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Annual Review of Pathology Jan 2024The enzyme ectonucleotide pyrophosphatase/phosphodiesterase 1 () codes for a type 2 transmembrane glycoprotein that hydrolyzes extracellular ATP to generate... (Review)
Review
The enzyme ectonucleotide pyrophosphatase/phosphodiesterase 1 () codes for a type 2 transmembrane glycoprotein that hydrolyzes extracellular ATP to generate pyrophosphate (PP) and adenosine monophosphate, thereby contributing to downstream purinergic signaling pathways. The clinical phenotypes induced by ENPP1 deficiency are seemingly contradictory and include early-onset osteoporosis in middle-aged adults and life-threatening vascular calcifications in the large arteries of infants with generalized arterial calcification of infancy. The progressive overmineralization of soft tissue and concurrent undermineralization of skeleton also occur in the general medical population, where it is referred to as paradoxical mineralization to highlight the confusing pathophysiology. This review summarizes the clinical presentation and pathophysiology of paradoxical mineralization unveiled by ENPP1 deficiency and the bench-to-bedside development of a novel ENPP1 biologics designed to treat mineralization disorders in the rare disease and general medical population.
Topics: Adult; Humans; Middle Aged; Phosphoric Diester Hydrolases; Vascular Calcification; Pyrophosphatases
PubMed: 37871131
DOI: 10.1146/annurev-pathmechdis-051222-121126 -
JACC. Case Reports Oct 2023Inorganic pyrophosphatase 2 (PPA2) deficiency is a genetic cause of sudden cardiac death, often triggered by viral infection or alcohol consumption. Literature on...
Inorganic pyrophosphatase 2 (PPA2) deficiency is a genetic cause of sudden cardiac death, often triggered by viral infection or alcohol consumption. Literature on management is limited because most cases are diagnosed post mortem. We report lethal and nonlethal cardiac presentations of PPA2 deficiency in 2 adolescent sisters that resulted from a novel pathogenic variant. ().
PubMed: 37869221
DOI: 10.1016/j.jaccas.2023.102024 -
Biomedicine & Pharmacotherapy =... Dec 2023Azathioprine is commonly used as an immunosuppressive antimetabolite in the treatment of acute lymphoblastic leukemia, autoimmune disorders (such as Crohn's disease and...
Azathioprine is commonly used as an immunosuppressive antimetabolite in the treatment of acute lymphoblastic leukemia, autoimmune disorders (such as Crohn's disease and rheumatoid arthritis), and in patients receiving organ transplants. Thiopurine-S-methyltransferase (TPMT) is a cytoplasmic trans-methylase catalyzing the S-methylation of thiopurines. The active metabolites obtained from thiopurines are hydrolyzed into inactive forms by the Nudix hydrolase 15 (NUDT15). The TPMT*2 (defined by rs1800462), *3A (defined by rs1800460 and rs1142345), *3B (defined by rs1800460), *3C (defined by rs1142345), *6 (defined by rs75543815), and NUDT15 rs116855232 genetic variant have been associated, with the highest level of evidence, with the response to azathioprine, and, the approved drug label for azathioprine and main pharmacogenetic dosing guidelines recommend starting with reduced initial doses in TPMT intermediate metabolizer (IM) patients and considering an alternative treatment in TPMT poor metabolizer (PM) patients. This study aims to assess the clinical impact of azathioprine dose tailoring based on TPMT genotyping studying the azathioprine toxicity and efficacy, treatment starts, and dose adjustments during follow-up, comparing TPMT IM/PM and normal metabolizer (NM) patients. It also studied the association of NUDT15 rs116855232 with response to azathioprine in patients receiving a tailored treatment based on TPMT and characterized the TMPT and NUDT15 studied variants in our population. Results show that azathioprine dose reduction in TPMT IM patients (TPMT*1/*2, *1/*3A, or *1/*3C genotypes) is related to lower toxicity events compared to TPMT NM (TPMT *1/*1 genotype), and lower azathioprine dose adjustments during follow-up without showing differences in the efficacy. The results support the hypothesis of existing other genetic variants affecting azathioprine toxicity.
Topics: Humans; Azathioprine; Pharmacogenetics; Immunosuppressive Agents; Genotype; Crohn Disease; Methyltransferases; Pyrophosphatases
PubMed: 37857254
DOI: 10.1016/j.biopha.2023.115706 -
Scientific Reports Oct 2023OA commonly affects the articular cartilage of the tibia, and its calcification worsens its advancement and its prevalence has recently increased. Vector potential (VP)...
