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Keywords = pyrophosphatases

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17 pages, 6119 KiB  
Article
Phosphorus Functional Genes Control Rice Yield via Microbial Biomass Phosphorus and Plant Phosphorus Uptake in a Rice–Oilseed Rape Rotation System Compared with a Rice–Wheat Rotation System
by Qingyue Zhang, Weijia Yu, Min Li, Wenlong Cheng, Shengchang Huai, Yuwen Jin, Guihua Li, Ji Wu and Changai Lu
Agronomy 2025, 15(4), 866; https://doi.org/10.3390/agronomy15040866 - 30 Mar 2025
Viewed by 1382
Abstract
Crop rotation and microbial driving force significantly influence soil phosphorus (P) bioavailability and crop yield. However, differences in underlying microbial mechanisms in rotations remain unclear. We examined rice yield, P uptake, soil and microbial P contents, enzyme activity, and P functional genes over [...] Read more.
Crop rotation and microbial driving force significantly influence soil phosphorus (P) bioavailability and crop yield. However, differences in underlying microbial mechanisms in rotations remain unclear. We examined rice yield, P uptake, soil and microbial P contents, enzyme activity, and P functional genes over six years (2016–2022) to elucidate microbial mechanisms driving rice yield in rice–wheat (RW) and rice–oilseed rape (RO) rotations. RO significantly increased rice yield and plant P uptake by 9.17% and 20.70%, respectively, compared to RW. Soil total (TP) and available (AP) P contents were significantly lower (4.83% and 18.31%, respectively) under RO than RW, whereas microbial biomass phosphorus (MBP) and acid phosphatase activity (EP) were greater (39.40% and 128.45%, respectively). PICRUSt2 results revealed that RO increased phoA phoB (alkaline phosphatase), phnX (phosphonoacetaldehyde hydrolase [EC:3.11.1.1]), gcd (Quinoprotein glucose dehydrogenase [EC:1.1.5.2]), and ppaC (manganese-dependent inorganic pyrophosphatase) and decreased phnD (phosphonate transport system substrate-binding protein), ugpE (sn-glycerol 3-phosphate transport system permease protein), ugpA (sn-glycerol 3-phosphate transport system permease protein), and phnO ((aminoalkyl)phosphonate N-acetyltransferase [EC:2.3.1.280]) abundance. Random forest analysis showed that ppaC, phnD, gcd, and phnX were important for rice yield and plant P uptake. Partial least squares analysis revealed that RO indirectly increased rice yield by influencing MBP and affecting plant P uptake through P functional genes. Overall, RO improves rice yield and P bioavailability by altering P functional genes (ppaC, phnD, gcd, and phnX), providing new perspectives on crop–microorganism interactions and resource use efficiency. Full article
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17 pages, 5140 KiB  
Article
Marker-Assisted Backcross Breeding of Drought-Tolerant Maize Lines Transformed by Vacuolar H+-Pyrophosphatase Gene (AnVP1) from Ammopiptanthus nanus
by Yang Cao, Haoqiang Yu, Xin Guo, Yanli Lu, Wanchen Li and Fengling Fu
Plants 2025, 14(6), 926; https://doi.org/10.3390/plants14060926 - 15 Mar 2025
Viewed by 689
Abstract
Maize is highly sensitive to water deficit but has high transpiration and biomass production, leading to a substantial water demand. Genetic engineering can overcome reproductive isolation and utilize drought-tolerant genes from distant species. Ammopiptanthus nanus is a relic of the Tertiary glaciation that [...] Read more.
