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Environment International Jun 2024PFAS are ubiquitous industrial chemicals with known adverse health effects, particularly on the liver. The liver, being a vital metabolic organ, is susceptible to...
PFAS are ubiquitous industrial chemicals with known adverse health effects, particularly on the liver. The liver, being a vital metabolic organ, is susceptible to PFAS-induced metabolic dysregulation, leading to conditions such as hepatotoxicity and metabolic disturbances. In this study, we investigated the phenotypic and metabolic responses of PFAS exposure using two hepatocyte models, HepG2 (male cell line) and HepaRG (female cell line), aiming to define phenotypic alterations, and metabolic disturbances at the metabolite and pathway levels. The PFAS mixture composition was selected based on epidemiological data, covering a broad concentration spectrum observed in diverse human populations. Phenotypic profiling by Cell Painting assay disclosed predominant effects of PFAS exposure on mitochondrial structure and function in both cell models as well as effects on F-actin, Golgi apparatus, and plasma membrane-associated measures. We employed comprehensive metabolic characterization using liquid chromatography combined with high-resolution mass spectrometry (LC-HRMS). We observed dose-dependent changes in the metabolic profiles, particularly in lipid, steroid, amino acid and sugar and carbohydrate metabolism in both cells as well as in cell media, with HepaRG cell line showing a stronger metabolic response. In cells, most of the bile acids, acylcarnitines and free fatty acids showed downregulation, while medium-chain fatty acids and carnosine were upregulated, while the cell media showed different response especially in relation to the bile acids in HepaRG cell media. Importantly, we observed also nonmonotonic response for several phenotypic features and metabolites. On the pathway level, PFAS exposure was also associated with pathways indicating oxidative stress and inflammatory responses. Taken together, our findings on PFAS-induced phenotypic and metabolic disruptions in hepatocytes shed light on potential mechanisms contributing to the broader comprehension of PFAS-related health risks.
PubMed: 38906088
DOI: 10.1016/j.envint.2024.108820 -
Nature Communications Jun 2024Disrupted glucose metabolism and protein misfolding are key characteristics of age-related neurodegenerative disorders including Parkinson's disease, however their...
Disrupted glucose metabolism and protein misfolding are key characteristics of age-related neurodegenerative disorders including Parkinson's disease, however their mechanistic linkage is largely unexplored. The hexosamine biosynthetic pathway utilizes glucose and uridine-5'-triphosphate to generate N-linked glycans required for protein folding in the endoplasmic reticulum. Here we find that Parkinson's patient midbrain cultures accumulate glucose and uridine-5'-triphosphate, while N-glycan synthesis rates are reduced. Impaired glucose flux occurred by selective reduction of the rate-limiting enzyme, GFPT2, through disrupted signaling between the unfolded protein response and the hexosamine pathway. Failure of the unfolded protein response and reduced N-glycosylation caused immature lysosomal hydrolases to misfold and accumulate, while accelerating glucose flux through the hexosamine pathway rescued hydrolase function and reduced pathological α-synuclein. Our data indicate that the hexosamine pathway integrates glucose metabolism with lysosomal activity, and its failure in Parkinson's disease occurs by uncoupling of the unfolded protein response-hexosamine pathway axis. These findings offer new methods to restore proteostasis by hexosamine pathway enhancement.
Topics: Humans; Hexosamines; Lysosomes; Parkinson Disease; Unfolded Protein Response; Neurons; Induced Pluripotent Stem Cells; Mesencephalon; Glucose; Biosynthetic Pathways; Glycosylation; alpha-Synuclein; Glutamine-Fructose-6-Phosphate Transaminase (Isomerizing)
PubMed: 38897986
DOI: 10.1038/s41467-024-49256-3 -
Molecules (Basel, Switzerland) May 2024The pomegranate processing industry generates worldwide enormous amounts of by-products, such as pomegranate peels (PPs), which constitute a rich source of phenolic...
The pomegranate processing industry generates worldwide enormous amounts of by-products, such as pomegranate peels (PPs), which constitute a rich source of phenolic compounds. In this view, PPs could be exploited as a sustainable source of ellagic acid, which is a compound that possesses various biological actions. The present study aimed at the liberation of ellagic acid from its bound forms via ultrasound-assisted alkaline hydrolysis, which was optimized using response surface methodology. The effects of duration of sonication, solvent:solid ratio, and NaOH concentration on total phenol content (TPC), antioxidant activity, and punicalagin and ellagic acid content were investigated. Using the optimum hydrolysis conditions (i.e., 32 min, 1:48 /, 1.5 mol/L NaOH), the experimental responses were found to be TCP: 4230 ± 190 mg GAE/100 g dry PPs; A: 32,398 ± 1817 µmol Trolox/100 g dry PPs; A: 29,816 ± 1955 µmol Trolox/100 g dry PPs; 59 ± 3 mg punicalagin/100 g dry PPs; and 1457 ± 71 mg ellagic acid/100 g dry PPs. LC-QTOF-MS and GC-MS analysis of the obtained PP extract revealed the presence of various phenolic compounds (e.g., ellagic acid), organic acids (e.g., citric acid), sugars (e.g., fructose) and amino acids (e.g., glycine). The proposed methodology could be of use for food, pharmaceutical, and cosmetics applications, thus reinforcing local economies.
