Search Results (9,424)

Perilla frutescens (L.) Britt. is a traditional medicinal and culinary plant with a long history of cultivation and significant potential for broader utilization. The basic helix-loop-helix (bHLH) gene family is essential for regulating plant growth, development, stress responses, and secondary metabolism. However, the bHLH gene family in P. frutescens has not yet been characterized. In this study, a total of 205 bHLH genes were identified in P. frutescens through genome mining and analysis. Phylogenetic analysis classified these PfbHLH genes into 23 distinct subfamilies. Promoter analysis revealed an enrichment of cis-acting elements linked to plant hormone signaling and stress responses, suggesting their potential regulatory roles in development, growth, and stress adaptation. Expression profiling based on publicly available RNA-seq data demonstrated tissue-specific expression patterns of PfbHLH genes in roots, stems, and leaves. Four PfbHLH genes (PfbHLH66, PfbHLH45, PfbHLH13, and PfbHLH5) showed significant responses to methyl jasmonate (MeJA) induction. Yeast one-hybrid assays confirmed that these PfbHLH proteins could bind to the cis-acting G-box (CACGTG) element. This study offers new perspectives on the evolution, regulatory mechanisms, and functional roles of the bHLH gene family in P. frutescens. The findings deepen our understanding of the functional diversity within this gene family and establish a foundation for genetic enhancement and the biosynthesis of medicinal compounds in the species. Full article

The adult male muskrat has a pair of scented glands, which show clear seasonal changes in their developmental status between the secretion season and non-secretion season. During the secretion season, the scented glands are much larger than in the non-secretion season, with the metabolism of glandular cells increasing and a large amount of musk being produced. In this work, the blood, musk, and scented gland tissue were collected from three healthy adult male muskrats during secretion season (September). And the blood and scented gland tissue from another three healthy adult male muskrats during the non-secretion season (November) were also sampled. The saccharides from blood and musk were detected by liquid chromatography–mass spectrometry (LC-MS), indicating the saccharides are concentrated in the scented glands during the secretion season. What is more, transcriptome analysis was employed to investigate the expression patterns of saccharides’ pathways, suggesting some saccharides’ metabolism-related genes undergo significant seasonal changes. Above all, scented gland saccharides’ metabolism displays seasonal differences, and the enhancement in saccharides’ metabolic activity during the secretion phase maintains glandular proliferation and secretion function. Full article

Mulberry branch extracts (MBEs) have garnered significant attention as natural feed additives and antioxidants; however, their antioxidant properties in meat post-slaughter and their influence on muscle-related metabolic processes remain largely unexplored. Herein, we evaluated the effects of MBEs on the antioxidant capacity and metabolic processes of breast muscle in yellow-feather broilers by adding 0 g/kg, 1.5 g/kg, 3.0 g/kg, and 4.5 g/kg of MBEs to their diets. The results demonstrate that MBEs enhanced the activity of antioxidant enzymes in muscle tissue. Specifically, a real-time quantitative PCR analysis revealed that MBEs increased the expression of antioxidant enzyme genes in a dose-dependent manner, activated the Nrf2 signaling pathway, and upregulated the expression of the Nrf2 gene and its downstream targets at doses of up to 3.0 g/kg. Furthermore, the results of widely targeted metabolomics indicate that the dietary supplementation of MBEs changed the amino acid profile of the muscle, increasing the levels of amino acids and small peptides that contribute to antioxidant properties while reducing the contents of oxidized lipids and carnitine (C5:1) and partially reducing the content of lysophosphatidylcholine (LPC). Notably, at doses of up to 3 g/kg, the levels of five signature bile acids increased in correlation with the added dose. A KEGG analysis indicated that the differential metabolites were predominantly enriched in the metabolism of xenobiotics by cytochrome P450, suggesting that the function of MBEs may be associated with the expression of P450 enzymes. In summary, this study demonstrates that MBEs are effective, safe, and natural antioxidants, offering a viable solution to mitigating oxidative stress in the yellow-feather broiler farming industry and even in livestock farming. Full article