Maize is highly sensitive to water deficit but has high transpiration and biomass production, leading to a substantial water demand. Genetic engineering can overcome reproductive isolation and utilize drought-tolerant genes from distant species. Ammopiptanthus nanus is a relic of the Tertiary glaciation that can adapt to harsh environmental conditions. In our previous study, five maize homozygous T8 lines overexpressing the AnVP1 gene from Ammopiptanthus nanus were generated and showed the enhancement of drought tolerance. However, the recipient inbred line Zh-1 was poor in yield and agronomic performance. In the present study, the AnVP1 gene was backcrossed from donor parent L10 (one of the five T8 lines) into recurrent parent Chang 7-2 (one of the elite parents of the commercial hybrid Zhengdan 958). In total, 103 InDel markers were developed and used for assisted background selection. After two generations of foreground selection through glufosinate spraying, the detection of CP4 EPSP MAb1 strips, and the PCR amplification of the AnVP1 gene, along with the similarity of agronomic traits to the recurrent parent, and background selection assisted by these InDel markers, the transgenic AnVP1 gene became homozygous in the BC2 lines. The average recovery rate of the genetic background of the recurrent parent reached 74.80% in the BC1 population and 91.93% in the BC2 population, respectively. The results of RT-PCR and RT-qPCR indicated the stable expression of the AnVP1 gene in the two ultimately selected BC2F3 lines, BC2-36-12 and BC2-5-15. The drought tolerance of these two BC2F3 lines were significantly improved compared to the recurrent parent Chang 7-2, as revealed by their wilting phenotype and survival rate of seedlings. This improvement was related to the enhancement of water-retention ability, as indicated by higher RWC and the reduction in damage, as shown by the decrease in REL, MDA, and H2O2 under drought stress. The result of field evaluation in two arid and semi-arid environments indicated that the drought tolerance of Chang 7-2 was significantly improved. This study suggests that the improved Chang 7-2 can be crossed with Zheng 58 to develop the transgenic commercial hybrid Zhengdan 958. Full article
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18 pages, 5105 KiB  
Article
Biochar Co-Applied with Lime Enhances Soil Phosphorus Availability via Microbial and Enzymatic Modulation of Paddy Soil
by Yang Zhang, Caidi Yang, Jun Wang and Shenggao Lu
Microorganisms 2025, 13(3), 582; https://doi.org/10.3390/microorganisms13030582 - 4 Mar 2025
Cited by 1 | Viewed by 949
Abstract
Soil microorganisms play a crucial role in improving soil phosphorus (P) availability. However, few studies have explored the changes in microbial community structure and their underlying mechanisms for improving soil P availability with the application of biochar and lime. Three kinds of biochar, [...] Read more.
Soil microorganisms play a crucial role in improving soil phosphorus (P) availability. However, few studies have explored the changes in microbial community structure and their underlying mechanisms for improving soil P availability with the application of biochar and lime. Three kinds of biochar, made from rice straw (SB), Chinese fir wood sawdust (WB), and pig manure (MB), alone and with lime (SBL, WBL, and MBL), were applied to paddy soil to reveal the biochemical mechanisms for enhancing soil P availability. High-throughput sequencing and real-time PCR were used to investigate soil microbial communities and P functional genes. The three biochars increased the soil’s available P in the order of MB > SB > WB. Biochar co-applied with lime increased the available P (Olsen-P by 169–209%) and inorganic P (Al-P by 53.4–161%, Fe-P by 96.3–198%, and Ca-P by 59.0–154%) more than biochar alone, compared to the control (CK). Both biochar alone and co-applied with lime increased the activities of alkaline phosphomonoesterase (ALP), phosphodiesterase (PD), and inorganic pyrophosphatase (IPP) by 369–806%, 28.4–67.3%, and 37.9–181%, respectively, while it decreased the activity of acidic phosphomonoesterase (ACP) by 15.1–44.0%, compared to CK. Biochar, both alone and co-applied with lime, reduced the copy number of phoC gene by 5.37–88.7%, while it increased the phoD, gcd, and pqqC genes by 51.3–533%, 62.1–275%, and 25.2–158%, respectively, compared to CK. A correlation analysis and partial least squares path modeling (PLS-PM) indicated that Olsen-P, Bray-1 P, and inorganic P were significantly positively correlated with the activities of ALP, PD, IPP, and the phoD gene. Biochar co-applied with lime increased the relative abundances of the phoD-harboring bacteria Proteobacteria, Firmicutes, and Acidobacteria, which promoted the transformation of P to the effective state. Meanwhile, the dominant species Anaerolinea, Ascomycota, Mucoromycota, and Chaetomium provided rich effective nutrients for the soil microorganisms by accelerating the decomposition of soil organic matter, thus promoting phosphatase activity. It could be inferred that the optimized microbial community structure improved phosphatase activity by increasing the phoD gene and available nutrients, thus promoting the soil P availability. Biochar co-applied with lime had a better effect on increasing the P availability and rice yields than biochar alone. Full article
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18 pages, 4442 KiB  
Article
Engineering Inorganic Pyrophosphate Metabolism as a Strategy to Generate a Fluoride-Resistant Saccharomyces cerevisiae Strain
by José R. Perez-Castiñeira, Francisco J. Ávila-Oliva and Aurelio Serrano
Microorganisms 2025, 13(2), 226; https://doi.org/10.3390/microorganisms13020226 - 21 Jan 2025
Viewed by 2789
Abstract
Fluorine accounts for 0.3 g/kg of the Earth’s crust, being widely distributed in the environment as fluoride. The toxic effects of this anion in humans and other organisms have been known for a long time. Fluoride has been reported to alter several cellular [...] Read more.
