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Biology Open Jul 2024Instead of red anthocyanins, birches synthesise colourless (to human eye), UV-absorbing flavonols during autumn senescence. To test if flavonols protect against insects,...
Instead of red anthocyanins, birches synthesise colourless (to human eye), UV-absorbing flavonols during autumn senescence. To test if flavonols protect against insects, and if leaves with high or low amounts of flavonols differ in their photosynthetic functions, aphid-free and aphid-infested green and senescing birch leaves were collected from outdoor-grown trees and analysed. Photosynthetic parameters were greatly affected by the leaf chlorophyll content (i.e. the phase of senescence). Photochemical quenching and the amount of functional Photosystem I decreased linearly with chlorophyll content, while FV/FM (Photosystem II functionality) decreased strongly only at the end of senescence. Non-photochemical quenching of excitation energy (NPQ) increased towards the end of senescence. However, no significant differences in the total flavonol amounts, nor in individual flavonol species, were found between aphid-free and aphid-infested leaves, suggesting that flavonols play no role in defence against aphid herbivory. Interestingly, both green and senescing leaves with a high flavonol content showed low FV/FM values. High flavonol content slowed down PSII photoinhibition and improved recovery, but only in green leaves. Previously, we proposed that anthocyanins provide an additional sink for photosynthates at the nitrogen resorption phase during autumn senescence, and the present data may suggest that flavonol synthesis plays a similar role.
Topics: Aphids; Plant Leaves; Animals; Photosystem II Protein Complex; Flavonols; Betula; Photosynthesis; Chlorophyll
PubMed: 38885004
DOI: 10.1242/bio.060325 -
Inhibition of human starch digesting enzymes and intestinal glucose transport by walnut polyphenols.Food Research International (Ottawa,... Aug 2024One approach to controlling type 2 diabetes (T2D) is to lower postprandialglucose spikesby slowing down the digestion of carbohydrates and the absorption of glucose in...
One approach to controlling type 2 diabetes (T2D) is to lower postprandialglucose spikesby slowing down the digestion of carbohydrates and the absorption of glucose in the small intestine. The consumption of walnuts is associated with a reduced risk of chronic diseases such as T2D, suggested to be partly due to the high content of (poly)phenols. This study evaluated, for the first time, the inhibitory effect of a (poly)phenol-rich walnut extract on human carbohydrate digesting enzymes (salivary and pancreatic α-amylases, brush border sucrase-isomaltase) and on glucose transport across fully differentiated human intestinal Caco-2/TC7 monolayers. The walnut extract was rich in multiple (poly)phenols (70 % w/w) as analysed by Folin-Ciocalteau and by LCMS. It exhibited potent inhibition of both human salivary (IC: 32.2 ± 2.5 µg walnut (poly)phenols (WP)/mL) and pancreatic (IC: 56.7 ± 1.7 µg WP/mL) α-amylases, with weaker effects on human sucrase (IC: 990 ± 20 µg WP/mL), maltase (IC: 1300 ± 80 µg WP/mL), and isomaltase (IC: 830 ± 60 µg WP/mL) activities. Selected individual walnut (poly)phenols inhibited human salivary α-amylase in the order: 1,3,4,6-tetragalloylglucose > ellagic acid pentoside > 1,2,6-tri-O-galloyl-β-D-glucopyranose, with no inhibition by ellagic acid, gallic acid and 4-O-methylgallic acid. The (poly)phenol-rich walnut extract also attenuated (up to 59 %) the transfer of 2-deoxy-D-glucose across differentiated Caco-2/TC7 cell monolayers. This is the first report on the effect of (poly)phenol-rich extracts from any commonly-consumed nut kernel on any human starch-digesting enzyme, and suggests a mechanism through which walnut consumption may lower postprandial glucose spikes and contribute to their proposed health benefits.
Topics: Humans; Polyphenols; Juglans; Caco-2 Cells; Glucose; Plant Extracts; Digestion; Nuts; Starch; alpha-Amylases; Biological Transport; Sucrase-Isomaltase Complex
PubMed: 38876610
DOI: 10.1016/j.foodres.2024.114572 -
Bioorganic & Medicinal Chemistry Jul 2024Targeted protein degradation (TPD), employing proteolysis-targeting chimeras (PROTACs) composed of ligands for both a target protein and ubiquitin ligase (E3) to...
Targeted protein degradation (TPD), employing proteolysis-targeting chimeras (PROTACs) composed of ligands for both a target protein and ubiquitin ligase (E3) to redirect the ubiquitin-proteasome system (UPS) to the target protein, has emerged as a promising strategy in drug discovery. However, despite the vast number of E3 ligases, the repertoire of E3 ligands utilized in PROTACs remains limited. Here, we report the discovery of a small-molecule degron with a phenylpropionic acid skeleton, derived from a known ligand of S-phase kinase-interacting protein 2 (Skp2), an E3 ligase. We used this degron to design PROTACs inducing proteasomal degradation of HaloTag-fused proteins, and identified key structural relationships. Surprisingly, our mechanistic studies excluded the involvement of Skp2, suggesting that this degron recruits other protein(s) within the UPS.
