PubMed

Comput Biol Med. 2023 Nov 1;167:107661. doi: 10.1016/j.compbiomed.2023.107661. Online ahead of print.ABSTRACTIn the realm of unraveling COVID-19's intricacies, numerous metabolomic investigations have been conducted to discern the unique metabolic traits exhibited within infected patients. These endeavors have yielded a substantial reservoir of potential data pertaining to metabolic biomarkers linked to the virus. Despite these strides, a comprehensive and meticulously structured database housing these crucial biomarkers remains absent. In this study, we developed MetaboliteCOVID, a manually curated database of COVID-19-related metabolite markers. The database currently comprises 665 manually selected entries of significantly altered metabolites associated with early diagnosis, disease severity, prognosis, and drug response in COVID-19, encompassing 337 metabolites. Additionally, the database offers a user-friendly interface, containing abundant information for querying, browsing, and analyzing COVID-19-related abnormal metabolites in different body fluids. In summary, we believe that this database will effectively facilitate research on the functions and mechanisms of COVID-19-related metabolic biomarkers, thereby advancing both basic and clinical research on COVID-19. MetaboliteCOVID is free available at: https://cellknowledge.com.cn/MetaboliteCOVID.PMID:37925911 | DOI:10.1016/j.compbiomed.2023.107661

J Chromatogr B Analyt Technol Biomed Life Sci. 2023 Oct 31;1230:123906. doi: 10.1016/j.jchromb.2023.123906. Online ahead of print.ABSTRACTAn important area within clinical research is in vivo metabolism of ketone bodies (β-hydroxybutyrate and acetoacetate) and in connection metabolites that may affect their production and/or cellular transport such as the keto-acids from the branched-chain amino acids, lactate and pyruvate. To determine in vivo metabolite turnover, availability of accurate and sensitive methods for analyzing the plasma concentrations of these metabolites and their stable isotopically labeled enrichments is mandatory. Therefore, the present study describes a high-performance liquid chromatography-tandem mass spectrometry (LC-MS/MS) method for simultaneous analysis of ketone bodies, α-keto acids, lactate, pyruvate, and their tracer enrichments in humans using 2 different derivatization techniques with 4-bromo-N-methylbenzylamine and O-benzylhydroxylamine as derivatization reagents, and 1-ethyl-3-dimethylaminopropyl carbodiimide as coupling compound followed by a single LC-MS/MS run. The method was validated for matrix effects, linearity, accuracy, precision, recovery, stability, and enrichment (ratio) analysis of a stable isotopically labelled analytes (tracers) continuously infused in humans divided by the unlabeled endogenous analyte (tracee) that makes it possible to quantify the analyte in vivo synthesis and degradation rates. The applied parallel derivatization procedure yielded good sensitivity for all analytes of interest and their tracers. Despite the double derivatization method, mixing the ethyl acetate portions at the final stage made it possible to simultaneously analyze all compounds in a single LC-MS/MS run. Moreover, the liquid chromatography method was optimized to robustly quantify the keto acids derived from leucine (α-keto-isocaproic acid) and isoleucine (α-keto-β-methylvaleric acid), the compounds with similar chemical structure and identical molecular weights. The presented method is designed and validated for human plasma. However, care should be taken in blood sampling and processing procedures as well as quick freezing and storage at -80 °C due to the instability of especially acetoacetate.PMID:37925904 | DOI:10.1016/j.jchromb.2023.123906