In cases in which a rapid metabolism is the cause of an unfavorable pharmacokinetic profile, it is important to determine the Sites of Metabolism (SoMs) of a molecule to introduce the necessary modifications to improve the stability of the compound. The substitution of hydrogen atoms by deuterium atoms has been proposed to ameliorate such properties due to the greater stability of the C-D bonds. IQS016, bearing a 2-phenylamino substituent, is a compound previously described by our group with good biological activity as a discoidin domain receptor (DDR2) inhibitor but suffers from low metabolic stability determined in a test with rat-liver microsomes (less than 50% of the initial compound after 60 min). We have obtained the corresponding 2-(penta-deuterophenyl) analog (IQS016-d₅) from aniline-2,3,4,5,6-d₅ showing that it has a better metabolic stability than IQS016 and a higher inhibitory effect on isolated tyrosine kinase receptors but not a better 2D in vitro effect. Full article

Background: Using dietary interventions to steer the metabolic output of the gut microbiota towards specific health-promoting metabolites is often challenging due to interpersonal variation in treatment responses. Methods: In this study, we combined the ex vivo SIFR^® (Systemic Intestinal Fermentation Research) technology with untargeted metabolite profiling to investigate the impact of carrot-derived rhamnogalacturonan-I (cRG-I) on ex vivo metabolite production by the gut microbiota of 24 human adults. Results: The findings reveal that at a dose equivalent to 1.5 g/d, cRG-I consistently promoted indole-3-propionic acid (IPA) production (+45.8% increase) across all subjects. At a dose equivalent to 0.3 g/d, increased IPA production was also observed (+14.6%), which was comparable to the effect seen for 1.5 g/d inulin (10.6%). IPA has been shown to provide protection against diseases affecting the gut and multiple organs. The Pearson correlation analysis revealed a strong correlation (R = 0.65, p_adjusted = 6.1 × 10⁻¹⁶) between the increases in IPA levels and the absolute levels of Bifidobacterium longum, a producer of indole-3-lactic acid (ILA), an intermediate in IPA production. Finally, the community modulation score, a novel diversity index, demonstrated that cRG-I maintained a high α-diversity which has previously been linked to elevated IPA production. Conclusions: The results from the ex vivo SIFR^® experiment mirrored clinical outcomes and provided novel insights into the impact of cRG-I on the gut microbiome function. Importantly, we demonstrated that cRG-I promotes tryptophan conversion into IPA via gut microbiome modulation, thus conferring benefits via amino acid derived metabolites extending beyond those previously reported for short chain fatty acids (SCFA) resulting from carbohydrate fermentation. Full article

Cocoa fermentation plays a key role in defining chocolate’s flavor, with yeasts being central to this process. This study aimed to explore intraspecific genetic diversity of major indigenous yeasts (i.e., Saccharomyces cerevisiae and Pichia kudriavzevii), and their potential interaction in the cocoa pulp environment. Their metabolic intraspecific diversity was characterized in synthetic cocoa pulp medium. Then, Saccharomyces cerevisiae, Pichia kudriavzevii, and other strains were introduced to each other to evaluate their potential negative interaction. Interesting strain associations were selected to further explore their interaction in synthetic cocoa pulp medium as well as real fresh cocoa pulp. From a fermentation campaign in Ivory Coast, a set of Saccharomyces (S.) cerevisiae and Pichia (P.) kudriavzevii strains were isolated from batches classified according to their chocolate quality (i.e., standard, intermediate, or premium chocolate). Less abundant species (i.e., Torulaspora franciscae, Kluyveromyces marxianus) were also isolated and tested for their potential negative interactions with S. cerevisiae and P. kudriavzevii. A set of strains were selected and cultured in single and in co-culture in a minimal cocoa pulp synthetic medium and in fresh cocoa pulp to highlight potential positive and/or negative interactions regarding fermentative aroma profile (i.e., higher alcohols, acetate esters, medium-chain fatty acids, and ethyl esters). The results highlighted the dominance of S. cerevisiae in fermentation kinetics and medium- to long-chain ester production, contrasted with P. kudriavzevii’s efficiency in short-chain ester synthesis. Intraspecific aroma profile variations can be pointed out. The co-cultures of P. kudriavzevii and S. cerevisiae strains isolated from the premium chocolate batch had a positive impact on the fermented pulp aroma profile. Negative interactions were observed with Torulaspora franciscae, which eliminated P. kudriavzevii’s aroma expression. Finally, the comparison of the data obtained for the minimal cocoa pulp synthetic medium compared to the cocoa pulp allowed us to draw conclusions about the use of synthetic media for studying cocoa fermentation. These findings emphasize the complex microbial interactions in cocoa fermentation that could shape future cocoa bean aroma. Full article

