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Current Opinion in Nephrology and... Jan 2020In chronic kidney disease (CKD), disturbance of several metabolic regulatory mechanisms cause premature ageing, accelerated cardiovascular disease (CVD), and mortality.... (Review)
Review
PURPOSE OF REVIEW
In chronic kidney disease (CKD), disturbance of several metabolic regulatory mechanisms cause premature ageing, accelerated cardiovascular disease (CVD), and mortality. Single-target interventions have repeatedly failed to improve the prognosis for CKD patients. Epigenetic interventions have the potential to modulate several pathogenetic processes simultaneously. Alkaline phosphatase (ALP) is a robust predictor of CVD and all-cause mortality and implicated in pathogenic processes associated with CVD in CKD.
RECENT FINDINGS
In experimental studies, epigenetic modulation of ALP by microRNAs or bromodomain and extraterminal (BET) protein inhibition has shown promising results for the treatment of CVD and other chronic metabolic diseases. The BET inhibitor apabetalone is currently being evaluated for cardiovascular risk reduction in a phase III clinical study in high-risk CVD patients, including patients with CKD (ClinicalTrials.gov Identifier: NCT02586155). Phase II studies demonstrate an ALP-lowering potential of apabetalone, which was associated with improved cardiovascular and renal outcomes.
SUMMARY
ALP is a predictor of CVD and mortality in CKD. Epigenetic modulation of ALP has the potential to affect several pathogenetic processes in CKD and thereby improve cardiovascular outcome.
Topics: Alkaline Phosphatase; Cardiovascular Diseases; Epigenesis, Genetic; Gene Expression Regulation, Enzymologic; Humans; Quinazolinones; Renal Insufficiency, Chronic
PubMed: 31725015
DOI: 10.1097/MNH.0000000000000570 -
Bone Jan 2024Hypophosphatasia (HPP) is an inherited multisystem disorder predominantly affecting the mineralization of bones and teeth. HPP is caused by pathogenic variants in ALPL,...
BACKGROUND
Hypophosphatasia (HPP) is an inherited multisystem disorder predominantly affecting the mineralization of bones and teeth. HPP is caused by pathogenic variants in ALPL, which encodes tissue non-specific alkaline phosphatase (TNSALP). Variants of uncertain significance (VUS) cause diagnostic delay and uncertainty amongst patients and health care providers.
RESULTS
The ALPL gene variant database (https://alplmutationdatabase.jku.at/) is an open-access archive for interpretation of the clinical significance of variants reported in ALPL. The database contains coding and non-coding variants, including single nucleotide variants, insertions/deletions and structural variants affecting coding or non-coding sequences of ALPL. Each variant in the database is displayed with details explaining the corresponding pathogenicity, and all reported genotypes and phenotypes, including references. In 2021, the ALPL gene variant classification project was established to reclassify VUS and continuously assess and update genetic, phenotypic, and functional variant information in the database. For this purpose, the database provides a unique submission system for clinicians, geneticists, genetic counselors, and researchers to submit VUS within ALPL for classification. An international, multidisciplinary consortium of HPP experts has been established to reclassify the submitted VUS using a multi-step process adhering to the stringent ACMG/AMP variant classification guidelines. These steps include a clinical phenotype assessment, deep literature research including artificial intelligence technology, molecular genetic assessment, and in-vitro functional testing of variants in a co-transfection model to measure ALP residual activity.
CONCLUSION
This classification project and the ALPL gene variant database will serve the global medical community, widen the genotypic and phenotypic HPP spectrum by reporting and characterizing new ALPL variants based on ACMG/AMP criteria and thus facilitate improved genetic counseling and medical decision-making for affected patients and families. The project may also serve as a gold standard framework for multidisciplinary collaboration for variant interpretation in other rare diseases.
Topics: Humans; Alkaline Phosphatase; Mutation; Artificial Intelligence; Delayed Diagnosis; Hypophosphatasia
PubMed: 37898381
DOI: 10.1016/j.bone.2023.116947 -
Clinical Chemistry and Laboratory... Jan 2017Interpretation of alkaline phosphatase activity in children is challenging due to extensive changes with growth and puberty leading to distinct sex- and age-specific...
BACKGROUND
Interpretation of alkaline phosphatase activity in children is challenging due to extensive changes with growth and puberty leading to distinct sex- and age-specific dynamics. Continuous percentile charts from birth to adulthood allow accurate consideration of these dynamics and seem reasonable for an analyte as closely linked to growth as alkaline phosphatase. However, the ethical and practical challenges unique to pediatric reference intervals have restricted the creation of such percentile charts, resulting in limitations when clinical decisions are based on alkaline phosphatase activity.