Phytomedicine. 2023 Oct 31;122:155171. doi: 10.1016/j.phymed.2023.155171. Online ahead of print.ABSTRACTBACKGROUND: Addressing brain metastases in cancer presents substantial challenges due to limited therapeutic options and high mortality rates. In clinical practice, the amalgamation of traditional Chinese medicine with other treatment modalities has exhibited noteworthy efficacy in managing disease progression and enhancing quality of life.OBJECTIVE: To substantiate the regulatory effects of Shenqi Fuzheng Injection (SFI) on the microenvironment of melanoma brain metastases and appraise whether SFI augments the anti-tumour effects of immune checkpoint inhibitors, with a specific focus on investigating the mechanisms underlying SFI's actions.METHODS: Initially, we established a B16-F10 brain transplant tumour model in C57BL/6 mice using a stereotaxic apparatus. The efficacy of the drug was evaluated through in vivo imaging technology, HE staining, and immunofluorescence. Mass Cytometry (CyTOF) and flow cytometry were employed to analyse the impact of SFI on immune cell subpopulations in the tumour microenvironment. Subsequently, transcriptome sequencing and metabolomics were utilised to examine the effects of SFI on melanoma-related genes and metabolism. Molecular docking, Western Blot, and ELISA assays were conducted to investigate the targets of SFI in intervening in melanoma fatty acid metabolism. Finally, the anti-tumour effects of SFI in combination with immune checkpoint inhibitors were scrutinised in the brain transplant tumour model.RESULTS: The pharmacological findings demonstrated that SFI inhibits the growth of melanoma brain transplant tumours in a dose-dependent manner. CyTOF, flow cytometry, and immunofluorescence results revealed that SFI significantly diminishes the levels of Myeloid-Derived Suppressor Cells (MDSCs) and Regulatory T cells (Tregs) in the tumour microenvironment while enhancing the levels of CD8+T and CD4+ T cells. Subsequently, transcriptomic and metabolomic findings, both in vitro and in vivo, indicate that SFI significantly inhibits the arachidonic acid metabolism process in melanoma cells. Molecular docking and biological experiments showed that SFI inhibits the expression of D6D and the activity of COX-2, leading to a reduction in downstream PGE2 production. Lastly, SFI significantly enhances the anti-tumour effects of PD-L1 antibody against intracranial melanoma.CONCLUSION: SFI improves the tumour immune microenvironment in melanoma by intervening in fatty acid metabolism, thereby reducing levels of MDSCs and Tregs while increasing levels of CD8+ T and CD4+ T cells. Ultimately, this augmentation leads to enhanced anti-tumour effects of the immune checkpoint inhibitor PD-L1 antibody.PMID:37925891 | DOI:10.1016/j.phymed.2023.155171

Phytomedicine. 2023 Nov 2;122:155179. doi: 10.1016/j.phymed.2023.155179. Online ahead of print.ABSTRACTBACKGROUND: Natural bioactive molecules are important sources for the development of new drugs. However, most of them were limited in clinical applications due to their low aqueous solubility and bioavailability. Oridonin (ORI) is a powerful anticancer compound with above characteristics.OBJECTIVE: This study aimed to find an effective method to improve the bioavailability of poorly soluble natural compounds, and explore the action mechanisms of them to promote their application.RESULTS: In this study, ORI-nicotinamide (NCT) cocrystal was successfully prepared for the first time to overcome the defects of ORI. The solubility and oral bioavailability of cocrystal (COC) increased 1.34 and 1.18 times compared with ORI. Moreover, MTT assay was applied to compare the cytotoxicity of positive control drug sorafenib with ORI and COC. The IC50 values of sorafenib, ORI and COC on HepG2 cells were 7.61, 8.79 and 7.36 nmol·mL-1, which indicated that the cytotoxicity of ORI could be enhanced by cocrystal preparation. The cellular metabolomics was innovatively introduced to gain insight into the difference of cytotoxicity mechanism between ORI and COC. The results showed that there were 78 metabolites with significant differences in content between the two groups, while these differential metabolites were related to 11 metabolic pathways. Among these, glycerophospholipid metabolism and cysteine and methionine metabolism were the significant differential pathways, and the downregulation of PC(14:0/16:1(9z)) and upregulation of homocysteine were the likely main reasons for higher cytotoxicity of COC.CONCLUSIONS: This study has presented novel approaches for enhancing the bioavailability and drug efficacy of natural compounds, while also offering fresh insights into the underlying action mechanisms of pharmaceutical cocrystals.PMID:37925890 | DOI:10.1016/j.phymed.2023.155179

Sci Rep. 2023 Nov 4;13(1):19103. doi: 10.1038/s41598-023-46566-2.ABSTRACTGastrointestinal symptoms are more prevalent in children with autism spectrum disorder (ASD) than in typically developing (TD) children. Constipation is a significant gastrointestinal comorbidity of ASD, but the associations among constipated autism spectrum disorder (C-ASD), microbiota and short-chain fatty acids (SCFAs) are still debated. We enrolled 80 children, divided into the C-ASD group (n = 40) and the TD group (n = 40). In this study, an integrated 16S rRNA gene sequencing and gas chromatography-mass spectrometry-based metabolomics approach was applied to explore the association of the gut microbiota and SCFAs in C-ASD children in China. The community diversity estimated by the Observe, Chao1, and ACE indices was significantly lower in the C-ASD group than in the TD group. We observed that Ruminococcaceae_UCG_002, Erysipelotrichaceae_UCG_003, Phascolarctobacterium, Megamonas, Ruminiclostridium_5, Parabacteroides, Prevotella_2, Fusobacterium, and Prevotella_9 were enriched in the C-ASD group, and Anaerostipes, Lactobacillus, Ruminococcus_gnavus_group, Lachnospiraceae_NK4A136_group, Ralstonia, Eubacterium_eligens_group, and Ruminococcus_1 were enriched in the TD group. The propionate levels, which were higher in the C-ASD group, were negatively correlated with the abundance of Lactobacillus taxa, but were positively correlated with the severity of ASD symptoms. The random forest model, based on the 16 representative discriminant genera, achieved a high accuracy (AUC = 0.924). In conclusion, we found that C-ASD is related to altered gut microbiota and SCFAs, especially decreased abundance of Lactobacillus and excessive propionate in faeces, which provide new clues to understand C-ASD and biomarkers for the diagnosis and potential strategies for treatment of the disorder. This study was registered in the Chinese Clinical Trial Registry ( www.chictr.org.cn ; trial registration number ChiCTR2100052106; date of registration: October 17, 2021).PMID:37925571 | DOI:10.1038/s41598-023-46566-2

