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Alkaline phosphatase (ALP; E.C.3.I.3.1.) is an ubiquitous membrane-bound glycoprotein that catalyzes the hydrolysis of phosphate monoesters at basic pH values. Alkaline phosphatase is divided into four isozymes depending upon the site of tissue expression that are Intestinal ALP, Placental ALP, Germ cell ALP and tissue nonspecific alkaline phosphatase or liver/bone/kidney (L/B/K) ALP. The intestinal and placental ALP loci are located near the end of long arm of chromosome 2 and L/B/K ALP is located near the end of the short arm of chromosome 1. Although ALPs are present in many mammalian tissues and have been studied for the last several years still little is known about them. The bone isoenzyme may be involved in mammalian bone calcification and the intestinal isoenzyme is thought to play a role in the transport of phosphate into epithelial cells of the intestine. In this review, we tried to provide an overview about the various forms, structure and functions of alkaline phosphatase with special focus on liver/bone/kidney alkaline phosphatase.

Metabolic syndrome comprises a cluster of related disorders that includes obesity, glucose intolerance, insulin resistance, dyslipidemia, and fatty liver. Recently, gut-derived chronic endotoxemia has been identified as a primary mediator for triggering the low-grade inflammation responsible for the development of metabolic syndrome. In the present study we examined the role of the small intestinal brush-border enzyme, intestinal alkaline phosphatase (IAP), in preventing a high-fat-diet–induced metabolic syndrome in mice. We found that both endogenous and orally supplemented IAP inhibits absorption of endotoxin (lipopolysaccharides) that occurs with dietary fat, and oral IAP supplementation prevents as well as reverses metabolic syndrome. Furthermore, IAP supplementation improves the lipid profile in mice fed a standard, low-fat chow diet. These results point to a potentially unique therapy against metabolic syndrome in at-risk humans.

Tissue nonspecific alkaline phosphatase (TNAP) is expressed widely in different tissues, modulating functions of metabolism and inflammation. However, the effect of TNAP on cardiac fibrosis remains controversial and needs to be further studied. The present study aims to investigate the role of TNAP on myocardial infarction (MI)-induced fibrosis and its mechanism. TNAP was upregulated in patients with MI, both in serum and injured hearts, and predicted in-hospital mortality. TNAP was also significantly upregulated after MI in rats, mostly in the border zone of the infarcted hearts combined with collagen synthesis. Administration of TNAP inhibitor, tetramisole, markedly improved cardiac function and fibrosis after MI. In the primary cultures of neonatal rat cardiac fibroblasts (CFs), TNAP inhibition significantly attenuated migration, differentiation, and expression of collagen-related genes. The TGF-β1/Smads signaling suppression, and p-AMPK and p53 upregulation were involved in the process. When p53 inhibitor was administered, the antifibrotic effect of TNAP inhibition can be blocked. This study provides a direct evidence that inhibition of TNAP might be a novel regulator in cardiac fibrosis and exert an antifibrotic effect mainly through AMPK-TGF-β1/Smads and p53 signals.

In this study of perinatal and infantile hypophosphatasia, patients received ENB-0040, a bone-targeted, recombinant, human tissue-nonspecific isozyme of alkaline phosphatase that is lacking in this disease. Rickets healed, and developmental milestones and pulmonary function improved. Hypophosphatasia is the inborn error of metabolism that is characterized by low serum alkaline-phosphatase activity from loss-of-function mutations, typically missense, within the gene for the tissue-nonspecific isozyme of alkaline phosphatase (TNSALP). 1 Natural substrates of TNSALP that accumulate in hypophosphatasia include inorganic pyrophosphate, 2 an inhibitor of mineralization, 3 and pyridoxal 5′-phosphate (PLP), the principal circulating form of vitamin B 6 . 4 High extracellular levels of inorganic pyrophosphate block hydroxyapatite crystal growth 3 , 5 and cause rickets or osteomalacia. Hypercalcemia and hyperphosphatemia can develop in severely affected patients. 1 The deranged vitamin B 6 metabolism shows that TNSALP functions as a cell-surface enzyme 6 and explains . . .

Alkaline phosphatase (ALP) declines and pain responses can occur during radium-223 ( Ra) treatment, but their association with treatment outcomes is unclear. For patients with metastatic castration-resistant prostate cancer treated with Ra in the REASSURE study, we investigated whether ALP decline (Week 12) and/or pain response (during treatment) are associated with improved overall survival (OS). The Brief Pain Inventory-Short Form (BPI-SF) was used to assess pain at baseline and pain response (in patients with baseline BPI-SF score ≥2). Of 785 patients with baseline and Week 12 ALP measurements, 779 were eligible for the OS analyses. Overall, 80% of patients had an ALP decline. Median OS was longer in patients with than without an ALP decline (18.1 versus 14.2 months; HR 0.74; 95% CI 0.60-0.92). In patients with an ALP decline, there was no clear OS difference between those with versus without a pain response. For patients without ALP decline, median OS was longer in those with versus without a pain response (16.2 versus 10.9 months; HR 0.50; 95% CI 0.32-0.77). Decreases in ALP and/or pain during Ra treatment are associated with improved OS. This may help support clinical decisions. ClinicalTrials.gov identifier NCT02141438. Analyses from the radium-223 REASSURE global study suggest that declines in alkaline phosphatase and pain during treatment may predict longer survival in patients with advanced prostate cancer and may help doctors make decisions with their patients.