Fluorine accounts for 0.3 g/kg of the Earth’s crust, being widely distributed in the environment as fluoride. The toxic effects of this anion in humans and other organisms have been known for a long time. Fluoride has been reported to alter several cellular processes although the mechanisms involved are largely unknown. Inorganic pyrophosphatases (PPases) are ubiquitous enzymes that hydrolyze inorganic pyrophosphate (PPi), a metabolite generated from ATP. In Saccharomyces cerevisiae, the enzyme responsible for PPi hydrolysis in the cytosol (IPP1) is strongly inhibited by fluoride in vitro. The essentiality of IPP1 for growth has been previously demonstrated using YPC3, a yeast mutant with conditional expression of the corresponding gene. Here, YPC3 was used to generate cells that tolerate high concentrations of fluoride by (a) the overexpression of IPP1 or its human ortholog, or (b) the substitution of IPP1 by the fluoride-insensitive PPase from Streptococcus mutans. The results obtained suggest that maintaining appropriate levels of PPase activity in the cytosol is essential for the adaptation of S. cerevisiae to high fluoride concentrations. The increase in fluoride tolerance allows YPC3 cells transformed with suitable plasmids to be selected on rich non-selective medium supplemented with this anion. Full article
(This article belongs to the Special Issue New Methods in Microbial Research, 4th Edition)
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22 pages, 23356 KiB  
Article
Conformational Dynamics of Mitochondrial Inorganic Pyrophosphatase hPPA2 and Its Changes Caused by Pathogenic Mutations
by Ekaterina Bezpalaya, Svetlana Kurilova, Nataliya Vorobyeva and Elena Rodina
Life 2025, 15(1), 100; https://doi.org/10.3390/life15010100 - 15 Jan 2025
Cited by 1 | Viewed by 923
Abstract
Inorganic pyrophosphatases, or PPases, are ubiquitous enzymes whose activity is necessary for a large number of biosynthetic reactions. The catalytic function of PPases is dependent on certain conformational changes that have been previously characterized based on the comparison of the crystal structures of [...] Read more.
Inorganic pyrophosphatases, or PPases, are ubiquitous enzymes whose activity is necessary for a large number of biosynthetic reactions. The catalytic function of PPases is dependent on certain conformational changes that have been previously characterized based on the comparison of the crystal structures of various complexes. The current work describes the conformational dynamics of a structural model of human mitochondrial pyrophosphatase hPPA2 using molecular dynamics simulation, all-atom principal component analysis, and coarse-grained normal mode analysis. In addition to the wild-type enzyme, four mutant variants of hPPA2 were characterized that correspond to the natural pathogenic variants causing severe mitochondrial dysfunction and cardio pathologies. As a result, we identified the global type of flexible motion that seems to be shared by other dimeric PPases. This motion is discussed in terms of the allosteric behavior of the protein. Analysis of the observed conformational dynamics revealed the formation of a binding site for anionic ligands in the active site that could be relevant to enzyme catalysis. Based on the comparison of the wild-type and mutant PPases dynamics, we suggest the possible molecular mechanisms of the functional incompetence of hPPA2 caused by mutations. The results of this work allow for deeper insight into the structural basis of PPase function and the possible effects of pathogenic mutations on the protein structure and function. Full article
(This article belongs to the Special Issue Applications of Molecular Dynamics to Biological Systems)
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21 pages, 9220 KiB  
Review
Structural and Functional Integration of Tissue-Nonspecific Alkaline Phosphatase Within the Alkaline Phosphatase Superfamily: Evolutionary Insights and Functional Implications
by Iliass Imam, Gilles Jean Philippe Rautureau, Sébastien Violot, Eva Drevet Mulard, David Magne and Lionel Ballut
Metabolites 2024, 14(12), 659; https://doi.org/10.3390/metabo14120659 - 25 Nov 2024
Cited by 2 | Viewed by 1368
Abstract
Phosphatases are enzymes that catalyze the hydrolysis of phosphate esters. They play critical roles in diverse biological processes such as extracellular nucleotide homeostasis, transport of molecules across membranes, intracellular signaling pathways, or vertebrate mineralization. Among them, tissue-nonspecific alkaline phosphatase (TNAP) is today increasingly [...] Read more.
