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Early Human Development Aug 2023Necrotizing enterocolitis (NEC) is a devastating neonatal disease that affects neonates worldwide and often leads to high morbidity and mortality rates. Despite... (Review)
Review
Necrotizing enterocolitis (NEC) is a devastating neonatal disease that affects neonates worldwide and often leads to high morbidity and mortality rates. Despite extensive research, the cause of NEC remains unclear, and current treatment options are limited. An important novel finding is the potential role of intestinal Alkaline Phosphatase (IAP) in both pathogenesis and treatment of NEC. IAP can play a vital role in detoxifying liposaccharides (LPS), a key mediator of many pathological processes, thereby reducing the inflammatory response associated with NEC. Furthermore, IAP can help prevent dysbiosis, improve intestinal perfusion, and promote autophagy. In this comprehensive review, we present evidence of the possible connection between IAP and the LPS/Toll-like receptor 4 (TLR4) pathway, impaired gut immunity, and dysbiosis in the preterm gut. Based on these findings, the administration of exogenous IAP might provide promising preventive and therapeutic avenues for the management of NEC.
Topics: Infant, Newborn; Humans; Alkaline Phosphatase; Enterocolitis, Necrotizing; Dysbiosis; Lipopolysaccharides; Infant, Newborn, Diseases
PubMed: 37300991
DOI: 10.1016/j.earlhumdev.2023.105797 -
Annals of Translational Medicine Dec 2023Increased plasma levels of alkaline phosphatase (ALP) have been associated to a worse prognosis in several types of diseases. In the present review, the authors aimed to... (Review)
Review
BACKGROUND
Increased plasma levels of alkaline phosphatase (ALP) have been associated to a worse prognosis in several types of diseases. In the present review, the authors aimed to study the relationship between plasma levels of ALP and overall mortality in patients with stroke.
METHODS
A systematic review was carried out, searching two databases: Web of Science and Medline/PubMed.
RESULTS
A total of nine studies that included data on overall mortality in stroke patients were selected. The selected studies were published between 2010 and 2022 and were predominantly from Asia. The articles reviewed quantified ALP levels through different methods: highest versus lowest quintiles of plasma ALP (three reports); highest versus lowest quartiles of plasma ALP (four reports); and plasma ALP levels in deceased versus in surviving patients (two reports). All selected studies showed an increased mortality associated to elevated ALP levels, irrespective of stroke type and length of follow-up, from a mean of 10 days to 2.5 years. The studies comparing the highest to the lowest ALP quintiles showed an aggregate value of 1.8 times greater risk of mortality for the former, when compared to the latter. Whereas, the studies comparing the highest to the lowest ALP quartiles showed an aggregate value of 2.4 times greater risk of mortality for the former, when compared to the latter.
CONCLUSIONS
Elevated ALP levels are associated with increased mortality in stroke patients and provide cost effective prognostic indicators of mortality in stroke.
PubMed: 38213797
DOI: 10.21037/atm-23-1627 -
Intensive Care Medicine Jan 2024Ilofotase alfa is a human recombinant alkaline phosphatase with reno-protective effects that showed improved survival and reduced Major Adverse Kidney Events by 90 days... (Randomized Controlled Trial)
Randomized Controlled Trial
PURPOSE
Ilofotase alfa is a human recombinant alkaline phosphatase with reno-protective effects that showed improved survival and reduced Major Adverse Kidney Events by 90 days (MAKE90) in sepsis-associated acute kidney injury (SA-AKI) patients. REVIVAL, was a phase-3 trial conducted to confirm its efficacy and safety.
METHODS
In this international double-blinded randomized-controlled trial, SA-AKI patients were enrolled < 72 h on vasopressor and < 24 h of AKI. The primary endpoint was 28-day all-cause mortality. The main secondary endpoint was MAKE90, other secondary endpoints were (i) days alive and free of organ support through day 28, (ii) days alive and out of the intensive care unit (ICU) through day 28, and (iii) time to death through day 90. Prior to unblinding, the statistical analysis plan was amended, including an updated MAKE90 definition.
RESULTS
Six hundred fifty patients were treated and analyzed for safety; and 649 for efficacy data (ilofotase alfa n = 330; placebo n = 319). The observed mortality rates in the ilofotase alfa and placebo groups were 27.9% and 27.9% at 28 days, and 33.9% and 34.8% at 90 days. The trial was stopped for futility on the primary endpoint. The observed proportion of patients with MAKE90A and MAKE90B were 56.7% and 37.4% in the ilofotase alfa group vs. 64.6% and 42.8% in the placebo group. Median [interquartile range (IQR)] days alive and free of organ support were 17 [0-24] and 14 [0-24], number of days alive and discharged from the ICU through day 28 were 15 [0-22] and 10 [0-22] in the ilofotase alfa and placebo groups, respectively. Adverse events were reported in 67.9% and 75% patients in the ilofotase and placebo group.
CONCLUSION
Among critically ill patients with SA-AKI, ilofotase alfa did not improve day 28 survival. There may, however, be reduced MAKE90 events. No safety concerns were identified.