Sci Rep. 2023 Nov 4;13(1):19083. doi: 10.1038/s41598-023-46553-7.ABSTRACTUntargeted serum metabolomics was combined with machine learning-powered data analytics to develop a test for the concurrent detection of multiple cancers in women. A total of fifteen cancers were tested where the resulting metabolome data was sequentially analysed using two separate algorithms. The first algorithm successfully identified all the cancer-positive samples with an overall accuracy of > 99%. This result was particularly significant given that the samples tested were predominantly from early-stage cancers. Samples identified as cancer-positive were next analysed using a multi-class algorithm, which then enabled accurate discernment of the tissue of origin for the individual samples. Integration of serum metabolomics with appropriate data analytical tools, therefore, provides a powerful screening platform for early-stage cancers.PMID:37925521 | DOI:10.1038/s41598-023-46553-7

Respir Res. 2023 Nov 4;24(1):265. doi: 10.1186/s12931-023-02576-2.ABSTRACTBACKGROUND: Quantitative interstitial abnormalities (QIA) are an automated computed tomography (CT) finding of early parenchymal lung disease, associated with worse lung function, reduced exercise capacity, increased respiratory symptoms, and death. The metabolomic perturbations associated with QIA are not well known. We sought to identify plasma metabolites associated with QIA in smokers. We also sought to identify shared and differentiating metabolomics features between QIA and emphysema, another smoking-related advanced radiographic abnormality.METHODS: In 928 former and current smokers in the Genetic Epidemiology of COPD cohort, we measured QIA and emphysema using an automated local density histogram method and generated metabolite profiles from plasma samples using liquid chromatography-mass spectrometry (Metabolon). We assessed the associations between metabolite levels and QIA using multivariable linear regression models adjusted for age, sex, body mass index, smoking status, pack-years, and inhaled corticosteroid use, at a Benjamini-Hochberg False Discovery Rate p-value of ≤ 0.05. Using multinomial regression models adjusted for these covariates, we assessed the associations between metabolite levels and the following CT phenotypes: QIA-predominant, emphysema-predominant, combined-predominant, and neither- predominant. Pathway enrichment analyses were performed using MetaboAnalyst.RESULTS: We found 85 metabolites significantly associated with QIA, with overrepresentation of the nicotinate and nicotinamide, histidine, starch and sucrose, pyrimidine, phosphatidylcholine, lysophospholipid, and sphingomyelin pathways. These included metabolites involved in inflammation and immune response, extracellular matrix remodeling, surfactant, and muscle cachexia. There were 75 metabolites significantly different between QIA-predominant and emphysema-predominant phenotypes, with overrepresentation of the phosphatidylethanolamine, nicotinate and nicotinamide, aminoacyl-tRNA, arginine, proline, alanine, aspartate, and glutamate pathways.CONCLUSIONS: Metabolomic correlates may lend insight to the biologic perturbations and pathways that underlie clinically meaningful quantitative CT measurements like QIA in smokers.PMID:37925418 | DOI:10.1186/s12931-023-02576-2