Flax (Linum usitatissimum) is a versatile plant used in a range of applications, from textiles to nutrition. Surfactin, a cyclic lipopeptide biosurfactant produced by bacteria such as Bacillus subtilis, has potential as a biocontrol agent or as a plant defense inducer in agriculture. This work aims to determine the effects of surfactin treatment at two kinetic points on the metabolism of flax hydroponic cultures, using advanced metabolomic techniques, including ¹H NMR and LC-MS analyses. Surfactin, detected in the roots, has a significant local impact on the metabolic profiles of flax roots, leading mainly to a higher content of cyanogenic compounds and amino acids and a lower content of carbohydrates. Surfactin, which is not detected in the aerial parts, also induces contrasted changes in amino acids, sugars, and secondary metabolite accumulation between stems and leaves. Surfactin treatment of flax leads to both a local and systemic effect on flax metabolism. These changes suggest that plant response to surfactin treatment could induce an enhanced plant defense. This could suggest potential applications of surfactin in the agricultural field as a biostimulant or biocontrol agent, to limit the use of chemical compounds in culture, and to limit their negative impact on both health and the environment. Full article

Background: Recent advancements in understanding plasma extracellular vesicles (EVs) and their role in disease biology have provided additional unique insights into the study of Colorectal Cancer (CRC). Methods: This study aimed to gain biological insights into disease progression from plasma-derived extracellular vesicle proteomic profiles of 80 patients (20 from each CRC stage I–IV) against 20 healthy age- and sex-matched controls using a high-resolution SWATH-MS proteomics with a reproducible centrifugation method to isolate plasma EVs. Results: We applied the High-Stringency Human Proteome Project (HPP) guidelines for SWATH-MS analysis, which refined our initial EV protein identification from 1362 proteins (10,993 peptides) to a more reliable and confident subset of 853 proteins (6231 peptides). In early-stage CRC, we identified 11 plasma EV proteins with differential expression between patients and healthy controls (three up-regulated and eight down-regulated), many of which are involved in key cancer hallmarks. Additionally, within the same cohort, we analysed EV proteins associated with tumour recurrence to identify potential prognostic indicators for CRC. A subset of up-regulated proteins associated with extracellular vesicle formation (GDI1, NSF, and TMED9) and the down-regulation of TSG101 suggest that micro-metastasis may have occurred earlier than previously anticipated. Discussion: By employing stringent proteomic analysis and a robust SWATH-MS approach, we identified dysregulated EV proteins that potentially indicate early-stage CRC and predict recurrence risk, including proteins involved in metabolism, cytoskeletal remodelling, and immune response. While our findings underline discrepancies with other studies due to differing isolation and stringency parameters, they provide valuable insights into the complexity of the EV proteome, emphasising the need for standardised protocols and larger, well-controlled studies to validate potential biomarkers. Full article

Glutaric aciduria type 1 (GA1) is a rare inherited metabolic disease increasingly included in newborn screening (NBS) programs worldwide. Because of the broad biochemical spectrum of individuals with GA1 and the lack of reliable second-tier strategies, NBS for GA1 is still confronted with a high rate of false positives. In this study, we aim to increase the specificity of NBS for GA1 and, hence, to reduce the rate of false positives through machine learning methods. Therefore, we studied NBS profiles from 1,025,953 newborns screened between 2014 and 2023 at the Heidelberg NBS Laboratory, Germany. We identified a significant sex difference, resulting in twice as many false-positives male than female newborns. Moreover, the proposed digital-tier strategy based on logistic regression analysis, ridge regression, and support vector machine reduced the false-positive rate by over 90% compared to regular NBS while identifying all confirmed individuals with GA1 correctly. An in-depth analysis of the profiles revealed that in particular false-positive results with high associated follow-up costs could be reduced significantly. In conclusion, understanding the origin of false-positive NBS and implementing a digital-tier strategy to enhance the specificity of GA1 testing may significantly reduce the burden on newborns and their families from false-positive NBS results. Full article