Effective treatments for patients with primary biliary cholangitis are limited. Seladelpar, a peroxisome proliferator-activated receptor delta agonist, has potential benefits. In this phase 3, 12-month, double-blind, placebo-controlled trial, we randomly assigned (in a 2:1 ratio) patients who had had an inadequate response to or who had a history of unacceptable side effects with ursodeoxycholic acid to receive oral seladelpar at a dose of 10 mg daily or placebo. The primary end point was a biochemical response, which was defined as an alkaline phosphatase level less than 1.67 times the upper limit of the normal range, with a decrease of 15% or more from baseline, and a normal total bilirubin level at month 12. Key secondary end points were normalization of the alkaline phosphatase level at month 12 and a change in the score on the pruritus numerical rating scale (range, 0 [no itch] to 10 [worst itch imaginable]) from baseline to month 6 among patients with a baseline score of at least 4 (indicating moderate-to-severe pruritus). Of the 193 patients who underwent randomization and treatment, 93.8% received ursodeoxycholic acid as standard-of-care background therapy. A greater percentage of the patients in the seladelpar group than in the placebo group had a biochemical response (61.7% vs. 20.0%; difference, 41.7 percentage points; 95% confidence interval [CI], 27.7 to 53.4, P<0.001). Normalization of the alkaline phosphatase level also occurred in a greater percentage of patients who received seladelpar than of those who received placebo (25.0% vs. 0%; difference, 25.0 percentage points; 95% CI, 18.3 to 33.2, P<0.001). Seladelpar resulted in a greater reduction in the score on the pruritus numerical rating scale than placebo (least-squares mean change from baseline, -3.2 vs. -1.7; least-squares mean difference, -1.5; 95% CI, -2.5 to -0.5, P = 0.005). Adverse events were reported in 86.7% of the patients in the seladelpar group and in 84.6% in the placebo group, and serious adverse events in 7.0% and 6.2%, respectively. In this trial involving patients with primary biliary cholangitis, the percentage of patients who had a biochemical response and alkaline phosphatase normalization was significantly greater with seladelpar than with placebo. Seladelpar also significantly reduced pruritus among patients who had moderate-to-severe pruritus at baseline. The incidence and severity of adverse events were similar in the two groups. (Funded by CymaBay Therapeutics; RESPONSE ClinicalTrials.gov number, NCT04620733; EudraCT number, 2020-004348-27.).

In a trial involving patients with primary biliary cholangitis, treatment with elafibranor, a dual PPAR-α and PPAR-δ agonist, led to greater improvements in biochemical indicators of cholestasis than placebo.

Nanoceria have demonstrated a wide array of catalytic activity similar to natural enzymes, holding considerable significance in the colorimetric detection of alkaline phosphatase (ALP), which is a biomarker of various biological disorders. However, the issues of physiological stability and formation of protein corona, which are strongly related to their surface chemistry, limit their practical application. In this work, CeO2 nanoparticles characterized by enhanced dimensional uniformity and specific surface area were synthesized, followed by encapsulation with various polymers to further increase catalytic activity and physiological stability. Notably, the CeO2 nanoparticles encapsulated within each polymer exhibited improved catalytic characteristics, with PAA-capped CeO2 exhibiting the highest performance. We further demonstrated that the PAA-CeO2 obtained with enhanced catalytic activity was attributed to an increase in surface negative charge. PAA-CeO2 enabled the quantitative assessment of AA activity within a wide concentration range of 10 to 60 μM, with a detection limit of 0.111 μM. Similarly, it allowed for the evaluation of alkaline phosphatase activity throughout a broad range of 10 to 80 U/L, with a detection limit of 0.12 U/L. These detection limits provided adequate sensitivity for the practical detection of ALP in human serum.

Alkaline phosphatases (ALPs) are a group of isoenzymes, situated on the external layer of the cell membrane; they catalyze the hydrolysis of organic phosphate esters present in the extracellular space. Zinc and magnesium are significant co-factors for the biological activity of these enzymes. Although ALPs are available in various body tissues and have distinct physiochemical properties, they are true isoenzymes since they catalyze a similar reaction. In the liver, ALP is cytosolic and present in the canalicular membrane of the hepatocytes. ALPs are available in placenta, ileal mucosa, kidney, bone, and liver. However, most of the ALPs in serum (over 80%) are delivered from liver and bone and in more modest quantities from the intestines. Despite the fact that alkaline phosphatases are found in numerous tissues all through the body, their exact physiological function remains largely unknown.

Alkaline phosphatases such as PhoD and PhoX are important in organic phosphorus cycling in soil. We identified the key organisms harboring the phoD and phoX genes in soil and explored the relationships between environmental factors and the phoD- and phoX-harboring community structures across three land uses located in arid to temperate climates on two continents using 454-sequencing. phoD was investigated using recently published primers, and new primers were designed to study phoX in soil. phoD was found in 1 archaeal, 13 bacterial and 2 fungal phyla, and phoX in 1 archaeal and 16 bacterial phyla. Dominant phoD-harboring phyla were Actinobacteria, Cyanobacteria, Deinococcus-Thermus, Firmicutes, Gemmatimonadetes, Planctomycetes and Proteobacteria, while abundant phoX-harboring phyla were Acidobacteria, Actinobacteria, Chloroflexi, Planctomycetes, Proteobacteria and Verrucomicrobia. Climate, soil group, land use and soil nutrient concentrations were the common environmental drivers of both community structures. In addition, the phoX-harboring community structure was affected by pH. Despite differences in environmental factors, the dominant phyla in the phoD-harboring community remained similar in all samples, while the composition of phoX differed substantially between the samples. This study shows that the composition of phoD and phoX is governed by the same environmental drivers but that phoD and phoX occur partly in different phyla.