Phosphatases are enzymes that catalyze the hydrolysis of phosphate esters. They play critical roles in diverse biological processes such as extracellular nucleotide homeostasis, transport of molecules across membranes, intracellular signaling pathways, or vertebrate mineralization. Among them, tissue-nonspecific alkaline phosphatase (TNAP) is today increasingly studied, due to its ubiquitous expression and its ability to dephosphorylate a very broad range of substrates and participate in several different biological functions. For instance, TNAP hydrolyzes inorganic pyrophosphate (PPi) to allow skeletal and dental mineralization. Additionally, TNAP hydrolyzes pyridoxal phosphate to allow cellular pyridoxal uptake, and stimulate vitamin B6-dependent reactions. Furthermore, TNAP has been identified as a key enzyme in non-shivering adaptive thermogenesis, by dephosphorylating phosphocreatine in the mitochondrial creatine futile cycle. This latter recent discovery and others suggest that the list of substrates and functions of TNAP may be much longer than previously thought. In the present review, we sought to examine TNAP within the alkaline phosphatase (AP) superfamily, comparing its sequence, structure, and evolutionary trajectory. The AP superfamily, characterized by a conserved central folding motif of a mixed beta-sheet flanked by alpha-helices, includes six subfamilies: AP, arylsulfatases (ARS), ectonucleotide pyrophosphatases/phosphodiesterases (ENPP), phosphoglycerate mutases (PGM), phosphonoacetate hydrolases, and phosphopentomutases. Interestingly, TNAP and several ENPP family members appear to participate in the same metabolic pathways and functions. For instance, extra-skeletal mineralization in vertebrates is inhibited by ENPP1-mediated ATP hydrolysis into the mineralization inhibitor PPi, which is hydrolyzed by TNAP expressed in the skeleton. Better understanding how TNAP and other AP family members differ structurally will be very useful to clarify their complementary functions. Structurally, TNAP shares the conserved catalytic core with other AP superfamily members but has unique features affecting substrate specificity and activity. The review also aims to highlight the importance of oligomerization in enzyme stability and function, and the role of conserved metal ion coordination, particularly magnesium, in APs. By exploring the structural and functional diversity within the AP superfamily, and discussing to which extent its members exert redundant, complementary, or specific functions, this review illuminates the evolutionary pressures shaping these enzymes and their broad physiological roles, offering insights into TNAP’s multifunctionality and its implications for health and disease. Full article
(This article belongs to the Section Cell Metabolism)
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16 pages, 2379 KiB  
Article
Na+ Translocation Dominates over H+-Translocation in the Membrane Pyrophosphatase with Dual Transport Specificity
by Alexander V. Bogachev, Viktor A. Anashkin, Yulia V. Bertsova, Elena G. Zavyalova and Alexander A. Baykov
Int. J. Mol. Sci. 2024, 25(22), 11963; https://doi.org/10.3390/ijms252211963 - 7 Nov 2024
Cited by 1 | Viewed by 906
Abstract
Cation-pumping membrane pyrophosphatases (mPPases; EC 7.1.3.1) vary in their transport specificity from obligatory H+ transporters found in all kingdoms of life, to Na+/H+-co-transporters found in many prokaryotes. The available data suggest a unique “direct-coupling” mechanism of H+ [...] Read more.
Cation-pumping membrane pyrophosphatases (mPPases; EC 7.1.3.1) vary in their transport specificity from obligatory H+ transporters found in all kingdoms of life, to Na+/H+-co-transporters found in many prokaryotes. The available data suggest a unique “direct-coupling” mechanism of H+ transport, in which the transported proton is generated from nucleophilic water molecule. Na+ transport is best rationalized by assuming that the water-borne proton propels a prebound Na+ ion through the ion conductance channel (“billiard” mechanism). However, the “billiard” mechanism, in its simple form, is not applicable to the mPPases that simultaneously transport Na+ and H+ without evident competition between the cations (Na+,H+-PPases). In this study, we used a pyranine-based fluorescent assay to explore the relationship between the cation transport reactions catalyzed by recombinant Bacteroides vulgatus Na+,H+-PPase in membrane vesicles. Under appropriately chosen conditions, including the addition of an H+ ionophore to convert Na+ influx into equivalent H+ efflux, the pyranine signal measures either H+ or Na+ translocation. Using a stopped-flow version of this assay, we demonstrate that H+ and Na+ are transported by Na+,H+-PPase in a ratio of approximately 1:8, which is independent of Na+ concentration. These findings were rationalized using an “extended billiard” model, whose most likely variant predicts the kinetic limitation of Na+ delivery to the pump-loading site. Full article
(This article belongs to the Special Issue 25th Anniversary of IJMS: Advances in Biochemistry)
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17 pages, 8835 KiB  
Essay
Overexpression of the EuSIP5 Gene to Improve Drought Resistance in Tobacco
by Yueling Lin, Xi Chen, Degang Zhao and Chao Li
Horticulturae 2024, 10(9), 1010; https://doi.org/10.3390/horticulturae10091010 - 23 Sep 2024
Viewed by 1181
Abstract
Soluble inorganic pyrophosphatase (s-PPase), a pyrophosphate hydrolase, is crucial for various physiological processes including plant growth and development, metabolic functions, and responses to abiotic stresses. However, research on s-PPase in woody plants is limited. To investigate the potential role of soluble inorganic pyrophosphatase [...] Read more.