METHODS
We applied an indirect method to generate percentile charts for alkaline phosphatase activity using clinical laboratory data collected during the clinical care of patients. A total of 361,405 samples from 124,440 patients from six German tertiary care centers and one German laboratory service provider measured between January 2004 and June 2015 were analyzed. Measurement of alkaline phosphatase activity was performed on Roche Cobas analyzers using the IFCC's photometric method.
RESULTS
We created percentile charts for alkaline phosphatase activity in girls and boys from birth to 18 years which can be used as reference intervals. Additionally, data tables of age- and sex-specific percentile values allow the incorporation of these results into laboratory information systems.
CONCLUSIONS
The percentile charts provided enable the appropriate differential diagnosis of changes in alkaline phosphatase activity due to disease and changes due to physiological development. After local validation, integration of the provided percentile charts into result reporting facilitates precise assessment of alkaline phosphatase dynamics in pediatrics.
Topics: Adolescent; Alkaline Phosphatase; Child; Child, Preschool; Female; Humans; Infant; Infant, Newborn; Male; Pediatrics; Reference Values
PubMed: 27505090
DOI: 10.1515/cclm-2016-0318 -
Biosensors Apr 2021As an important DNA 3'-phosphatase, alkaline phosphatase can repair damaged DNA caused by replication and recombination. It is essential to measure the level of alkaline...
As an important DNA 3'-phosphatase, alkaline phosphatase can repair damaged DNA caused by replication and recombination. It is essential to measure the level of alkaline phosphatase to indicate some potential diseases, such as cancer, related to alkaline phosphatase. Here, we designed a simple and fast method to detect alkaline phosphatase quantitively. When alkaline phosphatase is present, the resulting poly T-DNA with a 3'-hydroxyl end was cleaved by exonuclease I, prohibiting the formation of fluorescent copper nanoparticles. However, the fluorescent copper nanoparticles can be monitored with the absence of alkaline phosphatase. Hence, we can detect alkaline phosphatase with this turn-off strategy. The proposed method is able to quantify the concentration of alkaline phosphatase with the LOD of 0.0098 U/L. Furthermore, we utilized this method to measure the effects of inhibitor NaVO on alkaline phosphatase. In addition, it was successfully applied to quantify the level of alkaline phosphatase in human serum. The proposed strategy is sensitive, selective, cost effective, and timesaving, having a great potential to detect alkaline phosphatase quantitatively in clinical diagnosis.
Topics: Alkaline Phosphatase; Biological Assay; Copper; DNA; DNA Repair Enzymes; Exodeoxyribonucleases; Humans; Metal Nanoparticles
PubMed: 33946723
DOI: 10.3390/bios11050139 -
BMC Veterinary Research Sep 2014Nasal secretion (NS) was investigated as a source of information regarding the mucosal and systemic immune status of cattle challenged by respiratory disease. A method...
BACKGROUND
Nasal secretion (NS) was investigated as a source of information regarding the mucosal and systemic immune status of cattle challenged by respiratory disease. A method for the collection of substantial volumes (~12 ml) of NS from cattle was developed to establish a reference range of analytes that are present in the NS of healthy cattle. Biochemical profiles of NS from a group of 38 healthy Holstein-Friesian cows revealed high alkaline phosphatase (AP) activity of up to 2392 IU/L. The character and source of the high activity of AP in bovine NS was investigated.
RESULTS
Histochemical analysis confirmed the localization of the AP enzyme activity to epithelial cells and serous glands of the nasal respiratory mucosa. Analysis of mRNA levels from nasal mucosa by end point RT-PCR and PCR product sequencing confirmed that the AP was locally produced and is identical at the nucleotide level to the non-specific AP splice variant found in bovine liver, bone and kidney. Analysis by isoelectric focussing confirmed that AP was produced locally at a high level in nasal epithelium demonstrating that AP from nasal secretion and nasal mucosa had similar pI bands, though differing from those of the liver, kidney, bone and intestine, suggesting different post-translational modification (PTM) of AP in these tissues.
CONCLUSIONS
A nasal isozyme of AP has been identified that is present at a high activity in NS, resulting from local production and showing distinctive PTM and may be active in NS as an anti-endotoxin mediator.
