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Innovation (Cambridge (Mass.)) May 2024Pancreatic adenocarcinoma (PDAC) is one of the most deadly cancers, characterized by extremely limited therapeutic options and a poor prognosis, as it is often diagnosed...
Pancreatic adenocarcinoma (PDAC) is one of the most deadly cancers, characterized by extremely limited therapeutic options and a poor prognosis, as it is often diagnosed during late disease stages. Innovative and selective treatments are urgently needed, since current therapies have limited efficacy and significant side effects. Through proteomics analysis of extracellular vesicles, we discovered an imbalanced distribution of amino acids secreted by PDAC tumor cells. Our findings revealed that PDAC cells preferentially excrete proteins with certain preferential amino acids, including isoleucine and histidine, via extracellular vesicles. These amino acids are associated with disease progression and can be targeted to elicit selective toxicity to PDAC tumor cells. Both and experiments demonstrated that supplementation with these specific amino acids effectively eradicated PDAC cells. Mechanistically, we also identified XRN1 as a potential target for these amino acids. The high selectivity of this treatment method allows for specific targeting of tumor metabolism with very low toxicity to normal tissues. Furthermore, we found this treatment approach is easy-to-administer and with sustained tumor-killing effects. Together, our findings reveal that exocytosed amino acids may serve as therapeutic targets for designing treatments of intractable PDAC and potentially offer alternative treatments for other types of cancers.
PubMed: 38699777
DOI: 10.1016/j.xinn.2024.100626 -
Frontiers in Pharmacology 2024The relationship between sleep loss and cognitive impairment has long been widely recognized, but there is still a lack of complete understanding of the underlying...
The relationship between sleep loss and cognitive impairment has long been widely recognized, but there is still a lack of complete understanding of the underlying mechanisms and potential biomarkers. The purpose of this study is to further explore the shared biological mechanisms and common biomarkers between sleep loss and cognitive impairment. The mitochondria-related genes and gene expression data were downloaded from the MitoCarta3.0 and Gene Expression Omnibus (GEO) databases. We identified the differentially expressed mitochondrial-related genes by combing the differentially expressed genes (DEGs) in sleep deprivation (SD) and mild cognitive impairment (MCI) datasets with mitochondria-related gene lists. Shared DEGs were then further analyzed for enrichment analysis. Next, the common biomarker was identified using two machine learning techniques and further validated using two independent GEO datasets. Then GSEA and GSVA were conducted to analyze the functional categories and pathways enriched for the common biomarker. Finally, immune infiltration analysis was used to investigate the correlation of immune cell infiltration with the common biomarker in SD and MCI. A total of 32 mitochondrial-related differentially expressed genes were identified in SD and MCI. GO analysis indicated that these genes were significantly enriched for mitochondrial transport, and KEGG analysis showed they were mainly involved in pathways of neurodegenerative diseases. In addition, ATPAF1, which was significantly down-regulated in both SD and MCI, was identified through machine learning algorithms as the common biomarker with favorable diagnostic performance. GSEA and GSVA revealed that ATPAF1 was mainly involved in metabolic pathways, such as oxidative phosphorylation, acetylcholine metabolic process, valine, leucine and isoleucine degradation. Immune infiltration analysis showed that the expression of ATPAF1 was correlated with changes in immune cells, especially those key immune cell types associated with SD and MCI. This study firstly revealed that mitochondrial dysfunction may be the common pathogenesis of sleep loss and mild cognitive impairment and identified ATPAF1 as a possible biomarker and therapeutic target involved in SD and MCI.
PubMed: 38694919
DOI: 10.3389/fphar.2024.1387569 -
ACS Omega Apr 202417β-Estradiol is an ovarian hormone that regulates energy circulation and storage by acting on the central nervous system. However, the metabolic differences between...
17β-Estradiol is an ovarian hormone that regulates energy circulation and storage by acting on the central nervous system. However, the metabolic differences between the blood and brain when stimulated by 17β-estradiol are poorly understood. Moreover, research using menopause-induced models to investigate primary metabolites in the blood and brain is limited. Thus, this study aimed to identify metabolic changes in the plasma and brain resulting from 17β-estradiol supplementation in an estrogen-deficient mouse model. Three groups of mice were utilized: sham-operated mice (Sham), ovariectomized mice (OVX), and ovariectomized mice that received a weekly supplementation of 17β-estradiol (E2). Plasma and brain samples from these mice were subjected to metabolic analysis using gas chromatography-time-of-flight-mass spectrometry. Compared with the plasma samples from the Sham and OVX groups, the plasma samples from the E2 group contained higher contents of branched-chain amino acids (BCAAs), such as valine, isoleucine, and leucine. Meanwhile, the brain samples from the E2 group contained higher contents of most metabolites, including BCAAs, neurotransmitters, tricarboxylic acid cycle intermediates, and fatty acids, than those from the two other groups. This study is the first to reveal differences in energy metabolism induced by 17β-estradiol supplementation through brain metabolic profiling of ovariectomized mice, emphasizing the importance of brain metabolic profiling in menopausal hormone research.