J Equine Vet Sci. 2023 Nov 2:104958. doi: 10.1016/j.jevs.2023.104958. Online ahead of print.ABSTRACTPastures are used for grazing and the production of conserved roughage in horses. Yet, the nutritional profile of the forage varies from spring to late summer, affecting equine nutrient supply and health. In addition, environmental factors may also favor plant contaminants such as mycotoxins. This study aimed to determine the nutritional profile and contaminant load of selected horse pastures from early spring till late summer. The nutrient composition (main macronutrients, macro elements and trace elements), as well as mycotoxins, metabolites, pesticides, and plant-derived compounds of seven horse pastures were analyzed. Each pasture was sampled three times and the samples were categorized according to the status of the pasture plants: ear emergence, early- till full bloom, and drought-damaged vegetation. Drought-damaged pastures demonstrated a rise in the acid to neutral detergent fiber ratio, calcium, iron, and magnesium but lower potassium contents. Mycotoxins and other contaminants were found in the pastures including 64 fungal compounds (ergot alkaloids (13) and metabolites from Fusarium (21), Aspergillus (2), Penicillium (8), Alternaria (8) and other fungal species (12), one bacterial metabolite (cereulide), twelve plant metabolites (including eight phytoestrogens and three cyanogenic glycosides (linamarin, lotaustralin and prunasin)), 11 nonspecific metabolites and six pesticides. Fusarium metabolites showed the highest concentrations among the fungal metabolites (range: 123 - 3873 µg/kg DM) and drought-induced stress increased the contamination levels. In conclusion, there was a dominant effect of the developmental stages of the plants, botanical composition of the pastures and weather conditions on the nutritional composition and presence of contaminants on pastures.PMID:37925115 | DOI:10.1016/j.jevs.2023.104958

Am J Pathol. 2023 Nov 2:S0002-9440(23)00410-8. doi: 10.1016/j.ajpath.2023.09.016. Online ahead of print.ABSTRACTAlcohol-associated liver disease (ALD) is a serious public health problem with limited pharmacological options. The goal of the current study was to investigate the efficacy of pharmacological inhibition of soluble epoxide hydrolase (sEH, an enzyme involved in lipid metabolism) in experimental ALD and to examine the underlying mechanisms. C57BL/6J male mice underwent acute-on-chronic ethanol (EtOH) feeding with or without the sEH inhibitor, TUCB. Liver injury was assessed by multiple end-points. Liver epoxy- and dihydroxy-fatty acids were measured by targeted metabolomics. Whole liver RNA sequencing was performed and free modified RNA bases were measured by mass spectrometry. EtOH-induced liver injury was ameliorated by TUCB treatment as evidenced by reduced plasma alanine aminotransferase levels, and was associated with attenuated alcohol-induced endoplasmic reticulum stress, reduced neutrophil infiltration, and increased numbers of hepatic M2 macrophages. TUCB altered liver epoxy- and dihydroxy-fatty acids and led to a unique hepatic transcriptional profile characterized by decreased expression of genes involved in apoptosis, inflammation, fibrosis, and carcinogenesis. Several modified RNA bases were robustly changed by TUCB, including m6A and ms2t6A. These findings demonstrated the beneficial effects of sEH inhibition by TUCB in experimental EtOH-induced liver injury, warranting further mechanistic studies to explore the underlying mechanisms, and highlighting the translational potential of sEH as a drug target for this disease.PMID:37925018 | DOI:10.1016/j.ajpath.2023.09.016

J Ethnopharmacol. 2023 Nov 2:117383. doi: 10.1016/j.jep.2023.117383. Online ahead of print.ABSTRACTETHNOPHARMACOLOGICAL RELEVANCE: Danggui Shaoyao San (DSS) is a traditional Chinese medicine (TCM) first recorded in the Synopsis of the Golden Chamber. DSS has proven efficacy in treating hepatic fibrosis (HF). However, the effects and mechanisms of DSS on HF are not clear.AIM OF THE STUDY: To investigate the effect of DSS on HF via gut microbiota and its metabolites (SCFAs, BAs).MATERIALS AND METHODS: HF rats were induced with CCl4 and treated with DSS. Firstly, the therapeutic efficacy of DSS in HF rats and the protection of gut barrier were assessed. Then, 16S rRNA gene sequencing and untargeted fecal metabolomics preliminarily explored the mechanism of DSS in treating HF, and identified different microbiota and metabolic pathways. Finally, targeted metabolomics, RT-qPCR and Elisa were used to further validate the mechanism of DSS for HF based on the metabolism of SCFAs and BAs.RESULTS: After 8 weeks of administration, DSS significantly reduced the degree of HF. In addition, DSS alleviated inflammation in the ileum and reduced the levels of LPS and D-lactate. Furthermore, DSS altered the structure of gut microbiota, especially Veillonella, Romboutsia, Monoglobus, Parabacteroides, norank_f_Coriobacteriales_ Incertae_Sedis. These bacteria have been linked to the production of SCFAs and the metabolism of BAs. Untargeted metabolomics suggested that DSS may play a role via BAs metabolism. Subsequently, targeted metabolomics, RT-qPCR and Elisa further confirmed the key role of DSS in increasing SCFAs levels and regulating BAs metabolism.CONCLUSIONS: DSS can alleviate CCl4-induced HF and protect the intestinal barrier. DSS may exert its beneficial effects on HF by affecting the gut microbiota and its metabolites (SCFAs, BAs).PMID:37925004 | DOI:10.1016/j.jep.2023.117383