Topics: Humans; S-Phase Kinase-Associated Proteins; Small Molecule Libraries; Proteolysis; Phenylpropionates; Structure-Activity Relationship; Proteasome Endopeptidase Complex; Molecular Structure; Ligands; HEK293 Cells; Degrons
PubMed: 38870716
DOI: 10.1016/j.bmc.2024.117789 -
Nature Communications Jun 2024Cryptophytes are ancestral photosynthetic organisms evolved from red algae through secondary endosymbiosis. They have developed alloxanthin-chlorophyll a/c2-binding...
Cryptophytes are ancestral photosynthetic organisms evolved from red algae through secondary endosymbiosis. They have developed alloxanthin-chlorophyll a/c2-binding proteins (ACPs) as light-harvesting complexes (LHCs). The distinctive properties of cryptophytes contribute to efficient oxygenic photosynthesis and underscore the evolutionary relationships of red-lineage plastids. Here we present the cryo-electron microscopy structure of the Photosystem II (PSII)-ACPII supercomplex from the cryptophyte Chroomonas placoidea. The structure includes a PSII dimer and twelve ACPII monomers forming four linear trimers. These trimers structurally resemble red algae LHCs and cryptophyte ACPI trimers that associate with Photosystem I (PSI), suggesting their close evolutionary links. We also determine a Chl a-binding subunit, Psb-γ, essential for stabilizing PSII-ACPII association. Furthermore, computational calculation provides insights into the excitation energy transfer pathways. Our study lays a solid structural foundation for understanding the light-energy capture and transfer in cryptophyte PSII-ACPII, evolutionary variations in PSII-LHCII, and the origin of red-lineage LHCIIs.
Topics: Photosystem II Protein Complex; Light-Harvesting Protein Complexes; Cryptophyta; Cryoelectron Microscopy; Photosynthesis; Models, Molecular; Energy Transfer; Photosystem I Protein Complex; Chlorophyll A
PubMed: 38866834
DOI: 10.1038/s41467-024-49453-0 -
Redox Biology Aug 2024Hydrogen sulfide (HS) has recently been recognized as an important gaseous transmitter with multiple physiological effects in various species. Previous studies have...
Hydrogen sulfide (HS) has recently been recognized as an important gaseous transmitter with multiple physiological effects in various species. Previous studies have shown that HS alleviated heat-induced ganoderic acids (GAs) biosynthesis, an important quality index of Ganoderma lucidum. However, a comprehensive understanding of the physiological effects and molecular mechanisms of HS in G. lucidum remains unexplored. In this study, we found that heat treatment reduced the mitochondrial membrane potential (MMP) and mitochondrial DNA copy number (mtDNAcn) in G. lucidum. Increasing the intracellular HS concentration through pharmacological and genetic means increased the MMP level, mtDNAcn, oxygen consumption rate level and ATP content under heat treatment, suggesting a role for HS in mitigating heat-caused mitochondrial damage in G. lucidum. Further results indicated that HS activates sulfide-quinone oxidoreductase (SQR) and complex III (Com III), thereby maintaining mitochondrial homeostasis under heat stress in G. lucidum. Moreover, SQR also mediated the negative regulation of HS to GAs biosynthesis under heat stress. Furthermore, SQR might be persulfidated under heat stress in G. lucidum. Thus, our study reveals a novel physiological function and molecular mechanism of HS signalling under heat stress in G. lucidum with broad implications for research on the environmental response of microorganisms.
Topics: Hydrogen Sulfide; Reishi; Triterpenes; Mitochondria; Homeostasis; Heat-Shock Response; Membrane Potential, Mitochondrial; Quinone Reductases; DNA, Mitochondrial; Electron Transport Complex III
PubMed: 38865903
DOI: 10.1016/j.redox.2024.103227 -
Diagnostic Pathology Jun 2024Osteosarcoma is a bone tumor that is characterized by high malignancy and a high mortality rate, and that originates from primitive osteoblastic mesenchymal cells and is...
BACKGROUND
Osteosarcoma is a bone tumor that is characterized by high malignancy and a high mortality rate, and that originates from primitive osteoblastic mesenchymal cells and is most common in rapidly growing long bones. PSMD14, also known as RPN11 or POH1, is a member of the JAMM isopeptidase family, which is able to remove the substrate protein ubiquitination label, thereby regulating the stability and function of the substrate protein. In this study, we explored the expression and potential biological significance of the PSMD14 deubiquitinating enzyme in osteosarcoma.