Soluble inorganic pyrophosphatase (s-PPase), a pyrophosphate hydrolase, is crucial for various physiological processes including plant growth and development, metabolic functions, and responses to abiotic stresses. However, research on s-PPase in woody plants is limited. To investigate the potential role of soluble inorganic pyrophosphatase in Eucommia ulmoides Oliver (E. ulmoides) in drought stress, the E. ulmoides soluble inorganic pyrophosphatase 5 (EuSIP5) cDNA sequence was amplified via RT-PCR. A bioinformatic analysis suggested that EuSIP5 may be an unstable amphipathic protein predominantly localized in the cytoplasm. In E. ulmoides, the highest expression of the EuSIP5 gene was detected in the leaves and pericarp of male plants from April to October, and in the leaves in July and September. Under drought conditions, the expression of EuSIP5 in E. ulmoides leaves was significantly greater than that in the control. An overexpression vector containing EuSIP5 was constructed and introduced into Nicotiana tabacum L. cv. Xanthi (N. tabacum L.). Compared with that in wild-type (WT) plants, wilting in N. tabacum L. EuSIP5-overexpressing (OE) plants was delayed by 4 days under drought stress. Additionally, the expression levels of the drought-related genes DET2, CYP85A1, P5CS, ERF1, F-box, and NCED1 were elevated in the leaves of transgenic N. tabacum L. Moreover, the activities of the protective enzymes peroxidase, superoxide dismutase, and catalase were significantly greater, whereas the malondialdehyde content was lower in the transgenic plants than in the WT plants. These findings suggest that the introduction of the EuSIP5 gene into N. tabacum L. enhances drought-related gene expression, increases antioxidant capacity, and reduces oxidative stress damage, thereby improving drought resistance. Full article
(This article belongs to the Section Biotic and Abiotic Stress)
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10 pages, 1535 KiB  
Article
Generation of Two-Line Restorer Line with Low Chalkiness Using Knockout of Chalk5 through CRISPR/Cas9 Editing
by Gucheng Fan, Jiefeng Jiang, Yu Long, Run Wang, Famao Liang, Haiyang Liu, Junying Xu, Xianjin Qiu and Zhixin Li
Biology 2024, 13(8), 617; https://doi.org/10.3390/biology13080617 - 15 Aug 2024
Cited by 2 | Viewed by 1489
Abstract
Chalkiness is an important grain quality trait in rice. Chalk5, encoding a vacuolar H+-translocating pyrophosphatase, is a major gene affecting both the percentage of grains with chalkiness (PGWC) and chalkiness degree (DEC) in rice. Reducing its expression can decrease both [...] Read more.
Chalkiness is an important grain quality trait in rice. Chalk5, encoding a vacuolar H+-translocating pyrophosphatase, is a major gene affecting both the percentage of grains with chalkiness (PGWC) and chalkiness degree (DEC) in rice. Reducing its expression can decrease both PGEC and DEC. In this study, the first exon of Chalk5 was edited in the elite restorer line 9311 using the CRISPR/Cas9 system and two knockout mutants were obtained, one of which did not contain the exogenous Cas9 cassette. PGWC and DEC were both significantly reduced in both mutants, while the seed setting ratio (SSR) was also significantly decreased. Staggered sowing experiments showed that the chalkiness of the mutants was insensitive to temperature during the grain-filling stage, and the head milled rice rate (HMRR) could be improved even under high-temperature conditions. Finally, in the hybrid background, the mutants showed significantly reduced PGWC and DEC without changes in other agronomic traits. The results provide important germplasm and allele resources for breeding high-yield rice varieties with superior quality, especially for high-yield indica hybrid rice varieties with superior quality in high-temperature conditions. Full article
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59 pages, 2461 KiB  
Review
From Classical to Alternative Pathways of 2-Arachidonoylglycerol Synthesis: AlterAGs at the Crossroad of Endocannabinoid and Lysophospholipid Signaling
by Fabienne Briand-Mésange, Isabelle Gennero, Juliette Salles, Stéphanie Trudel, Lionel Dahan, Jérôme Ausseil, Bernard Payrastre, Jean-Pierre Salles and Hugues Chap
Molecules 2024, 29(15), 3694; https://doi.org/10.3390/molecules29153694 - 4 Aug 2024
Cited by 2 | Viewed by 4030
Abstract
2-arachidonoylglycerol (2-AG) is the most abundant endocannabinoid (EC), acting as a full agonist at both CB1 and CB2 cannabinoid receptors. It is synthesized on demand in postsynaptic membranes through the sequential action of phosphoinositide-specific phospholipase Cβ1 (PLCβ1) and diacylglycerol lipase α (DAGLα), contributing [...] Read more.