J Ethnopharmacol. 2023 Nov 2:117384. doi: 10.1016/j.jep.2023.117384. Online ahead of print.ABSTRACTETHNOPHARMACOLOGICAL RELEVANCE: The overuse of antibiotics has resulted in Clostridium difficile infection (CDI) as a significant global public health concern. Studies have shown that imbalances in gut microbiota and metabolism play a vital role in the onset of CDI. Shengjiang Xiexin decoction (SJT), a traditional Chinese medicinal formula widely employed in the treatment of gastrointestinal ailments, demonstrates effectiveness in addressing murine CDI. However, the precise mechanistic role of SJT in CDI treatment remains uncertain, particularly regarding its impact on gut microbiota and intestinal metabolism. Thus, further investigation is imperative to shed light on these mechanisms.AIM OF THE STUDY: This study aims to thoroughly investigate the therapeutic potential of SJT in the treatment of CDI, while also examining its impact on the intricate interplay between gut microbiota and bile acid metabolism. By employing a mouse model, we aspire to uncover novel insights that could pave the way for the development of more effective strategies in combating CDI.MATERIALS AND METHODS: We developed a mouse model for CDI and assessed SJT's potential as a therapeutic agent through pharmacological analyses. Our study employed high-throughput sequencing of 16S rRNA to identify changes in gut microbiota composition and untargeted metabolomics analysis to evaluate SJT's intervention on intestinal metabolism. We also conducted targeted analysis of bile acid metabolism to examine the specific effects of SJT. Finally, the growth-inhibitory effect of SJT on C. difficile was confirmed through ex vivo cultivation of the pathogen using cecal contents, supporting its potential role in treating CDI by modulating gut microbiota and bile acid metabolism.RESULTS: In pharmacological studies, SJT was found to effectively reduce the levels of A&B toxins and alleviate colonic inflammation in CDI mice. Mechanistically, SJT demonstrated a mild increase in the abundance and diversity of the gut microbiota. However, its most significant impact was observed in the substantial improvement of the structural composition of the gut microbiota. Specifically, SJT decreased the abundance of gut Polymorphs and Firmicutes while restoring the proportions of family Trichophyton and Bacteroides_S24-7 spp (P < 0.001). Moreover, SJT not only decreased the levels of primary bile acids but also elevated the levels of secondary bile acids. Notably, it enhanced the conversion of taurocholic acid (TCA) to deoxycholic acid (DCA), leading to a balanced bile acid metabolism. Finally, cecal contents of SJT-treated mice showed a significant reduction in the growth of C. difficile, underscoring the therapeutic potential of SJT via modulation of gut microbiota and bile acid metabolism.CONCLUSION: SJT demonstrates remarkable efficacy in treating CDI in mice by not only effectively combating the infection but also restoring the intricate balance of gut microbiota and bile acid metabolism. Furthermore, promising indications suggest that SJT may have the potential to prevent CDI recurrence. These findings underscore the comprehensive therapeutic value of SJT in managing CDI. Moving forward, we plan to transition from the laboratory to clinical settings to conduct further studies, validating our conclusions on SJT's efficacy.PMID:37925000 | DOI:10.1016/j.jep.2023.117384

J Control Release. 2023 Nov 2:S0168-3659(23)00714-9. doi: 10.1016/j.jconrel.2023.10.053. Online ahead of print.ABSTRACTAs the main cause of destructive plant diseases, pathogenic oomycete in plant rhizosphere brings about enormous losses to agricultural production. Although chemical pesticides are still one of the most important prevention and control methods for phytopathogens, the usage of chemical pesticides was limited by the 3R (resistance, residue, and rampant) problem. In the early stage of our research, analysis and comparison of the metabolome of resistance to Phytophthora nicotianae and common strain suggested that naringenin might be a highly efficient potential biogenic antimicrobial agent to prevent and control soil rhizosphere diseases. Unfortunately, the bioactivity and absorption capacity of active ingredients in the environment made it unsuitable for field application; thus, for efficient field application of naringenin, the 24 nm-sized naringenin-loaded nano-star-shaped polymerized (NSPs) were prepared with good loading efficiency 37.3% for naringenin. The soil mobility test indicated that NSPs could effectively reduce the adsorption of active ingredients and enhance the mobility of active ingredients in soil. The bacteriostatic test proved that these NSPs had better antimicrobial activity than the naringenin used alone and could efficiently induce the expression of plant resistance phenylpropanoid compounds. Finally, pot and field experiments showed improved control efficiency of NSPs 41% loaded with naringenin. Transcriptome analysis found that a large number of energy-related genes were downregulated in NSPs nematodes, suggesting that disturbed energy-related genes might lead to the disturbance of energy synthesis and metabolism. Naringenin-loaded nano-carriers were used to prevent and control plant disease-causing pathogens in the rhizosphere, which is of great significance to improve the prevention and control effect and reduce the environmental load of these anti-pathogenic agents.PMID:37924956 | DOI:10.1016/j.jconrel.2023.10.053