METHODS
Immunohistochemical methods were used to detect the expression of PSMD14 in biopsies of 91 osteosarcoma patients, and the specimens were classified into high and low PSMD14 expression groups. The correlation between PSMD14 expression and clinical indicators and prognosis was compared.SiRNA was used to downregulate PSMD14 in two osteosarcoma cell lines (HOS and SJSA-1), and the effects of downregulation of PSMD14 on the viability, proliferation, and invasion ability of osteosarcoma cells were analyzed.
RESULTS
We identified significant differences in recurrence, metastasis, and survival time of the osteosarcoma patients on the basis of PSMD14 expression. High expression of PSMD14 in osteosarcoma patients was associated with a low survival rate and high risk of metastasis and recurrence. Down-regulation of PSMD14 inhibited the viability, proliferation, and invasiveness of osteosarcoma cell lines.
CONCLUSIONS
PSMD14 may be a new prognostic marker and therapeutic target for osteosarcoma.
Topics: Osteosarcoma; Humans; Bone Neoplasms; Male; Biomarkers, Tumor; Female; Prognosis; Cell Line, Tumor; Adult; Cell Proliferation; Proteasome Endopeptidase Complex; Adolescent; Young Adult; Middle Aged; Neoplasm Invasiveness; Trans-Activators
PubMed: 38863002
DOI: 10.1186/s13000-024-01489-y -
Cell Death & Disease Jun 2024Low glucose is a common microenvironment for rapidly growing solid tumors, which has developed multiple approaches to survive under glucose deprivation. However, the...
Low glucose is a common microenvironment for rapidly growing solid tumors, which has developed multiple approaches to survive under glucose deprivation. However, the specific regulatory mechanism remains largely elusive. In this study, we demonstrate that glucose deprivation, while not amino acid or serum starvation, transactivates the expression of DCAF1. This enhances the K48-linked polyubiquitination and proteasome-dependent degradation of Rheb, inhibits mTORC1 activity, induces autophagy, and facilitates cancer cell survival under glucose deprivation conditions. This study identified DCAF1 as a new cellular glucose sensor and uncovered new insights into mechanism of DCAF1-mediated inactivation of Rheb-mTORC1 pathway for promoting cancer cell survival in response to glucose deprivation.
Topics: Humans; Mechanistic Target of Rapamycin Complex 1; Ras Homolog Enriched in Brain Protein; Glucose; Cell Survival; Cell Line, Tumor; Autophagy; Ubiquitination; Signal Transduction; Neoplasms; Proteasome Endopeptidase Complex; HEK293 Cells; Monomeric GTP-Binding Proteins; Ubiquitin-Protein Ligases
PubMed: 38862475
DOI: 10.1038/s41419-024-06808-1 -
Nan Fang Yi Ke Da Xue Xue Bao = Journal... May 2024To analyze the expression level of ATP5A1 in gastric carcinoma and its influence on the prognosis of the patients and glucose metabolism in the tumor cells.
OBJECTIVE
To analyze the expression level of ATP5A1 in gastric carcinoma and its influence on the prognosis of the patients and glucose metabolism in the tumor cells.
METHODS
We retrospectively analyzed the data of 115 patients undergoing radical resection of gastric carcinoma in our hospital from February, 2013 to November, 2016. ATP5A1 expression in the surgical specimens were detected using immunohistochemistry, and the long-term prognosis of the patients with high (=58) and low ATP5A1 expression (=57) were analyzed. In gastric carcinoma MGC803 cells, the effects of lentivirus-mediated ATP5A1 knockdown or overexpression on glucose metabolism were investigated. We also observed the growth and glucose metabolism of xenografts derived from MGC803 cells with ATP5A1 knockdown or overexpression in nude mice.
RESULTS
ATP5A1 was significantly overexpressed in gastric carcinoma tissues in close correlation with blood CEA and CA19-9 levels, pathological grade, T stage and N stage ( < 0.05). ATP5A1 overexpression was an independent risk factor for a significantly lowered 5-year survival rate of patients with gastric carcinoma ( < 0.05). ROC curve analysis demonstrated the predictive value of high ATP5A1 expression for the patients'prognosis ( < 0.001). In MGC803 cells, ATP5A1 overexpression significantly upregulated cellular glucose uptake and lactate production and increased the protein levels of HK2, PFK1, and LDHA ( < 0.05), while ATP5A1 knockdown produced the opposite changes ( < 0.05). In the tumor-bearing mice, overexpression of ATP5A1 increased glucose metabolism of the tumor cells and promoted tumor growth ( < 0.05). Overexpression of ATP5A1 promoted the expressions of p-JNK and p-JUN in MGC803 cells ( < 0.05), and the JNK inhibitor SP600125 significantly inhibited the enhancement of cellular glucose metabolism induced by ATP5A1 overexpression ( < 0.05).