2-arachidonoylglycerol (2-AG) is the most abundant endocannabinoid (EC), acting as a full agonist at both CB1 and CB2 cannabinoid receptors. It is synthesized on demand in postsynaptic membranes through the sequential action of phosphoinositide-specific phospholipase Cβ1 (PLCβ1) and diacylglycerol lipase α (DAGLα), contributing to retrograde signaling upon interaction with presynaptic CB1. However, 2-AG production might also involve various combinations of PLC and DAGL isoforms, as well as additional intracellular pathways implying other enzymes and substrates. Three other alternative pathways of 2-AG synthesis rest on the extracellular cleavage of 2-arachidonoyl-lysophospholipids by three different hydrolases: glycerophosphodiesterase 3 (GDE3), lipid phosphate phosphatases (LPPs), and two members of ecto-nucleotide pyrophosphatase/phosphodiesterases (ENPP6–7). We propose the names of AlterAG-1, -2, and -3 for three pathways sharing an ectocellular localization, allowing them to convert extracellular lysophospholipid mediators into 2-AG, thus inducing typical signaling switches between various G-protein-coupled receptors (GPCRs). This implies the critical importance of the regioisomerism of both lysophospholipid (LPLs) and 2-AG, which is the object of deep analysis within this review. The precise functional roles of AlterAGs are still poorly understood and will require gene invalidation approaches, knowing that both 2-AG and its related lysophospholipids are involved in numerous aspects of physiology and pathology, including cancer, inflammation, immune defenses, obesity, bone development, neurodegeneration, or psychiatric disorders. Full article
(This article belongs to the Special Issue Bioactive Lipids in Inflammatory Diseases)
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13 pages, 3461 KiB  
Article
DCTPP1 Expression as a Predictor of Chemotherapy Response in Luminal A Breast Cancer Patients
by Juan P. Muñoz, Diego Soto-Jiménez and Gloria M. Calaf
Biomedicines 2024, 12(8), 1732; https://doi.org/10.3390/biomedicines12081732 - 2 Aug 2024
Cited by 2 | Viewed by 1632
Abstract
Breast cancer (BRCA) remains a significant global health challenge due to its prevalence and lethality, exacerbated by the development of resistance to conventional therapies. Therefore, understanding the molecular mechanisms underpinning chemoresistance is crucial for improving therapeutic outcomes. Human deoxycytidine triphosphate pyrophosphatase 1 (DCTPP1) [...] Read more.
Breast cancer (BRCA) remains a significant global health challenge due to its prevalence and lethality, exacerbated by the development of resistance to conventional therapies. Therefore, understanding the molecular mechanisms underpinning chemoresistance is crucial for improving therapeutic outcomes. Human deoxycytidine triphosphate pyrophosphatase 1 (DCTPP1) has emerged as a key player in various cancers, including BRCA. DCTPP1, involved in nucleotide metabolism and maintenance of genomic stability, has been linked to cancer cell proliferation, survival, and drug resistance. This study evaluates the role of DCTPP1 in BRCA prognosis and chemotherapy response. Data from the Cancer Genome Atlas Program (TCGA), Genotype-Tissue Expression (GTEx), and Gene Expression Omnibus (GEO) repositories, analyzed using GEPIA and Kaplan–Meier Plotter, indicate that high DCTPP1 expression correlates with poorer overall survival and increased resistance to chemotherapy in BRCA patients. Further analysis reveals that DCTPP1 gene expression is up-regulated in non-responders to chemotherapy, particularly in estrogen receptor (ER)-positive, luminal A subtype patients, with significant predictive power. Additionally, in vitro studies show that DCTPP1 gene expression increases in response to 5-fluorouracil and doxorubicin treatments in luminal A BRCA cell lines, suggesting a hypothetical role in chemoresistance. These findings highlight DCTPP1 as a potential biomarker for predicting chemotherapy response and as a therapeutic target to enhance chemotherapy efficacy in BRCA patients. Full article
(This article belongs to the Collection Feature Papers in Gene and Cell Therapy)
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16 pages, 10571 KiB  
Article
Activation of Nuclear Factor Erythroid 2-Related Factor 2 Transcriptionally Upregulates Ectonucleotide Pyrophosphatase/Phosphodiesterase 1 Expression and Inhibits Ectopic Calcification in Mice
by Ida Tomomi, Hiroyuki Kanzaki, Miho Shimoyama, Syunnosuke Tohyama, Misao Ishikawa, Yuta Katsumata, Chihiro Arai, Satoshi Wada, Shugo Manase and Hiroshi Tomonari
Antioxidants 2024, 13(8), 896; https://doi.org/10.3390/antiox13080896 - 24 Jul 2024
Cited by 1 | Viewed by 1885
Abstract
Calcification plays a key role in biological processes, and breakdown of the regulatory mechanism results in a pathological state such as ectopic calcification. We hypothesized that ENPP1, the enzyme that produces the calcification inhibitor pyrophosphate, is transcriptionally regulated by Nrf2, and that Nrf2 [...] Read more.
