.PMID:38382301 | DOI:10.1016/j.talanta.2024.125788

Phytomedicine. 2024 Jan 17;126:155372. doi: 10.1016/j.phymed.2024.155372. Online ahead of print.ABSTRACTBACKGROUND: Renal fibrosis is a common pathway that drives the advancement of numerous kidney maladies towards end-stage kidney disease (ESKD). Suppressing renal fibrosis holds paramount clinical importance in forestalling or retarding the transition of chronic kidney diseases (CKD) to renal failure. Schisandrin A (Sch A) possesses renoprotective effect in acute kidney injury (AKI), but its effects on renal fibrosis and underlying mechanism(s) have not been studied.STUDY DESIGN: Serum biochemical analysis, histological staining, and expression levels of related proteins were used to assess the effect of PKCβ knockdown on renal fibrosis progression. Untargeted metabolomics was used to assess the effect of PKCβ knockdown on serum metabolites. Unilateral Ureteral Obstruction (UUO) model and TGF-β induced HK-2 cells and NIH-3T3 cells were used to evaluate the effect of Schisandrin A (Sch A) on renal fibrosis. PKCβ overexpressed NIH-3T3 cells were used to verify the possible mechanism of Sch A.RESULTS: PKCβ was upregulated in the UUO model. Knockdown of PKCβ mitigated the progression of renal fibrosis by ameliorating perturbations in serum metabolites and curbing oxidative stress. Sch A alleviated renal fibrosis by downregulating the expression of PKCβ in kidney. Treatment with Sch A significantly attenuated the upregulated proteins levels of FN, COL-I, PKCβ, Vimentin and α-SMA in UUO mice. Moreover, Sch A exhibited a beneficial impact on markers associated with oxidative stress, including MDA, SOD, and GSH-Px. Overexpression of PKCβ was found to counteract the renoprotective efficacy of Sch A in vitro.CONCLUSION: Sch A alleviates renal fibrosis by inhibiting PKCβ and attenuating oxidative stress.PMID:38382281 | DOI:10.1016/j.phymed.2024.155372

Phytomedicine. 2024 Jan 30;126:155382. doi: 10.1016/j.phymed.2024.155382. Online ahead of print.ABSTRACTBACKGROUND: Diabetes is a metabolic disorder characterized by chronic hyperglycaemia. Chronic metabolic abnormalities and long-term hyperglycaemia may result in a wide range of acute and chronic consequences. Previous studies have demonstrated that artesunate(ART) has antidiabetic, anti-inflammatory, antiatherosclerotic, and other beneficial effects, but the specific regulatory mechanism is not completely clear.AIM: This study investigated the effects of ART on metabolic disorders in type 2 diabetes mellitus (T2DM) model db/db mice and explored the underlying mechanisms involved.METHODS: C57BL/KsJ-db/db mice were used to identify the targets and molecular mechanism of ART. Metabolomic methods were used to evaluate the efficacy of ART in improving T2DM-related metabolic disorders. Network pharmacology and transcriptomic sequencing were used to analyse the targets and pathways of ART in T2DM. Finally, molecular biology experiments were performed to verify the key targets and pathways selected by network pharmacology and transcriptomic analyses.RESULTS: After a 7-week ART intervention (160 mg/kg), the glucose and lipid metabolism levels of the db/db mice improved. Additionally, the oxidative stress indices, namely, the MDA and SOD levels, significantly improved (p<0.01). Linoleic acid and glycerophospholipid metabolism, amino acid metabolism, bile acid synthesis, and purine metabolism disorders in db/db mice were partially corrected after ART treatment. Network pharmacology analysis identified important targets of ART for the treatment of metabolic disorders in T2DM . These targets are involved in key signalling pathways, including the highest scores observed for the PI3K/Akt signalling pathway. Transcriptomic analysis revealed that ART could activate the MAPK signalling pathway and two key gene targets, HGK and GADD45. Immunoblotting revealed that ART increases p-PI3K, p-AKT, Glut2, and IRS1 protein expression and suppresses the phosphorylation of p38, ERK1/2, and JNK, returning HGK and GADD45 to their preartesunate levels.CONCLUSION: Treatment of db/db mice with 160 mg/kg ART for 7 weeks significantly reduced fasting blood glucose and lipid levels. It also improved metabolic imbalances in amino acids, lipids, purines, and bile acids, thereby improving metabolic disorders. These effects are achieved by activating the PI3K/AKT pathway and inhibiting the MAPK pathway, thus demonstrating the efficacy of the drug.PMID:38382280 | DOI:10.1016/j.phymed.2024.155382