Sci Total Environ. 2023 Nov 2:168219. doi: 10.1016/j.scitotenv.2023.168219. Online ahead of print.ABSTRACTThe effect of microplastics (MPs) on plant growth has received increasing attention. However, whether soil texture and MPs size influence the toxicological effects of MPs on plants is unknown. To address this knowledge gap, two soils with different physical structures (lime concretion black and silty loam soils) were selected to explore the potential toxicity of MPs of different particle sizes to maize growth. The results showed that, in both soils, the harm caused by small MPs on maize growth was greater than that caused by large MPs. Low MPs concentrations had no significant effect on maize growth between two soil types; however, when exposed to a concentration of 1 % large MPs, the dry biomass of maize was promoted in lime concretion black soil but inhibited in silty loam soil. All MPs-exposed treatments resulted in a high level of superoxide anions in maize roots, resulting in an increase in the root aerenchyma area and reducing the metabolic activity of maize roots. Metabolomics showed that MPs exposure affected multiple amino acid metabolic pathways, including phenylalanine and tyrosine metabolism, and inhibited lignin biosynthesis in roots. This study provides a theoretical basis for a more comprehensive assessment of the effect of MPs pollution on agricultural production.PMID:37924875 | DOI:10.1016/j.scitotenv.2023.168219

Biomed Pharmacother. 2023 Nov 2;168:115825. doi: 10.1016/j.biopha.2023.115825. Online ahead of print.ABSTRACTAlzheimer's disease (AD) is a progressive neurodegenerative disease for which there is a lack of effective therapeutic drugs. There is great potential for natural products to be used in the development of anti-AD drugs. P-coumaric acid (PCA), a small molecule phenolic acid widely distributed in the plant kingdom, has pharmacological effects such as neuroprotection, but its anti-AD mechanism has not been fully elucidated. In the current study, we investigated the mechanism of PCA intervention in the Aβ25-35-induced AD model using gut microbiomics and serum metabolomics combined with in vitro and in vivo pharmacological experiments. PCA was found to ameliorate cognitive dysfunction and neuronal cell damage in Aβ25-35-injected mice as measured by behavioral, pathological and biochemical indicators. 16S rDNA sequencing and serum metabolomics showed that PCA reduced the abundance of pro-inflammatory-associated microbiota (morganella, holdemanella, fusicatenibacter and serratia) in the gut, which were closely associated with metabolites of the glucose metabolism, arachidonic acid metabolism, tyrosine metabolism and phospholipid metabolism pathways in serum. Next, in vivo and in vitro pharmacological investigations revealed that PCA regulated Aβ25-35-induced disruption of glucose metabolism through activation of PI3K/AKT/Glut1 signaling. Additionally, PCA ameliorated Aβ25-35-induced neuroinflammation by inhibiting nuclear translocation of NF-κB and by modulating upstream MAPK signaling. In conclusion, PCA ameliorated cognitive deficits in Aβ25-35-induced AD mice by regulating glucose metabolism and neuroinflammation, and the mechanism is related not only to restoring homeostasis of gut microbiota and serum metabolites, but also to PI3K/AKT/Glut1 and MAPK/NF-κB signaling.PMID:37924791 | DOI:10.1016/j.biopha.2023.115825

Phytomedicine. 2023 Sep 21;122:155112. doi: 10.1016/j.phymed.2023.155112. Online ahead of print.ABSTRACTBACKGROUND: The prevalence of cardiac fibrosis, intricately linked to various cardiovascular diseases, continues to rise. Aconite, a traditional Chinese herb renowned for its cardiovascular benefits, holds promise in treating heart ailments. However, the mechanisms underlying its anti-fibrotic effects, particularly in cardiac fibrosis, remain elusive.HYPOTHESIS/PURPOSE: This study aims to shed light on aconite's potential as an anti-fibrotic agent and elucidate its mechanisms in a rat model of isoproterenol (ISO)-induced cardiac fibrosis.METHODS: By inducing cardiac fibrosis through ISO injection, the study investigates the role of decoction of white aconite (DWA) in mitigating fibrotic processes. Techniques including metabolomics, RT-qPCR, western blot, and immunofluorescence were employed to unveil the molecular changes induced by DWA.RESULTS: DWA exhibited a remarkable reduction in echocardiographic parameters, cardiac weight increase, myocardial infarction extent, inflammatory cell infiltration, collagen deposition in heart tissue, and serum CK-MB, cTnT, cTnI levels post ISO injection. Metabolomic analysis unveiled DWA's modulation of 27 metabolites, especially in galactose metabolism, addressing metabolic disturbances in cardiac fibrosis. Additionally, DWA suppressed mRNA expression of fibrosis markers (Collagen I, CTGF, TGF-β), inhibited protein levels of MMP-9, α-SMA, and Galectin-3, while elevating TIMP1 expression.CONCLUSION: DWA demonstrated potent anti-fibrotic effects by curbing collagen deposition and alleviating metabolic disruptions in cardiac fibrosis via the galactose metabolism pathway, possibly mediated by the Gal-3/TGF-β/Smad signaling pathway.PMID:37924690 | DOI:10.1016/j.phymed.2023.155112