Calcification plays a key role in biological processes, and breakdown of the regulatory mechanism results in a pathological state such as ectopic calcification. We hypothesized that ENPP1, the enzyme that produces the calcification inhibitor pyrophosphate, is transcriptionally regulated by Nrf2, and that Nrf2 activation augments ENPP1 expression to inhibit ectopic calcification. Cell culture experiments were performed using mouse osteoblastic cell line MC3T3-E1. Nrf2 was activated by 5-aminolevulinic acid and sodium ferrous citrate. Nrf2 overexpression was induced by the transient transfection of an Nrf2 expression plasmid. ENPP1 expression was monitored by real-time RT-PCR. Because the promoter region of ENPP1 contains several Nrf2-binding sites, chromatin immunoprecipitation using an anti-Nrf2 antibody followed by real-time PCR (ChIP-qPCR) was performed. The relationship between Nrf2 activation and osteoblastic differentiation was examined by alkaline phosphatase (ALP) and Alizarin red staining. We used mice with a hypomorphic mutation in ENPP1 (ttw mice) to analyze whether Nrf2 activation inhibits ectopic calcification. Nrf2 and Nrf2 overexpression augmented ENPP1 expression and inhibited osteoblastic differentiation, as indicated by ALP expression and calcium deposits. ChIP-qPCR showed that some putative Nrf2-binding sites in the ENPP1 promoter region were bound by Nrf2. Nrf2 activation inhibited ectopic calcification in mice. ENPP1 gene expression was transcriptionally regulated by Nrf2, and Nrf2 activation augmented ENPP1 expression, leading to the attenuation of osteoblastic differentiation and ectopic calcification in vitro and in vivo. Nrf2 activation has a therapeutic potential for preventing ectopic calcification. Full article
(This article belongs to the Special Issue Role of Nrf2 and ROS in Bone Metabolism)
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15 pages, 2865 KiB  
Article
Effect of Near-Freezing Temperature Storage on the Quality and Organic Acid Metabolism of Apple Fruit
by Chang Shu, Bangdi Liu, Handong Zhao, Kuanbo Cui and Weibo Jiang
Agriculture 2024, 14(7), 1057; https://doi.org/10.3390/agriculture14071057 - 30 Jun 2024
Cited by 4 | Viewed by 1814
Abstract
Organic acids play critical roles in fruit physiological metabolism and sensory quality. However, the conventional storage of apple fruit at 0 ± 0.1 °C cannot maintain fruit acidity efficiently. This study investigated near-freezing temperature (NFT) storage for ‘Golden Delicious’ apples, and the quality [...] Read more.
Organic acids play critical roles in fruit physiological metabolism and sensory quality. However, the conventional storage of apple fruit at 0 ± 0.1 °C cannot maintain fruit acidity efficiently. This study investigated near-freezing temperature (NFT) storage for ‘Golden Delicious’ apples, and the quality parameters, organic acid content, and malate metabolism were studied. The results indicate that NFT storage at −1.7 ± 0.1 °C effectively maintained the postharvest quality of apple fruit when compared to traditional storage at 0 ± 0.1 °C. Fruit that underwent NFT storage showed a better appearance and lower respiratory rate, ethylene production, weight loss, and malondialdehyde (MDA) content but higher firmness and soluble solids content. Further, fruit after NFT storage contained higher titratable acid (18.75%), malate (51.61%), citrate (36.59%), and succinate (2.12%) content when compared to the control after 250 days. This was achieved by maintaining higher cytosolic NAD-dependent malate dehydrogenase (cyNAD-MDH), phosphoenolpyruvate carboxylase (PEPC), vacuolar H+-ATPase (V-ATPase), and vacuolar inorganic pyrophosphatase (V-PPase) activities that promote malate biosynthesis and accumulation while inhibiting enzyme activity that is responsible for malate decomposition, including phosphoenolpyruvate carboxylase kinase (PEPCK) as well as the cytosolic NAD phosphate-dependent malic enzyme (cyNADP-ME). Further, storage at NFTs maintained a higher expression of malate biosynthesis-related genes (MdcyNAD-MDH and MdPEPC) and transport-related genes (MdVHA and MdVHP) while suppressing malate consumption-related genes (MdcyME and MdPEPCK). The results demonstrate that NFT storage could be an effective application for apple fruit, which maintains postharvest quality and alleviates organic acid degradation. Full article
(This article belongs to the Special Issue Analysis of Agricultural Food Physicochemical and Sensory Properties)
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16 pages, 7441 KiB  
Article
Inhibition of Vascular Smooth Muscle Cell Proliferation by ENPP1: The Role of CD73 and the Adenosine Signaling Axis
by Boris Tchernychev, Yvonne Nitschke, Di Chu, Caitlin Sullivan, Lisa Flaman, Kevin O’Brien, Jennifer Howe, Zhiliang Cheng, David Thompson, Daniel Ortiz, Frank Rutsch and Yves Sabbagh
Cells 2024, 13(13), 1128; https://doi.org/10.3390/cells13131128 - 29 Jun 2024
Cited by 4 | Viewed by 3517
Abstract
The Ectonucleotide Pyrophosphatase/Phosphodiesterase 1 (ENPP1) ectoenzyme regulates vascular intimal proliferation and mineralization of bone and soft tissues. ENPP1 variants cause Generalized Arterial Calcification of Infancy (GACI), a rare genetic disorder characterized by ectopic calcification, intimal proliferation, and stenosis of large- and medium-sized arteries. [...] Read more.