Topics: Ellagic Acid; Pomegranate; Hydrolysis; Antioxidants; Phenols; Plant Extracts; Hydrolyzable Tannins; Fruit
PubMed: 38893299
DOI: 10.3390/molecules29112424 -
International Journal of Molecular... Jun 2024Diabetic retinopathy (DR) is a very serious diabetes complication. Changes in the O-linked N-acetylglucosamine (O-GlcNAc) modification are associated with many diseases....
Diabetic retinopathy (DR) is a very serious diabetes complication. Changes in the O-linked N-acetylglucosamine (O-GlcNAc) modification are associated with many diseases. However, its role in DR is not fully understood. In this research, we explored the effect of O-GlcNAc modification regulation by activating AMP-activated protein kinase (AMPK) in DR, providing some evidence for clinical DR treatment in the future. Bioinformatics was used to make predictions from the database, which were validated using the serum samples of diabetic patients. As an in vivo model, diabetic mice were induced using streptozotocin (STZ) injection with/without an AMPK agonist (metformin) or an AMPK inhibitor (compound C) treatment. Electroretinogram (ERG) and H&E staining were used to evaluate the retinal functional and morphological changes. In vitro, 661 w cells were exposed to high-glucose conditions, with or without metformin treatment. Apoptosis was evaluated using TUNEL staining. The protein expression was detected using Western blot and immunofluorescence staining. The angiogenesis ability was detected using a tube formation assay. The levels of O-GlcNAc transferase (OGT) and O-GlcNAcase (OGA) in the serum changed in the DR patients in the clinic. In the diabetic mice, the ERG wave amplitude and retinal thickness decreased. In vitro, the apoptotic cell percentage and Bax expression were increased, and Bcl2 expression was decreased in the 661 w cells under high-glucose conditions. The O-GlcNAc modification was increased in DR. In addition, the expression of GFAT/TXNIP O-GlcNAc was also increased in the 661 w cells after the high-glucose treatment. Additionally, the Co-immunoprecipitation(CO-IP) results show that TXNIP interacted with the O-GlcNAc modification. However, AMPK activation ameliorated this effect. We also found that silencing the AMPKα1 subunit reversed this process. In addition, the conditioned medium of the 661 w cells may have affected the tube formation in vitro. Taken together, O-GlcNAc modification was increased in DR with photoreceptor cell degeneration and neovascularization; however, it was reversed after activating AMPK. The underlying mechanism is linked to the GFAT/TXNIP-O-GlcNAc modification signaling axis. Therefore, the AMPKα1 subunit plays a vital role in the process.
Topics: Diabetic Retinopathy; Animals; Mice; Acetylglucosamine; N-Acetylglucosaminyltransferases; Diabetes Mellitus, Experimental; Humans; AMP-Activated Protein Kinases; Male; Apoptosis; Metformin; beta-N-Acetylhexosaminidases; Retina; Mice, Inbred C57BL; Cell Line
PubMed: 38892474
DOI: 10.3390/ijms25116286 -
International Journal of Molecular... May 2024Rice ( L.) is an important social-economic crop, and rice seedlings are easily affected by salt stress. Chitosan oligosaccharide (COS) plays a positive role in promoting...