OA commonly affects the articular cartilage of the tibia, and its calcification worsens its advancement and its prevalence has recently increased. Vector potential (VP) represents a novel physical therapy for treating OA. Since the impact of VP on articular cartilage remains unknown, we aimed to assess its effects on articular cartilage and its potential as a new treatment for OA. Here, we divided 24 male Wistar rats, 6-week-old, into control (CO, n = 12) and VP stimulus (n = 12) groups (VP conditions: volt, 67 mV; frequency, 20 kHz; current, 0.12 mA; experimental frequency, 30 min/days, 5 days/week, and 3 weeks). Articular cartilage can be classified into four layers: superficial, medial, deep, and calcified. Moreover, the number of chondrocytes in the articular cartilage was higher in the CO group compared to the VP group, although the calcified layer was thinner in the VP group. Furthermore, MKi67 exhibited higher expression in the VP group than in the CO group, while ectonucleotide pyrophosphatase/phosphodiesterase 1 was downregulated in the VP group. Our findings indicate that VP positively influenced chondrocyte proliferation and inhibited calcification in articular cartilage. Thus, VP stimulation may assist in the development of novel strategies for preventing OA.
Topics: Rats; Animals; Male; Chondrocytes; Cartilage, Articular; Rats, Wistar; Cell Proliferation
PubMed: 37803162
DOI: 10.1038/s41598-023-43949-3 -
Haematologica Apr 20246-mercaptopurine (6-MP) serves as the backbone in the maintenance regimens of acute lymphoblastic leukemia (ALL). We aimed to evaluate the influence of NUDT15 gene... (Meta-Analysis)
Meta-Analysis
Association of gene polymorphism with adverse reaction, treatment efficacy, and dose of 6-mercaptopurine in patients with acute lymphoblastic leukemia: a systematic review and meta-analysis.
6-mercaptopurine (6-MP) serves as the backbone in the maintenance regimens of acute lymphoblastic leukemia (ALL). We aimed to evaluate the influence of NUDT15 gene polymorphism on the risk of myelosupression, hepatotoxicity and interruption of 6-MP, as well as treatment efficacy and dose of 6-MP in ALL patients. A total of 24 studies with 3,374 patients were included in this meta-analysis. We found 9-fold higher risk of 6-MP induced leukopenia (odds ratio [OR] =9.00, 95% confidence interval [CI]: 3.73-21.74) and 2.5-fold higher risk of 6-MP-induced neutropenia (OR=2.52, 95% CI: 1.72-3.69) for NUDT15 c.415C>T variant carriers in the dominant model. Moreover, we found that the dose intensity of 6-MP in ALL patients with one NUDT15 c.415C>T variant alleles (CT) was 19% less than that in wild-type patients (CC) (mean differences: 19.43%, 95% CI: -25.36 to -13.51). The tolerable dose intensity of 6-MP in NUDT15 c.415C>T homozygote variant (TT) and heterozygote variant (CT) carriers was 49% and 15% less than that in wild-type patients, respectively. The NUDT15 c.415C>T variant group (CT+TT) had seven times (OR=6.98, 95% CI: 2.83-17.22) higher risk of developing 6-MP intolerance than the CC group. However, NUDT15 c.415C>T polymorphism did not appear significantly associated with hepatotoxicity, treatment interruption or relapse incidence. We concluded that NUDT15 c.415C>T was a good predictor for 6-MP-induced myelosuppression in ALL patients. The dose intensity of 6-MP in ALL patients with NUDT15 c.415C>T variants was significantly lower than that in wild-type patients. This research provided a basis for further investigation into relations between NUDT15 gene and adverse reaction, treatment efficacy and dose intensity of 6-MP.
Topics: Humans; Mercaptopurine; Pyrophosphatases; Precursor Cell Lymphoblastic Leukemia-Lymphoma; Polymorphism, Genetic; Neutropenia; Treatment Outcome; Chemical and Drug Induced Liver Injury
PubMed: 37794799
DOI: 10.3324/haematol.2023.282761 -
MBio Oct 2023The inositol pyrophosphate signaling molecule 1,5-IP modulates fission yeast phosphate homeostasis via its action as an agonist of RNA 3'-processing and transcription...