PubMed: 38680363
DOI: 10.1021/acsomega.3c10399 -
Viruses Mar 2024Avian metapneumovirus (aMPV), classified within the family, wreaks havoc on poultry health. It typically causes upper respiratory tract and reproductive tract...
Avian metapneumovirus (aMPV), classified within the family, wreaks havoc on poultry health. It typically causes upper respiratory tract and reproductive tract infections, mainly in turkeys, chickens, and ducks. Four subtypes of AMPV (A, B, C, D) and two unclassified subtypes have been identified, of which subtypes A and B are widely distributed across the world. In January 2024, an outbreak of severe respiratory disease occurred on turkey and chicken farms across different states in the US. Metagenomics sequencing of selected tissue and swab samples confirmed the presence of aMPV subtype B. Subsequently, all samples were screened using an aMPV subtype A and B multiplex real-time RT-PCR kit. Of the 221 farms, 124 (56%) were found to be positive for aMPV-B. All samples were negative for subtype A. Six whole genomes were assembled, five from turkeys and one from chickens; all six assembled genomes showed 99.29 to 99.98% nucleotide identity, indicating a clonal expansion event for aMPV-B within the country. In addition, all six sequences showed 97.74 to 98.58% nucleotide identity with previously reported subtype B sequences, e.g., VCO3/60616, Hungary/657/4, and BR/1890/E1/19. In comparison to these two reference strains, the study sequences showed unique 49-62 amino acid changes across the genome, with maximum changes in glycoprotein (G). One unique AA change from T (Threonine) to I (Isoleucine) at position 153 in G protein was reported only in the chicken aMPV sequence, which differentiated it from turkey sequences. The twelve unique AA changes along with change in polarity of the G protein may indicate that these unique changes played a role in the adaptation of this virus in the US poultry. This is the first documented report of aMPV subtype B in US poultry, highlighting the need for further investigations into its genotypic characterization, pathogenesis, and evolutionary dynamics.
Topics: Animals; Metapneumovirus; Paramyxoviridae Infections; Poultry Diseases; Phylogeny; Turkeys; Genome, Viral; United States; Chickens; Poultry; Metagenomics; Disease Outbreaks
PubMed: 38675851
DOI: 10.3390/v16040508 -
Molecules (Basel, Switzerland) Apr 2024The allelopathic autotoxicity of ginsenosides is an important cause of continuous cropping obstacles in ginseng planting. There is no report on the potential molecular...
The allelopathic autotoxicity of ginsenosides is an important cause of continuous cropping obstacles in ginseng planting. There is no report on the potential molecular mechanism of the correlation between polarity of ginsenoside components and their allelopathic autotoxicity. This study applied a combination of metabolomics and transcriptomics analysis techniques, combined with apparent morphology, physiological indexes, and cell vitality detection of the ginseng hairy roots, through which the molecular mechanism of correlation between polarity and allelopathic autotoxicity of ginsenosides were comprehensively studied. The hairy roots of ginseng presented more severe cell apoptosis under the stress of low-polarity ginsenoside components (ZG70). ZG70 exerted allelopathic autotoxicity by regulating the key enzyme genes of cis-zeatin (cZ) synthesis pathway, indole-3-acetic acid (IAA) synthesis pathway, and jasmonates (JAs) signaling transduction pathway. The common pathway for high-polarity ginsenoside components (ZG50) and ZG70 to induce the development of allelopathic autotoxicity was through the expression of key enzymes in the gibberellin (GA) signal transduction pathway, thereby inhibiting the growth of ginseng hairy roots. cZ, indole-3-acetamid (IAM), gibberellin A1 (GA1), and jasmonoyl-L-isoleucine (JA-ILE) were the key response factors in this process. It could be concluded that the polarity of ginsenoside components were negatively correlated with their allelopathic autotoxicity.
Topics: Panax; Plant Roots; Ginsenosides; Plant Growth Regulators; Transcriptome; Gene Expression Regulation, Plant; Gene Expression Profiling; Allelopathy; Signal Transduction; Metabolomics
PubMed: 38675697
DOI: 10.3390/molecules29081877 -
Nutrients Apr 2024This study aimed to investigate the impact of a common non-synonymous gene variant (C>G, rs738409) in patatin-like phospholipase domain-containing 3 (), leading to the...