J Pharm Biomed Anal. 2023 Oct 20;238:115801. doi: 10.1016/j.jpba.2023.115801. Online ahead of print.ABSTRACTLiver injury is a strong independent predictor of mortality in patients with sepsis, in which gut dysbiosis plays a crucial role. Hydroxyl safflower yellow A (HSYA), an important component of safflower, has been used to treat liver injury in animal models. However, its role in sepsis-induced liver dysfunction and the specific molecular mechanisms remain unclear. In the current study, we first discussed the discrepancy in the gut microbiota between the cecal ligation puncture (CLP) and HSYA groups using 16 S RNA sequencing. Our data demonstrated that HSYA supplementation significantly decreased the relative abundance of Proteobacteria, Firmicutes, and Campylobacterota, and further decreased the abundance of Bacteroidota, suggesting that the protective effects of HSYA against sepsis-induced liver injury may be partially attributed to the alteration of these bacteria. In addition, the metabolomic data identified 823 differentially expressed metabolites associated with sepsis-induced liver injury. After HSYA supplementation, the levels of 56 metabolites were restored to sham-like levels. Transcriptomic analysis revealed 4990 differentially expressed genes (DEGs) between the sham and CLP groups, and after HSYA injection, 1613 genes were modulated. Comprehensive analysis demonstrated that the enrichment pathways of the 903 DEGs mainly focused on inflammatory responses, amino acid metabolism, and Lipid reactions. In conclusion, our study revealed the potential mechanism of action of HSYA in sepsis-induced liver injury through a comprehensive analysis of 16 S RNA sequencing, metabolomics, and transcriptomics, thus providing a theoretical basis for further clinical applications of HSYA.PMID:37924577 | DOI:10.1016/j.jpba.2023.115801

J Pharm Biomed Anal. 2023 Oct 21;238:115807. doi: 10.1016/j.jpba.2023.115807. Online ahead of print.ABSTRACTBACKGROUND: Yueju Wan (YJW), defined in Danxi's Mastery of Medicine, has Qi-regulating and Qi-promoting effects. YJW has frequently been applied in the clinic for the treatment of depression. Substantial evidence has shown that depression is related to metabolic abnormalities of the gut microbiota, and traditional Chinese medicine (TCM) can treat depression by adjusting gut microbiota metabolism. The antidepressant effect of YJW is well established, but thus far, whether its mechanism of action is achieved by regulating the intestinal flora has not been elucidated.METHODS: In this study, chronic unpredictable mild stress (CUMS) along with isolated feeding created a rat depression model, and YJW was administered for intervention. Rats were put through behavioral tests to determine their level of depression, and ELISA was utilized for measuring the level of monoamine neurotransmitters (MNTs) in the hippocampus. Metagenomic gene sequencing analysis was used to study the effect of depression on the intestinal flora in rats and the regulatory mechanism of YJW on the intestinal flora. Furthermore, ultra-performance liquid chromatography-quadrupole time-of-flight mass spectrometry (UPLC-Q/TOF-MS) was utilized for fecal metabolomics studies to further reveal the antidepressant mechanism of YJW. The antidepressant mechanism of YJW was explored and further verified by Western blot analysis.RESULTS: Different doses of YJW improved the depressive state of rats and raised the levels of MNTs in the hippocampus. The results of metagenomic sequencing indicated that the YJW recovered the structure and diversity of the intestinal flora in depressed rats. Metabolomics revealed sustained changes in 21 metabolites after the treatment of YJW, suggesting that YJW can play an antidepressant role by improving abnormal metabolic pathways. The results of correlation analysis suggested that YJW might mediate Eubacterium, Oscillibacter, Roseburia, Romboutsia and Bacterium to regulate purine metabolism, tryptophan metabolism, primary bile acid biosynthesis, and glutamate metabolism and exert antidepressant effects. Western blot analysis showed that YJW reduced the content of IL-1β in the hippocampus, inhibited the activation of the NLRP3 inflammasome in the hippocampus of rats, and increased the content of ZO-1 in the colon of rats.CONCLUSION: YJW can alleviate depressive symptoms in depressed rats, and its mechanism is connected to improving intestinal flora and regulating body metabolism.PMID:37924576 | DOI:10.1016/j.jpba.2023.115807