Rice ( L.) is an important social-economic crop, and rice seedlings are easily affected by salt stress. Chitosan oligosaccharide (COS) plays a positive role in promoting plant growth and development. To gain a better understanding of the salt tolerance mechanism of rice under the action of COS, Nipponbare rice seedlings were selected as the experimental materials, and the physiological and biochemical indexes of rice seedlings in three stages (normal growth, salt stress and recovery) were measured. Unlabelled quantitative proteomics technology was used to study differential protein and signaling pathways of rice seedlings under salt stress, and the mechanism of COS to improve rice tolerance to salt stress was elucidated. Results showed that after treatment with COS, the chlorophyll content of rice seedlings was 1.26 times higher than that of the blank group (CK). The root activity during the recovery stage was 1.46 times that of the CK group. The soluble sugar in root, stem and leaf increased by 53.42%, 77.10% and 9.37%, respectively. The total amino acid content increased by 77% during the stem recovery stage. Furthermore, the malondialdehyde content in root, stem and leaf increased by 21.28%, 26.67% and 32.69%, respectively. The activity of oxide dismutase (SOD), peroxidase (POD) and oxygenase (CAT) were increased. There were more differentially expressed proteins in the three parts of the experimental group than in the CK group. Gene Ontology (GO) annotation of these differentially expressed proteins revealed that the experimental group was enriched for more entries. Then, through the Kyoto Encyclopedia of Genes and Genomes (KEGG), the top ten pathways enriched with differentially expressed proteins in the two groups (COS and CK groups) were utilized, and a detailed interpretation of the glycolysis and photosynthesis pathways was provided. Five key proteins, including phosphofructokinase, fructose bisphosphate aldolases, glycer-aldehyde-3-phosphate dehydrogenase, enolase and pyruvate kinase, were identified in the glycolysis pathway. In the photosynthesis pathway, oxygen evolution enhancement proteins, iron redox proteins and ferredoxin-NADPH reductase were the key proteins. The addition of COS led to an increase in the abundance of proteins, a response of rice seedlings to salt stress. COS helped rice seedlings resist salt stress. Furthermore, using COS as biopesticides and biofertilizers can effectively increase the utilization of saline-affected farmland, thereby contributing to the alleviating of the global food crisis.
Topics: Oryza; Chitosan; Seedlings; Salt Tolerance; Oligosaccharides; Proteome; Plant Proteins; Proteomics; Gene Expression Regulation, Plant; Chlorophyll
PubMed: 38892141
DOI: 10.3390/ijms25115953 -
International Journal of Molecular... May 2024Alginate lyases cleave the 1,4-glycosidic bond of alginate by eliminating sugar molecules from its bond. While earlier reported alginate lyases were primarily single...
Alginate lyases cleave the 1,4-glycosidic bond of alginate by eliminating sugar molecules from its bond. While earlier reported alginate lyases were primarily single catalytic domains, research on multi-module alginate lyases has been lfiguimited. This study identified VsAly7A, a multi-module alginate lyase present in sp. QY108, comprising a "Pro-Asp-Thr(PDT)" fragment and two PL-7 catalytic domains (CD I and CD II). The "PDT" fragment enhances the soluble expression level and increases the thermostability and binding affinity to the substrate. Moreover, CD I exhibited greater catalytic efficiency than CD II. The incorporation of PDT-CD I resulted in an increase in the optimal temperature of VsAly7A, whereas CD II displayed a preference for polyG degradation. The multi-domain structure of VsAly7A provides a new idea for the rational design of alginate lyase, whilst the "PDT" fragment may serve as a fusion tag in the soluble expression of recombinant proteins.
Topics: Polysaccharide-Lyases; Vibrio; Alginates; Enzyme Stability; Protein Binding; Catalytic Domain; Bacterial Proteins; Solubility; Amino Acid Sequence; Temperature; Recombinant Proteins
PubMed: 38891987
DOI: 10.3390/ijms25115801 -
International Journal of Molecular... May 2024Dipeptidyl peptidase-IV (DPPIV) inhibitory peptides are a class of antihyperglycemic drugs used in the treatment of type 2 diabetes mellitus, a metabolic disorder...
Dipeptidyl peptidase-IV (DPPIV) inhibitory peptides are a class of antihyperglycemic drugs used in the treatment of type 2 diabetes mellitus, a metabolic disorder resulting from reduced levels of the incretin hormone GLP-1. Given that DPPIV degrades incretin, a key regulator of blood sugar levels, various antidiabetic medications that inhibit DPPIV, such as vildagliptin, sitagliptin, and linagliptin, are employed. However, the potential side effects of these drugs remain a matter of debate. Therefore, we aimed to investigate food-derived peptides from (hemp) seeds. Our developed bioinformatics pipeline was used to identify the putative hydrolyzed peptidome of three highly abundant proteins: albumin, edestin, and vicilin. These proteins were subjected to in silico digestion by different proteases (trypsin, chymotrypsin, and pepsin) and then screened for DPPIV inhibitory peptides using IDPPIV-SCM. To assess potential adverse effects, several prediction tools, namely, TOXINpred, AllerCatPro, and HemoPred, were employed to evaluate toxicity, allergenicity, and hemolytic effects, respectively. COPID was used to determine the amino acid composition. Molecular docking was performed using GalaxyPepDock and HPEPDOCK, 3D visualizations were conducted using the UCSF Chimera program, and MD simulations were carried out with AMBER20 MD software. Based on the predictive outcomes, FNVDTE from edestin and EAQPST from vicilin emerged as promising candidates for DPPIV inhibitors. We anticipate that our findings may pave the way for the development of alternative DPPIV inhibitors.