The Role of _rs738409 Gene Variant, Lifestyle Factors, and Bioactive Compounds in Nonalcoholic Fatty Liver Disease: A Population-Based and Molecular Approach towards Healthy Nutrition.
This study aimed to investigate the impact of a common non-synonymous gene variant (C>G, rs738409) in patatin-like phospholipase domain-containing 3 (), leading to the substitution of isoleucine with methionine at position 148 (-I148M), on susceptibility to nonalcoholic fatty liver disease (NAFLD) and explore potential therapeutic nutritional strategies targeting . It contributed to understanding sustainable dietary practices for managing NAFLD, recently referred to as metabolic-dysfunction-associated fatty liver. NAFLD had been diagnosed by ultrasound in a metropolitan hospital-based cohort comprising 58,701 middle-aged and older Korean individuals, identifying 2089 NAFLD patients. The interaction between and lifestyle factors was investigated. In silico analyses, including virtual screening, molecular docking, and molecular dynamics simulations, were conducted to identify bioactive compounds from foods targeting (I148M). Subsequent cellular experiments involved treating oleic acid (OA)-exposed HepG2 cells with selected bioactive compounds, both in the absence and presence of compound C (AMPK inhibitor), targeting expression. Carriers of the risk allele _rs738409G showed an increased association with NAFLD risk, particularly with adherence to a plant-based diet, avoidance of a Western-style diet, and smoking. Delphinidin 3-caffeoyl-glucoside, pyranocyanin A, delta-viniferin, kaempferol-7-glucoside, and petunidin 3-rutinoside emerged as potential binders to the active site residues of , exhibiting a reduction in binding energy. These compounds demonstrated a dose-dependent reduction in intracellular triglyceride and lipid peroxide levels in HepG2 cells, while pretreatment with compound C showed the opposite trend. Kaempferol-7-glucoside and petunidin-3-rutinoside showed potential as inhibitors of expression by enhancing AMPK activity, ultimately reducing intrahepatic lipogenesis. In conclusion, there is potential for plant-based diets and specific bioactive compounds to promote sustainable dietary practices to mitigate NAFLD risk, especially in individuals with genetic predispositions.
Topics: Humans; Non-alcoholic Fatty Liver Disease; Male; Membrane Proteins; Lipase; Female; Middle Aged; Hep G2 Cells; Life Style; Genetic Predisposition to Disease; Molecular Docking Simulation; Polymorphism, Single Nucleotide; Diet, Healthy; Aged; Phytochemicals; Acyltransferases; Phospholipases A2, Calcium-Independent
PubMed: 38674929
DOI: 10.3390/nu16081239 -
Antioxidants (Basel, Switzerland) Apr 2024The aim of this experiment was to investigate the effects of dietary Phytosterol Ester (PSE) supplementation on egg characteristics, eggshell ultrastructure, antioxidant...
Effects of Phytosterol Ester Supplementation on Egg Characteristics, Eggshell Ultrastructure, Antioxidant Capacity, Liver Function and Hepatic Metabolites of Laying Hens during Peak Laying Period.
The aim of this experiment was to investigate the effects of dietary Phytosterol Ester (PSE) supplementation on egg characteristics, eggshell ultrastructure, antioxidant capacity, liver function, hepatic metabolites, and its mechanism of action in Hy-Line Brown laying hens during peak laying period. A total of 256 healthy Hy-Line Brown laying hens were randomly allocated into four groups. The hens in the control group were fed a basal diet, while those in the experimental groups were fed a basal diet further supplemented with 10, 20, and 40 mg/kg PSE, respectively. It was found that the addition of 20 mg/kg and 40 mg/kg PSE to the diets increased egg weight, but decreased egg breaking strength ( < 0.05). The addition of PSEs to the diets increased albumen height and Haugh unit in all experimental groups ( < 0.05). Electron microscopic observation revealed that the mammillary thickness increased significantly at doses of 20 and 40 mg/kg, but the total thickness decreased, and the effective thickness also thinned ( < 0.05). The mammillary width narrowed in all experimental groups ( < 0.001). Dietary supplementation with 40 mg/kg PSE significantly increased egg yolk Phenylalanine, Leucine, and Isoleucine levels ( < 0.05). In untargeted liver metabolomic analyses, L-Phenylalanine increased significantly in all experimental groups. Leucyl-Lysine, Glutamyl-Leucyl-Arginine, and L-Tryptophan increased significantly at doses of 10 and 20 mg/kg ( < 0.05), and L-Tyrosine increased significantly at doses of 10 and 40 mg/kg ( = 0.033). Aspartyl-Isoleucine also increased significantly at a dose of 10 mg/kg ( = 0.044). The concentration of total protein in the liver was significantly higher at doses of 20 and 40 mg/kg than that of the control group, and the concentrations of total cholesterol and