Background/Objectives: Glioblastoma (GBM) is the most common malignant primary central nervous system tumor with extremely poor prognosis and survival outcomes. Non-invasive methods like radiomic feature extraction, which assess sub-visual imaging features, provide a potentially powerful tool for distinguishing molecular profiles across groups of patients with GBM. Using consensus clustering of MRI-based radiomic features, this study aims to investigate differential gene expression profiles based on radiomic clusters. Methods: Patients from the TCGA and CPTAC datasets (n = 114) were included in this study. Radiomic features including T1, T1 with contrast, T2, and FLAIR MRI sequences were extracted using PyRadiomics. Selected radiomic features were then clustered using ConsensusClusterPlus (k-means base algorithm and Euclidean distance), which iteratively subsamples and clusters 80% of the data to identify stable clusters by calculating the frequency in which each patient is a member of a cluster across iterations. Gene expression data (available for n = 69 patients) was analyzed using differential gene expression (DEG) and gene set enrichment (GSEA) approaches, after batch correction using ComBat-seq. Results: Three distinct clusters were identified based on the relative consensus matrix and cumulative distribution plots (Cluster 1, n = 25; Cluster 2, n = 46; Cluster 3, n = 43). No significant differences in patient demographic characteristics, MGMT methylation status, tumor location, or overall survival were identified across clusters. Differentially expressed genes were identified in Cluster 1, which have been previously associated with GBM prognosis, recurrence, and treatment sensitivity. GSEA of Cluster 1 showed an enrichment of genes upregulated for immune-related and DNA metabolism pathways and genes downregulated in pathways associated with protein and histone deacetylation. Clusters 2 and 3 exhibited fewer DEGs which failed to reach significance after multiple testing corrections. Conclusions: Consensus clustering of radiomic features revealed unique gene expression profiles in the GBM cohort which likely represent subtle differences in tumor biology and radiosensitivity that are not visually discernible, underscoring the potential of radiomics to serve as a non-invasive alternative for identifying GBM molecular heterogeneity. Further investigation is still required to validate these findings and their clinical implications. Full article

Background and Objectives: Percutaneous coronary intervention (PCI) is a proven therapy for acute myocardial infarction (AMI) cardiogenic shock (CS). Dual anti-platelet therapy (i.e., aspirin plus an oral P2Y12 inhibitor) is recommended in patients treated with PCI. However, CS patients present severe hemodynamic instability, deranged hemostatic balance, and the need for invasive mechanical circulatory support (MCS) alongside invasive procedures, resulting in an increased risk of both bleeding and thrombotic complications, leaving uncertainty about the best anti-thrombotic treatment. Recently, the parenteral short-acting P2Y12 inhibitor has been increasingly used in the acute cardiac care setting, mainly in light of its favourable pharmacokinetic profile and organ-independent metabolism. Materials and Methods: In accordance with the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) guidelines, we performed a systematic review and single-arm meta-analysis of the safety and efficacy outcomes (i.e., rates of major bleeding, occurrence of stent/any thrombosis, and hospital survival) of all existing original studies reporting on the intravenous administration of cangrelor in AMI-CS patients. Results: Ten studies (678 patients with CS) published between 2017 and 2023 were included in the present review: nine were observational and one had a randomized design. Percutaneous revascularization was performed in >80% of patients across the studies. Moreover, 26% of patients were treated with temporary MCS, and in all studies, concomitant systemic anticoagulation was performed. Cangrelor was administered intravenously at the dosage of 4 mcg/kg/min in 57% of patients, 0.75 mcg/kg/min in 37% of patients, and <0.75 mcg/kg/min in 6%. The pooled rate of major bleeding was 17% (11–23%, confidence interval [CI]), and the pooled rate of stent thrombosis and any thrombosis were 1% (0.3–2.3% CI) and 3% (0.4–7% CI), respectively. Pooled hospital survival was 66% (59–73% CI). Conclusions: Cangrelor administration in AMI-CS patients was feasible and safe with a low rate of thromboembolic complications. Haemorrhagic complications were more frequent than thrombotic events. Nevertheless, to date, the optimal dosage of cangrelor in this clinical context still remains not universally recognized. Full article