Topics: Alkaline Phosphatase; Animals; Bodily Secretions; Cattle; Female; Isoelectric Focusing; Nasal Mucosa; Protein Isoforms; Reverse Transcriptase Polymerase Chain Reaction
PubMed: 25927913
DOI: 10.1186/s12917-014-0204-9 -
FEBS Letters Nov 1999The proposed double in-line displacement mechanism of Escherichia coli alkaline phosphatase (AP) involving two-metal ion catalysis is based on NMR spectroscopic and... (Review)
Review
The proposed double in-line displacement mechanism of Escherichia coli alkaline phosphatase (AP) involving two-metal ion catalysis is based on NMR spectroscopic and X-ray crystallographic studies. This mechanism is further supported by the X-ray crystal structures of the covalent phospho-enzyme intermediate of the H331Q mutant AP and of the transition state complex between the wild-type enzyme and vanadate, a transition state analog. Kinetic and structural studies on several genetically engineered versions of AP illustrate the overall importance of the active site's metal geometry, hydrogen bonding network and electrostatic potential in the catalytic mechanism.
Topics: Alkaline Phosphatase; Crystallography, X-Ray; Escherichia coli; Kinetics; Magnetic Resonance Spectroscopy; Metals; Models, Molecular; Mutagenesis, Site-Directed
PubMed: 10580082
DOI: 10.1016/s0014-5793(99)01448-9 -
Adipocyte 2018Intestinal alkaline phosphatase 3 (AKP3) is an enzyme that was reported to play a role in lipid metabolism and to prevent high fat diet-induced metabolic syndrome in...
Intestinal alkaline phosphatase 3 (AKP3) is an enzyme that was reported to play a role in lipid metabolism and to prevent high fat diet-induced metabolic syndrome in mice. To investigate a potential functional role of AKP3 in diet-induced adiposity and metabolic health, we have kept male and female wild-type or AKP3 deficient mice on a high fat diet for 15 weeks to induce obesity and compared those with mice kept on standard fat diet. Body weight as well as adipose tissue mass were statistically significantly higher upon high fat diet feeding for mice of both genders and genotypes. Female mice of either genotype kept on high fat diet gained less weight, resulting in smaller adipose tissue depots with smaller adipocytes. However, AKP3 deficiency had no significant effect on body weight gain or adipose tissue mass and did not affect adipocyte size or density. Gene expression analysis revealed no effect of the genotype on inflammatory parameters in adipose tissue, except for tumor necrosis factor alpha, which was higher in mesenteric adipose tissue of female obese mice. Plasma glucose and insulin levels were also not affected in obese AKP3 deficient mice. Overall, our data do not support a functional role of AKP3 in adipose tissue development, or insulin sensitivity.
Topics: Adipose Tissue; Adiposity; Alkaline Phosphatase; Animals; Body Weight; Diet; Female; Genotype; Intestines; Male; Mice; Mice, Inbred C57BL; Mice, Knockout
PubMed: 30064292
DOI: 10.1080/21623945.2018.1493899 -
Journal of Bone and Mineral Research :... Apr 2017Hypophosphatasia (HPP) is caused by loss-of-function mutation(s) of the gene that encodes the tissue-nonspecific isoenzyme of alkaline phosphatase (TNSALP). Autosomal... (Review)
Review
Hypophosphatasia (HPP) is caused by loss-of-function mutation(s) of the gene that encodes the tissue-nonspecific isoenzyme of alkaline phosphatase (TNSALP). Autosomal inheritance (dominant or recessive) from among more than 300 predominantly missense defects of TNSALP (ALPL) explains HPP's broad-ranging severity, the greatest of all skeletal diseases. In health, TNSALP is linked to cell surfaces and richly expressed in the skeleton and developing teeth. In HPP,TNSALP substrates accumulate extracellularly, including inorganic pyrophosphate (PPi), an inhibitor of mineralization. The PPi excess can cause tooth loss, rickets or osteomalacia, calcific arthropathies, and perhaps muscle weakness. Severely affected infants may seize from insufficient hydrolysis of pyridoxal 5'-phosphate (PLP), the major extracellular vitamin B . Now, significant successes are documented for newborns, infants, and children severely affected by HPP given asfotase alfa, a hydroxyapatite-targeted recombinant TNSALP. Since fall 2015, this biologic is approved by regulatory agencies multinationally typically for pediatric-onset HPP. Safe and effective treatment is now possible for this last rickets to have a medical therapy, but a number of challenges involving diagnosis, understanding prognosis, and providing this treatment are reviewed herein. © 2017 American Society for Bone and Mineral Research.