Topics: Dipeptidyl-Peptidase IV Inhibitors; Seeds; Molecular Docking Simulation; Hypoglycemic Agents; Cannabis; Dipeptidyl Peptidase 4; Peptides; Humans; Plant Proteins; Hydrolysis; Seed Storage Proteins; Computational Biology
PubMed: 38891918
DOI: 10.3390/ijms25115730 -
Polymers Jun 2024Over the past decades, the research on optically active polymers (OAPs) has significantly grown, and extensive studies have been carried out on their syntheses,...
Over the past decades, the research on optically active polymers (OAPs) has significantly grown, and extensive studies have been carried out on their syntheses, conformations, and applications. The most commonly used OAPs are based on natural products such as sugars or amino acids, which limits their scope. A broader range of applications can be achieved by synthesizing lab-tailored monomers, which allow precise control over structure and properties. This research developed a four-step synthetic route to a previously unreported chiral [2.2]paracyclophane-based epoxide monomer. An aluminum catalyst and an alkylammonium initiating system were applied and optimized for its polymerization to provide access to a novel class of chiral polyethers. Furthermore, we demonstrated the copolymerization viability of the (4-[2.2]paracyclophanyl)oxirane monomer using phthalic anhydride.
PubMed: 38891548
DOI: 10.3390/polym16111603 -
Plants (Basel, Switzerland) May 2024Moso bamboo () is known for its high capacity to sequester atmospheric carbon (C), which has a unique role to play in the fight against global warming. However, due to...
Moso bamboo () is known for its high capacity to sequester atmospheric carbon (C), which has a unique role to play in the fight against global warming. However, due to rising labor costs and falling bamboo prices, many Moso bamboo forests are shifting to an extensive management model without fertilization, resulting in gradual degradation of Moso bamboo forests. However, many Moso bamboo forests are being degraded due to rising labor costs and declining bamboo timber prices. To delineate the effect of degradation on soil microbial carbon sequestration, we instituted a rigorous analysis of Moso bamboo forests subjected to different degradation durations, namely: continuous management (CK), 5 years of degradation (D-5), and 10 years of degradation (D-10). Our inquiry encompassed soil strata at 0-20 cm and 20-40 cm, scrutinizing alterations in soil organic carbon(SOC), water-soluble carbon(WSOC), microbial carbon(MBC)and microbial residues. We discerned a positive correlation between degradation and augmented levels of SOC, WSOC, and MBC across both strata. Furthermore, degradation escalated concentrations of specific soil amino sugars and microbial residues. Intriguingly, extended degradation diminished the proportional contribution of microbial residuals to SOC, implying a possible decline in microbial activity longitudinally. These findings offer a detailed insight into microbial C processes within degraded bamboo ecosystems.
PubMed: 38891335
DOI: 10.3390/plants13111526 -
Foods (Basel, Switzerland) Jun 2024Pulsed electric field (PEF) pretreatment has been shown to improve the quality of dried fruits in terms of antioxidant activity and bioactive compounds. In this study,...
Pulsed electric field (PEF) pretreatment has been shown to improve the quality of dried fruits in terms of antioxidant activity and bioactive compounds. In this study, apricots were pretreated with PEF at different field strengths (0.7 kV/cm; 1.2 kV/cm and 1.8 kv/cm) at a frequency of 50 Hz, and electric pulses coming in every 20 µs for 30 s, prior to freeze-drying and air-drying treatments. PEF treatments were carried out at different field strengths. The impact of different pretreatments on the quality of dried apricot was determined in terms of physical properties, antioxidant activity, total phenolic content, and metabolite profile. PEF pretreatments significantly ( < 0.05) increased firmness of all the air-dried samples the most by 4-7-fold and most freeze-dried apricot samples (44.2% to 98.64%) compared to the control group. However, PEF treatment at 1.2 kV/cm did not have any effect on hardness of the freeze-dried sample. The moisture content and water activity of freeze-dried samples were found to be significantly lower than those of air-dried samples. Scanning electron microscopy results revealed that air drying caused the loss of fruit structure due to significant moisture loss, while freeze drying preserved the honeycomb structure of the apricot flesh, with increased pore sizes observed at higher PEF intensities. PEF pretreatment also significantly increased the antioxidant activity and total phenol content of both air-dried and freeze-dried apricots. PEF treatment also significantly ( < 0.05) increased amino acid and fatty acid content of air-dried samples but significantly ( < 0.05) decreased sugar content. Almost all amino acids (except tyrosine, alanine, and threonine) significantly increased with increasing PEF intensity. The results of this study suggest that PEF pretreatment can influence the quality of air-dried and freeze-dried apricots in terms antioxidant activity and metabolites such as amino acids, fatty acids, sugar, organic acids, and phenolic compounds. The most effective treatment for preserving the quality of dried apricots is freeze drying combined with high-intensity (1.8 kv/cm) PEF treatment.
PubMed: 38890992
DOI: 10.3390/foods13111764