The inositol pyrophosphate signaling molecule 1,5-IP modulates fission yeast phosphate homeostasis via its action as an agonist of RNA 3'-processing and transcription termination. Cellular 1,5-IP levels are determined by a balance between the activities of the inositol polyphosphate kinase Asp1 and several inositol pyrophosphatase enzymes. Here, we characterize Siw14 (SpSiw14) as a cysteinyl-phosphatase-family pyrophosphatase enzyme capable of hydrolyzing the phosphoanhydride substrates inorganic pyrophosphate, inorganic polyphosphate, and inositol pyrophosphates 5-IP, 1-IP, and 1,5-IP. Genetic analyses implicate SpSiw14 in 1,5-IP catabolism , insofar as: loss of SpSiw14 activity is lethal in the absence of the Nudix-type inositol pyrophosphatase enzyme Aps1; and ∆ ∆ lethality depends on synthesis of 1,5-IP by the Asp1 kinase. Suppression of ∆ ∆ lethality by loss-of-function mutations of 3'-processing/termination factors points to precocious transcription termination as the cause of 1,5-IP toxicosis.
Topics: Schizosaccharomyces; Phosphoric Monoester Hydrolases; Pyrophosphatases; Substrate Specificity; Inositol Phosphates
PubMed: 37772819
DOI: 10.1128/mbio.02056-23 -
Biomolecules Sep 2023Glutamine amidotransferases (GATs) catalyze the hydrolysis of glutamine and transfer the generated ammonia to diverse metabolites. The two catalytic activities,... (Review)
Review
Glutamine amidotransferases (GATs) catalyze the hydrolysis of glutamine and transfer the generated ammonia to diverse metabolites. The two catalytic activities, glutaminolysis and the subsequent amination of the acceptor substrate, happen in two distinct catalytic pockets connected by a channel that facilitates the movement of ammonia. The pathway for the synthesis of guanosine monophosphate (GMP) from xanthosine monophosphate (XMP) is enabled by the GAT GMP synthetase (GMPS). In most available crystal structures of GATs, the ammonia channel is evident in their native state or upon ligand binding, providing molecular details of the conduit. In addition, conformational changes that enable the coordination of the two catalytic chemistries are also informed by the available structures. In contrast, despite the first structure of a GMPS being published in 1996, the understanding of catalysis in the acceptor domain and inter-domain crosstalk became possible only after the structure of a glutamine-bound mutant of GMPS was determined. In this review, we present the current status of our understanding of the molecular basis of catalysis in GMPS, becoming the first comprehensive assessment of the biochemical function of this intriguing enzyme.
PubMed: 37759779
DOI: 10.3390/biom13091379 -
Advanced Science (Weinheim,... Nov 2023Blood vessels play a role in osteogenesis and osteoporosis; however, the role of vascular metabolism in these processes remains unclear. The present study finds that...
Blood vessels play a role in osteogenesis and osteoporosis; however, the role of vascular metabolism in these processes remains unclear. The present study finds that ovariectomized mice exhibit reduced blood vessel density in the bone and reduced expression of the endothelial glycolytic regulator pyruvate kinase M2 (PKM2). Endothelial cell (EC)-specific deletion of Pkm2 impairs osteogenesis and worsens osteoporosis in mice. This is attributed to the impaired ability of bone mesenchymal stem cells (BMSCs) to differentiate into osteoblasts. Mechanistically, EC-specific deletion of Pkm2 reduces serum lactate levels secreted by ECs, which affect histone lactylation in BMSCs. Using joint CUT&Tag and RNA sequencing analyses, collagen type I alpha 2 chain (COL1A2), cartilage oligomeric matrix protein (COMP), ectonucleotide pyrophosphatase/phosphodiesterase 1 (ENPP1), and transcription factor 7 like 2 (TCF7L2) as osteogenic genes regulated by histone H3K18la lactylation are identified. PKM2 overexpression in ECs, lactate addition, and exercise restore the phenotype of endothelial PKM2-deficient mice. Furthermore, serum metabolomics indicate that patients with osteoporosis have relatively low lactate levels. Additionally, histone lactylation and related osteogenic genes of BMSCs are downregulated in patients with osteoporosis. In conclusion, glycolysis in ECs fuels BMSC differentiation into osteoblasts through histone lactylation, and exercise partially ameliorates osteoporosis by increasing serum lactate levels.