low-density lipoprotein cholesterol were significantly reduced ( < 0.05). The concentration of triglyceride and alkaline phosphatase were significantly reduced in all experimental groups ( < 0.05). Steatosis and hemorrhage in the liver were also improved by observing the H&E-stained sections of the liver. Concerning the antioxidant capacity in the liver, malondialdehyde concentration was significantly reduced ( < 0.05) at a dose of 40 mg/kg. In the ovary, malondialdehyde and nitric oxide concentrations were significantly reduced ( < 0.001). In all the experimental groups, plasma nitric oxide concentration was significantly decreased while superoxide dismutase was significantly increased, and total antioxidant capacity concentration was significantly increased ( < 0.05) in the 10 mg/kg and 40 mg/kg doses. Metabolomics analyses revealed that PSEs play a role in promoting protein synthesis by promoting Aminoacyl-tRNA biosynthesis and amino acid metabolism, among other pathways. This study showed that the dietary addition of PSEs improved egg characteristics, antioxidant capacity, liver function, and symptoms of fatty liver hemorrhagic syndrome in Hy-Line Brown laying hens at peak laying stage. The changes in liver metabolism suggest that the mechanism of action may be related to pathways such as Aminoacyl-tRNA biosynthesis and amino acid metabolism. In conclusion, the present study demonstrated that PSEs are safe and effective dietary additives as an alternative to antibiotics.
PubMed: 38671906
DOI: 10.3390/antiox13040458 -
Metabolites Apr 2024Rhubarb (RR), Chinese name Dahuang, is commonly used in the treatment of ischemic stroke (IS). However, its potential mechanism is not fully elucidated. This study...
Rhubarb (RR), Chinese name Dahuang, is commonly used in the treatment of ischemic stroke (IS). However, its potential mechanism is not fully elucidated. This study intended to verify the effect of RR on IS and investigate the possible mechanism of RR in preventing IS. IS in male rats was induced by embolic middle cerebral artery occlusion (MCAO) surgery, and drug administration was applied half an hour before surgery. RR dramatically decreased the neurological deficit scores, the cerebral infarct volume, and the cerebral edema rate, and improved the regional cerebral blood flow (rCBF) and histopathological changes in the brain of MCAO rats. The 16S rRNA analysis showed the harmful microbes such as and were decreased, and the beneficial microbes such as , , , and were significantly increased, after RR pretreatment. H-nuclear magnetic resonance (H-NMR) was used to detect serum metabolomics, and RR treatment significantly changed the levels of metabolites such as isoleucine, valine, N6-acetyllysine, methionine, 3-aminoisobutyric acid, N, N-dimethylglycine, propylene glycol, trimethylamine N-oxide, myo-inositol, choline, betaine, lactate, glucose, and lipid, and the enrichment analysis of differential metabolites showed that RR may participate in the regulation of amino acid metabolism and energy metabolism. RR exerts the role of anti-IS via regulating gut bacteria and metabolic pathways.
PubMed: 38668344
DOI: 10.3390/metabo14040216 -
Insects Apr 2024Artificial silkworm diets significantly impact farm profitability. Sustainable cocoon production depends on the continuous improvement of feed efficiency to reduce costs...
Artificial silkworm diets significantly impact farm profitability. Sustainable cocoon production depends on the continuous improvement of feed efficiency to reduce costs and nutrient losses in the feed. This study used metabolomics to explore the differences in silkworm cocoons and hemolymph under two modes of rearing: an artificial diet and a mulberry-leaf diet. Nine metabolites of silkworm cocoons and hemolymph in the mulberry-leaf group were higher than those in the artificial-diet group. Enrichment analysis of the KEGG pathways for these metabolites revealed that they were mainly enriched in the valine, leucine, and isoleucine biosynthesis and degradation pathways. Hence, the artificial silkworm diet was supplemented various concentrations of valine were supplemented to with the aim of examining the impact of valine on their feeding and digestion of the artificial diet. The results indicated that valine addition had no significant effect on feed digestibility in the fifth-instar silkworm. Food intake in the 2% and 4% valine groups was significantly lower than that in the 0% valine group. However, the 2% and 4% valine groups showed significantly improved cocoon-production efficiency, at 11.3% and 25.1% higher, respectively. However, the cocoon-layer-production efficiencies of the 2% and 4% valine groups decreased by 7.7% and 13.9%, respectively. The research confirmed that valine is an effective substance for enhancing the feed efficiency of silkworms.
PubMed: 38667421
DOI: 10.3390/insects15040291