The aim of this study was to examine the effect of free or immobilized Lacticaseibacillus rhamnosus OLXAL-1 cells on oat flakes on the gut microbiota and metabolic and inflammatory markers in a streptozotocin (STZ)-induced Type-1 Diabetes Mellitus (T1DM) animal model. Forty-eight male Wistar rats were assigned into eight groups (n = 6): healthy or diabetic animals that received either a control diet (CD and DCD), an oat-supplemented diet (OD and DOD), a diet supplemented with free L. rhamnosus OLXAL-1 cells (CFC and DFC), or a diet supplemented with immobilized L. rhamnosus OLXAL-1 cells on oat flakes (CIC and DIC). Neither L. rhamnosus OLXAL-1 nor oat supplementation led to any significant positive effects on body weight, insulin levels, plasma glucose concentrations, or lipid profile parameters. L. rhamnosus OLXAL-1 administration resulted in a rise in the relative abundances of Lactobacillus and Bifidobacterium, as well as increased levels of lactic, acetic, and butyric acids in the feces of the diabetic animals. Additionally, supplementation with oat flakes significantly reduced the microbial populations of E. coli, Enterobacteriaceae, coliforms, staphylococci, and enterococci and lowered IL-1β levels in the blood plasma of diabetic animals. These findings suggested that probiotic food-based strategies could have a potential therapeutic role in managing dysbiosis and inflammation associated with T1DM. Full article

The aim of this work was to evaluate the effect of CA and DCA on sugars, tricarboxylic acid cycle (TCA), anaerobic metabolism and some volatile compounds of ‘Elstar’ and ‘Nicoter’ apples. This study also aimed to evaluate the effect of ethylene action blocking by 1-MCP (0.650 ppm). The storage conditions tested for both cultivars were (1) CA; (2) DCA-CF; (3) DCA-RQ 1.3; (4) DCA-RQ 1.5; (5) DCA-CD 1.1; and (6) DCA-CD 1.3. The lowest oxygen limit (LOL) was higher for the ‘Nicoter’ apples, and the three DCA methods were able to detect this difference between the cultivars. Sorbitol had a trend of accumulation when the fruit was stored under DCA-RQ and DCA-CD, especially in higher RQ and CD, showing a negative Pearson correlation with the oxygen partial pressure over the storage period. The 1-MCP treatment induced sorbitol accumulation even when the fruit was stored under CA. The TCA intermediaries, such as citrate, 2-oxoglutarate, succinate, fumarate and oxaloacetate, were the most affected by the atmosphere conditions and the 1-MCP treatment for both cultivars. Malic acid was more affected by the storage time than the atmosphere conditions. Succinate and fumarate had an accumulation trend when the fruit was stored under DCA-RQ. Full article

Metabolite accumulation in the tumor microenvironment fosters immune evasion and limits the efficiency of immunotherapeutic approaches. Methylthioadenosine phosphorylase (MTAP), which catalyzes the degradation of 5′-deoxy-5′methylthioadenosine (MTA), is downregulated in many cancer entities. Consequently, MTA accumulates in the microenvironment of MTAP-deficient tumors, where it is known to inhibit tumor-infiltrating T cells and NK cells. However, the impact of MTA on other intra-tumoral immune cells has not yet been fully elucidated. To study the effects of MTA on dendritic cells (DCs), human monocytes were maturated into DCs with (MTA-DC) or without MTA (co-DC) and analyzed for activation, differentiation, and T cell-stimulating capacity. MTA altered the cytokine secretion profile of monocytes and impaired their maturation into dendritic cells. MTA-DCs produced less IL-12 and showed a more immature-like phenotype characterized by decreased expression of the co-stimulatory molecules CD80, CD83, and CD86 and increased expression of the monocyte markers CD14 and CD16. Consequently, MTA reduced the capability of DCs to stimulate T cells. Mechanistically, the MTA-induced effects on monocytes and DCs were mediated by a mechanism beyond adenosine receptor signaling. These results provide new insights into how altered polyamine metabolism impairs the maturation of monocyte-derived DCs and impacts the crosstalk between T and dendritic cells. Full article

Rehmannia glutinosa Libosch., which belongs to the Orobanchaceae family, is a perennial herb found in China, Japan, and Korea. In traditional medicine, it is used to cool the body, improve water metabolism in the kidney, and provide protection from metabolic diseases such as type 2 diabetes mellitus (T2DM) and obesity. In this study, three new compounds were isolated from the roots of R. glutinosa, along with eighteen known compounds. Structure elucidation was performed with spectroscopic analyses including nuclear magnetic resonance (NMR) and circular dichroism (CD) spectroscopy. As the AMP-activated protein kinase (AMPK) signaling pathway is reportedly related to metabolic diseases, AMPK activation studies were conducted using in silico simulations and in vitro assays. Among the isolated compounds, 1 showed a potential as an AMPK activator in both in silico simulations and in vitro experiments. Our findings expand the chemical profiles of the plant R. glutinosa and suggest that one newly found compound (1) activates AMPK. Full article