J Gastrointest Cancer. 2023 Nov 4. doi: 10.1007/s12029-023-00980-x. Online ahead of print.ABSTRACTBACKGROUND: Esophageal squamous cell carcinoma (ESCC) is one of the most common tumors in the gastrointestinal tract, and China has a high incidence area with a high burden on the disease. As early symptoms of ESCC are not obvious, the mortality rate is high, and it is often diagnosed in the intermediate and advanced stages. However, early screening and treatment may reduce morbidity and mortality.METHODS: Screening methods are divided into endoscopic and non-endoscopic screening.RESULTS: Endoscopic screening cannot be widely used because of its invasive nature and high cost. Currently, non-endoscopic screening consists primarily of tumor biomarkers and cytology, and tumor biomarkers including autoantibodies, circulating tumor cells, circulating tumor DNA, exosomes and serum metabolomics are more likely to be effective. But the efficiency of early diagnosis of esophageal cancer is low and the accuracy of screening needs to be improved. The aim of this study is to summarize advances in non-endoscopic esophageal cancer screening and strategies to provide a scientific basis and research idea for esophageal cancer prevention and control.CONCLUSIONS: Non-endoscopic screening is better than endoscopic screening. And the application of tumor biomarkers is much better than other non-endoscopic screening methods.PMID:37924487 | DOI:10.1007/s12029-023-00980-x

Adv Healthc Mater. 2023 Nov 4:e2301332. doi: 10.1002/adhm.202301332. Online ahead of print.ABSTRACTThe continuous reduction of clinically available antibiotics has made it imperative to exploit more effective antimicrobial therapies, especially for difficult-to-treat Gram-negative pathogens. Herein, we showed that the combination of an antimicrobial nanozyme with the clinically compatible basic amino acid L-arginine affords a potent treatment for infections with Gram-negative pathogens. In particular, the antimicrobial activity of the antimicrobial nanozyme was dramatically increased by approximately 1000-fold after L-arginine stimulation. Specifically, the combination therapy enhanced bacterial outer and inner membrane permeability and promoted intracellular reactive oxygen species (ROS) generation. Moreover, the metabolomic and transcriptomic results revealed that combination treatment led to the increased ROS-mediated damage by inhibiting the tricarboxylic acid cycle and oxidative phosphorylation, thereby inducing an imbalance of the antioxidant and oxidant systems. Importantly, L-arginine dramatically significantly accelerated the healing of infected wounds in mouse models of multidrug-resistant peritonitis-sepsis and skin wound infection. Overall, this work demonstrates a novel synergistic antibacterial strategy by combining the antimicrobial nanozymes with L-arginine, which substantively facilitates the nanozyme-mediated killing of pathogens by promoting ROS production. This article is protected by copyright. All rights reserved.PMID:37924312 | DOI:10.1002/adhm.202301332

Mol Plant. 2023 Nov 2:S1674-2052(23)00354-4. doi: 10.1016/j.molp.2023.10.018. Online ahead of print.ABSTRACTParaquat (PQ) has been used as an herbicide worldwide because of its potent activity against weeds. However, it is highly toxic to humans. The very high fatality of PQ poisoning is due to its inherent toxicity and the lack of any effective treatment. Consequently, developing a non-toxic herbicide with comparable efficacy to PQ will contribute to global food security and help prevent PQ-related fatalities. Herein, we report new herbicide called dienediamine, which was discovered from how to intervene the redox cycle of PQ, an inherent toxicity nature. The dienediamine as the "reduced" form of PQ, with no function as an electron transfer agent, proven to be non-toxic through comprehensive in vivo and in vitro experiments at molar concentrations equivalent to PQ's absolute lethal dose. Remarkably, dienediamine can undergo conversion to PQ under natural sunlight and ambient air conditions, exhibiting herbicidal activities that are comparable to those of PQ. The conversion of dienediamine to PQ is the key mechanism underlying its potent herbicidal activity through the chloroplast toxicity. Our study presents dienediamine as a safe and superior alternative to PQ, possessing significant potential for application in sustainable agriculture globally.PMID:37924209 | DOI:10.1016/j.molp.2023.10.018