Topics: Humans; Animals; Mice; Histones; Lactic Acid; Osteoporosis; Mesenchymal Stem Cells; Endothelial Cells
PubMed: 37752768
DOI: 10.1002/advs.202301300 -
BMC Pediatrics Sep 2023Children diagnosed with autism spectrum disorder (ASD) frequently suffer from persistent gastrointestinal symptoms, such as constipation and diarrhea. Various studies...
BACKGROUND
Children diagnosed with autism spectrum disorder (ASD) frequently suffer from persistent gastrointestinal symptoms, such as constipation and diarrhea. Various studies have highlighted differences in gut microbiota composition between individuals with ASD and healthy controls of similar ages. However, it's essential to recognize that these disparities may be influenced by cultural practices, dietary habits, and environmental factors.
METHODS
In this study, we collected fecal samples from both children diagnosed with ASD (n = 42) and healthy individuals (n = 41) residing in the southeastern coastal region of China. Subsequently, 16 S rRNA gene sequencing and advanced bioinformatics analyses were conducted to investigate the distinctive features of gut microbial communities within each group.
RESULTS
The ASD group consisted of 28 males and 14 females, with a median age of 5.8 years, while the control group included 25 males and 16 females, with a median age of 6.8 years. Among the 83 sequenced fecal samples, a total of 1031 operational taxonomic units (OTUs) were identified. These included 122 unique OTUs specific to the control group and 285 unique OTUs specific to the ASD group. Analyses of α-diversity and β-diversity unveiled significant differences in the abundance and composition of gut microbiota between the two groups. It was found that the dominant bacterial taxa in healthy individuals were UBA1819, Flavonifractor, and Bradyrhizobium. In contrast, the ASD group exhibited a prevalence of Streptococcus, Ruminococcus, and Ruminiclostridium. Further analysis using Kyoto Encyclopedia of Genes and Genomes (KEGG) and Clusters of Orthologous Groups (COG) showed significant differences in the metabolic functionalities of the gut microbiota between the two groups. Notably, the metabolic pathway related to alpha-linolenic acid (ALA) in the gut microbiota of the ASD group was notably diminished compared to the control group. Conversely, the ASD group demonstrated significantly elevated levels of metabolic pathways involving uncharacterized conserved proteins, aminoglycoside phosphotransferase, and inorganic pyrophosphatase compared to the control group.
CONCLUSIONS
Overall, these results confirm that there are significant differences in the gut microbiota structure between children with ASD and healthy controls in the southeast coastal region of China. This underscores the critical significance of delving into clinical interventions capable of mitigating the gastrointestinal and psychological symptoms encountered by children with ASD. A particularly encouraging path for such interventions lies in the realm of fecal microbiota transplantation, a prospect that merits deeper inquiry.
Topics: Female; Male; Child; Humans; Child, Preschool; Gastrointestinal Microbiome; Autism Spectrum Disorder; Microbiota; Anxiety; Constipation
PubMed: 37730588
DOI: 10.1186/s12887-023-04292-8 -
Frontiers in Immunology 2023Heparins, naturally occurring glycosaminoglycans, are widely used for thrombosis prevention. Upon application as anticoagulants in cancer patients, heparins were found...
INTRODUCTION
Heparins, naturally occurring glycosaminoglycans, are widely used for thrombosis prevention. Upon application as anticoagulants in cancer patients, heparins were found to possess additional antitumor activities. Ectonucleotidases have recently been proposed as novel targets for cancer immunotherapy.
METHODS AND RESULTS
In the present study, we discovered that heparin and its derivatives act as potent, selective, allosteric inhibitors of the poorly investigated ectonucleotidase NPP1 (nucleotide pyrophosphatase/phosphodiesterase-1, CD203a). Structure-activity relationships indicated that NPP1 inhibition could be separated from the compounds' antithrombotic effect. Moreover, unfractionated heparin (UFH) and different low molecular weight heparins (LMWHs) inhibited extracellular adenosine production by the NPP1-expressing glioma cell line U87 at therapeutically relevant concentrations. As a consequence, heparins inhibited the ability of U87 cell supernatants to induce CD4+ T cell differentiation into immunosuppressive Treg cells.
DISCUSSION
NPP1 inhibition likely contributes to the anti-cancer effects of heparins, and their specific optimization may lead to improved therapeutics for the immunotherapy of cancer.
Topics: Humans; Heparin; Immunotherapy; Anticoagulants; Heparin, Low-Molecular-Weight; Glioma
PubMed: 37711611
DOI: 10.3389/fimmu.2023.1173634