CONCLUSION
High ATP5A1 expression in gastric cancer is associated a poor long-term prognosis of the patients, and its effect is mediated at least partly by promoting glucose metabolism of the cells through the JNK/JUN pathway.
Topics: Stomach Neoplasms; Humans; Prognosis; Animals; Cell Line, Tumor; Mice; Mice, Nude; Retrospective Studies; Glucose; Female; Male; Survival Rate; Mitochondrial Proton-Translocating ATPases
PubMed: 38862456
DOI: 10.12122/j.issn.1673-4254.2024.05.20 -
PloS One 2024All-trans retinoic acid (ATRA), recognized as the principal and most biologically potent metabolite of vitamin A, has been identified for its inhibitory effects on...
All-trans retinoic acid (ATRA), recognized as the principal and most biologically potent metabolite of vitamin A, has been identified for its inhibitory effects on hepatitis B virus (HBV) replication. Nevertheless, the underlying mechanism remains elusive. The present study reveals that ATRA induces E6-associated protein (E6AP)-mediated proteasomal degradation of HBx to suppress HBV replication in human hepatoma cells in a p53-dependent pathway. For this effect, ATRA induced promoter hypomethylation of E6AP in the presence of HBx, which resulted in the upregulation of E6AP levels in HepG2 but not in Hep3B cells, emphasizing the p53-dependent nature of this effect. As a consequence, ATRA augmented the interaction between E6AP and HBx, resulting in substantial ubiquitination of HBx and consequent reduction in HBx protein levels in both the HBx overexpression system and the in vitro HBV replication model. Additionally, the knockdown of E6AP under ATRA treatment reduced the interaction between HBx and E6AP and decreased the ubiquitin-dependent proteasomal degradation of HBx, which prompted a recovery of HBV replication in the presence of ATRA, as confirmed by increased levels of intracellular HBV proteins and secreted HBV levels. This study not only contributes to the understanding of the complex interactions between ATRA, p53, E6AP, and HBx but also provides an academic basis for the clinical employment of ATRA in the treatment of HBV infection.
Topics: Humans; Viral Regulatory and Accessory Proteins; Trans-Activators; Proteasome Endopeptidase Complex; Virus Replication; Hepatitis B virus; Tretinoin; Tumor Suppressor Protein p53; Ubiquitin-Protein Ligases; Hep G2 Cells; Down-Regulation; Ubiquitination; Proteolysis; Promoter Regions, Genetic; DNA Methylation; Cell Line, Tumor
PubMed: 38861553
DOI: 10.1371/journal.pone.0305350 -
Parasitology Research Jun 2024Mastophorus muris (Gmelin, 1790) is a globally distributed parasitic nematode of broad range mammals. The taxonomy within the genus Mastophorus and the cryptic diversity...
Mastophorus muris (Gmelin, 1790) is a globally distributed parasitic nematode of broad range mammals. The taxonomy within the genus Mastophorus and the cryptic diversity among the genus are controversial among taxonomists. This study provides a detailed morphological description of M. muris from Mus musculus combined with a molecular phylogenetic approach. Moreover, descriptions and molecular data of M. muris from non-Mus rodents and wildcats complement our findings and together provide new insights into their taxonomy. The analysis of M. muris was based on light microscopy and scanning electron microscopy. The morphological description focused on the dentition pattern of the two trilobed pseudolabia. Additionally, we described the position of the vulva, arrangement of caudal pairs of papillae, spicules and measured specimens from both sexes and the eggs. For the molecular phylogenetic approach, we amplified the small subunit ribosomal RNA gene and the internal transcribed spacer, and the cytochrome c oxidase subunit 1. Mastophorus morphotypes based on dentition patterns and phylogenetic clustering indicate a subdivision of the genus in agreement with their host. We recognize two groups without a change to formal taxonomy: One group including those specimens infecting Mus musculus, and the second group including organisms infecting non-Mus rodents. Our genetic and morphological data shed light into the cryptic diversity within the genus Mastopohorus. We identified two host-associated groups of M. muris. The described morphotypes and genotypes of M. muris allow a consistent distinction between host-associated parasites.
Topics: Animals; Phylogeny; Female; Male; Mice; Microscopy, Electron, Scanning; Spiruroidea; Electron Transport Complex IV; Genetic Variation; Sequence Analysis, DNA; Microscopy; DNA, Helminth; DNA, Ribosomal; DNA, Ribosomal Spacer; Cluster Analysis; Molecular Sequence Data
PubMed: 38856825
DOI: 10.1007/s00436-024-08259-1