Topics: Alkaline Phosphatase; Animals; Child; Child, Preschool; Enzyme Replacement Therapy; Female; Humans; Hypophosphatasia; Immunoglobulin G; Infant; Male; Mutation; Osteogenesis; Pyridoxal Phosphate; Recombinant Fusion Proteins
PubMed: 28084648
DOI: 10.1002/jbmr.3075 -
Biochemia Medica Jun 2020By quantifying the measurement uncertainty (MU), both the laboratory and the physician can have an objective estimate of the results' quality. There is significant... (Review)
Review
INTRODUCTION
By quantifying the measurement uncertainty (MU), both the laboratory and the physician can have an objective estimate of the results' quality. There is significant flexibility on how to determine the MU in laboratory medicine and different approaches have been proposed by Nordtest, Eurolab and Cofrac to obtain the data and apply them in formulas. The purpose of this study is to compare three different top-down approaches for the estimation of the MU and to suggest which of these approaches could be the most suitable choice for routine use in clinical laboratories.
MATERIALS AND METHODS
Imprecision and bias of the methods were considered as components of the MU. The bias was obtained from certified reference calibrators (CRC), proficiency tests (PT), and inter-laboratory internal quality control scheme (IQCS) programs. The bias uncertainty, the combined and the expanded uncertainty were estimated using the Nordtest, Eurolab and Cofrac approaches.
RESULTS
Using different approaches, the expanded uncertainty estimates ranged from 18.9-40.4%, 18.2-22.8%, 9.3-20.9%, and 7.1-18.6% for cancer antigen (CA) 19-9, testosterone, alkaline phosphatase (ALP), and creatinine, respectively. Permissible values for MU and total error ranged from 16.0-46.1%, 13.1-21.6%, 10.7-26.2%, and 7.5-17.3%, respectively.
CONCLUSION
The bias was highest using PT, followed by CRC and IQCS data, which were similar. The Cofrac approach showed the highest uncertainties, followed by Eurolab and Nordtest. However, the Eurolab approach requires additional measurements to obtain uncertainty data. In summary, the Nordtest approach using IQCS data was therefore found to be the most practical formula.
Topics: Alkaline Phosphatase; Antigens, Neoplasm; Clinical Laboratory Techniques; Creatinine; Diagnostic Errors; Humans; Quality Control; Testosterone; Uncertainty
PubMed: 32292278
DOI: 10.11613/BM.2020.020101 -
Langmuir : the ACS Journal of Surfaces... Nov 2019Matrix vesicles (MVs) are a special class of extracellular vesicles that drive bone and dentin mineralization by providing the essential enzymes and ions for the...
Matrix vesicles (MVs) are a special class of extracellular vesicles that drive bone and dentin mineralization by providing the essential enzymes and ions for the nucleation and propagation of mineral crystals. Tissue-nonspecific alkaline phosphatase (TNAP) is an integral protein of MV membrane and participates in biomineralization by hydrolyzing extracellular pyrophosphate (PP), a strong mineralization inhibitor, and forming inorganic phosphate (P), necessary for the growth of mineral crystals inside MVs and their propagation once released in the extracellular matrix. MV membrane is enriched in cholesterol (CHOL), which influences the incorporation and activity of integral proteins in biologic membranes; however, how CHOL controls the incorporation and activity of TNAP in MV membrane has not yet been elucidated. In the present study, Langmuir monolayers were used as a MV membrane biomimetic model to assess how CHOL affects TNAP incorporation and activity. Surface pressure-area (π-) isotherms of binary dipalmitoilphosphatidylcholine (DPPC)/CHOL monolayers showed that TNAP incorporation increases with CHOL concentration. Infrared spectroscopy showed that CHOL influences the conformation and orientation of the enzyme. Optical-fluorescence micrographs of the monolayers revealed the tendency of TNAP to incorporate into CHOL-rich microdomains. These data suggest that TNAP penetrates more efficiently and occupies a higher surface area into monolayers with a lower CHOL concentration due to the higher membrane fluidity. However, the quantity of enzyme transferred to solid supports as well as the enzymatic activity were higher using monolayers with a higher CHOL concentration due to increased rigidity that changes the enzyme orientation at the air-solid interface. These data provide new insights regarding the interfacial behavior of TNAP and CHOL in MVs and shed light on the biochemical and biophysical processes occurring in the MV membrane during biomineralization at the molecular level.
Topics: 1,2-Dipalmitoylphosphatidylcholine; Alkaline Phosphatase; Catalysis; Cholesterol; Membranes, Artificial; Protein Binding
PubMed: 31702926
DOI: 10.1021/acs.langmuir.9b02590