The Ectonucleotide Pyrophosphatase/Phosphodiesterase 1 (ENPP1) ectoenzyme regulates vascular intimal proliferation and mineralization of bone and soft tissues. ENPP1 variants cause Generalized Arterial Calcification of Infancy (GACI), a rare genetic disorder characterized by ectopic calcification, intimal proliferation, and stenosis of large- and medium-sized arteries. ENPP1 hydrolyzes extracellular ATP to pyrophosphate (PPi) and AMP. AMP is the precursor of adenosine, which has been implicated in the control of neointimal formation. Herein, we demonstrate that an ENPP1-Fc recombinant therapeutic inhibits proliferation of vascular smooth muscle cells (VSMCs) in vitro and in vivo. Addition of ENPP1 and ATP to cultured VSMCs generated AMP, which was metabolized to adenosine. It also significantly decreased cell proliferation. AMP or adenosine alone inhibited VSMC growth. Inhibition of ecto-5′-nucleotidase CD73 decreased adenosine accumulation and suppressed the anti-proliferative effects of ENPP1/ATP. Addition of AMP increased cAMP synthesis and phosphorylation of VASP at Ser157. This AMP-mediated cAMP increase was abrogated by CD73 inhibitors or by A2aR and A2bR antagonists. Ligation of the carotid artery promoted neointimal hyperplasia in wild-type mice, which was exacerbated in ENPP1-deficient ttw/ttw mice. Prophylactic or therapeutic treatments with ENPP1 significantly reduced intimal hyperplasia not only in ttw/ttw but also in wild-type mice. These findings provide the first insight into the mechanism of the anti-proliferative effect of ENPP1 and broaden its potential therapeutic applications beyond enzyme replacement therapy. Full article
(This article belongs to the Special Issue New Insights into Vascular Biology in Health and Disease)
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16 pages, 2480 KiB  
Article
Synovial Membrane Is a Major Producer of Extracellular Inorganic Pyrophosphate in Response to Hypoxia
by Émilie Velot, Sylvie Sébillaud and Arnaud Bianchi
Pharmaceuticals 2024, 17(6), 738; https://doi.org/10.3390/ph17060738 - 5 Jun 2024
Cited by 1 | Viewed by 1221
Abstract
Calcium pyrophosphate dehydrate (CPPD) crystals are found in the synovial fluid of patients with articular chondrocalcinosis or sometimes with osteoarthritis. In inflammatory conditions, the synovial membrane (SM) is subjected to transient hypoxia, especially during movement. CPPD formation is supported by an increase in [...] Read more.
Calcium pyrophosphate dehydrate (CPPD) crystals are found in the synovial fluid of patients with articular chondrocalcinosis or sometimes with osteoarthritis. In inflammatory conditions, the synovial membrane (SM) is subjected to transient hypoxia, especially during movement. CPPD formation is supported by an increase in extracellular inorganic pyrophosphate (ePPi) levels, which are mainly controlled by the transporter Ank and ectonucleotide pyrophosphatase/phosphodiesterase 1 (ENPP1). We demonstrated previously that transforming growth factor (TGF)-β1 increased ePPi production by inducing Ank and Enpp1 expression in chondrocytes. As the TGF-β1 level raises in synovial fluid under hypoxic conditions, we investigated whether hypoxia may transform SM as a major source of ePPi production. Synovial fibroblasts and SM explants were exposed to 10 ng/mL of TGF-β1 in normoxic or hypoxic (5% O2) culture conditions. Ank and Enpp1 expression were assessed by quantitative PCR, Western blot and immunohistochemistry. ePPi was quantified in culture supernatants. RNA silencing was used to define the respective roles of Ank and Enpp1 in TGF-β1-induced ePPi generation. The molecular mechanisms involved in hypoxia were investigated using an Ank promoter reporter plasmid for transactivation studies, as well as gene overexpression and RNA silencing, the respective role of hypoxia-induced factor (HIF)-1 and HIF-2. Our results showed that TGF-β1 increased Ank, Enpp1, and therefore ePPi production in synovial fibroblasts and SM explants. Ank was the major contributor in ePPi production compared to ENPP1. Hypoxia increased ePPi levels on its own and enhanced the stimulating effect of TGF-β1. Hypoxic conditions enhanced Ank promoter transactivation in an HIF-1-dependent/HIF-2-independent fashion. We demonstrated that under hypoxia, SM is an important contributor to ePPi production in the joint through the induction of Enpp1 and Ank. These findings are of interest as a rationale for the beneficial effect of anti-inflammatory drugs on SM in crystal depositions. Full article
(This article belongs to the Section Pharmacology)
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