Topics: Humans; Acute Kidney Injury; Alkaline Phosphatase; Intensive Care Units; Sepsis
PubMed: 38172296
DOI: 10.1007/s00134-023-07271-w -
Journal of Orthopaedic Surgery and... Sep 2023Osteoporosis is a bone metabolic disease that usually causes fracture. The improvement of the clinical diagnostic efficiency of osteoporosis is of great significance for...
BACKGROUND
Osteoporosis is a bone metabolic disease that usually causes fracture. The improvement of the clinical diagnostic efficiency of osteoporosis is of great significance for the prevention of fracture. The predictive and diagnostic values of bone alkaline phosphatase (B-ALP) and 25-oxhydryl-vitamin D (25-OH-VD) for osteoporotic vertebral compression fractures (OVCFs) were evaluated.
METHODS
110 OVCFs patients undergoing percutaneous vertebroplasty were included as subjects and their spinal computed tomography (CT) images were collected. After that, deep convolutional neural network model was employed for intelligent fracture recognition. Next, the patients were randomly enrolled into Ctrl group (65 cases receiving postoperative routine treatment) and VD2 group (65 cases injected with vitamin D2 into muscle after the surgery). In addition, 100 healthy people who participated in physical examination were included in Normal group. The differences in Oswestry dysfunction indexes (ODI), imaging parameters, B-ALP and 25-OH-VD expressions, and quality of life (QOL) scores of patients among the three groups were compared. The values of B-ALP and 25-OH-VD in predicting and diagnosing OVCFs and their correlation with bone density were analyzed.
RESULTS
It was demonstrated that computer intelligent medical image technique was more efficient in fracture CT recognition than artificial recognition. In contrast to those among patients in Normal group, B-ALP rose while 25-OH-VD declined among patients in Ctrl and VD2 groups (P < 0.05). Versus those among patients in Ctrl group, ODI, Cobb angle, and B-ALP reduced, while bone density, the height ratio of the injured vertebrae, 25-OH-VD, and QOL score increased among patients in VD2 group after the treatment (P < 0.05). The critical values, accuracy, and areas under the curve (AUC) of the diagnosis of OVCFs by B-ALP and 25-OH-VD amounted to 87.8 μg/L versus 30.3 nmol/L, 86.7% versus 83.3%, and 0.86 versus 0.82, respectively. B-ALP was apparently negatively correlated with bone density (r = - 0.602, P < 0.05), while 25-OH-VD was remarkably positively correlated with bone density (r = 0.576, P < 0.05).
CONCLUSION
To sum up, deep learning-based computer CT image intelligent detection technique could improve the diagnostic efficacy of fracture. B-ALP rose while 25-OH-VD declined among patients with OVCFs and OVCFs could be predicted and diagnosed based on B-ALP and 25-OH-VD. Postoperative intramuscular injection of VD2 could effectively improve the therapeutic effect on patients with OVCFs and QOL.
Topics: Humans; Fractures, Compression; Vitamin D; Alkaline Phosphatase; Quality of Life; Spinal Fractures; Osteoporosis; Osteoporotic Fractures; Vertebroplasty; Kyphoplasty; Bone Cements; Treatment Outcome; Retrospective Studies
PubMed: 37775805
DOI: 10.1186/s13018-023-04144-2 -
The Journal of Clinical Endocrinology... Sep 2023Childhood hyperphosphatasemia is usually transient and may be associated with infections. It remains less well known how hyperphosphatasemia is related to growth and...
CONTEXT
Childhood hyperphosphatasemia is usually transient and may be associated with infections. It remains less well known how hyperphosphatasemia is related to growth and bone mineralization.
OBJECTIVE
We explored alkaline phosphatase (ALP) concentrations and prevalence of hyperphosphatasemia, and their association with vitamin D, growth, infections, and bone parameters in healthy children.
METHODS
The study was a secondary analysis of a vitamin D intervention trial. Participants received vitamin D3 10 or 30 µg daily from age 2 weeks to 2 years. Children with data on ALP at 12 and/or 24 months (n = 813, girls 51.9%) were included. Anthropometrics and bone parameters were measured at 12 and 24 months. Infections were recorded prospectively by the parents.
RESULTS
Boys had higher ALP than girls at 12 months (median [IQR] 287 [241-345] U/L vs 266 [218-341] U/L; P = .02). At 24 months concentrations were lower than at 12 months (240 [202-284]; P < .001) but without sex difference. The prevalence of hyperphosphatasemia (ALP > 1000 U/L) at 12 months was 5.3% and at 24 months 0.6%. Body size, growth rate, and bone mineral content associated positively with ALP, while vitamin D intervention had no effect. Infants with hyperphosphatasemia were smaller than infants with ALP ≤ 1000 U/L. Hyperphosphatasemia was not associated with previous infections.
CONCLUSION
Approximately 5% of infants had hyperphosphatasemia at 12 months, but <1% at 24 months. ALP concentrations and hyperphosphatasemia were associated with sex, anthropometry, and bone mineralization. Infections did not contribute to hyperphosphatasemia.
Topics: Humans; Male; Infant; Female; Child, Preschool; Child; Vitamin D; Alkaline Phosphatase; Vitamins; Bone and Bones; Cholecalciferol
PubMed: 37061810
DOI: 10.1210/clinem/dgad208 -
Translational Cancer Research Oct 2023Alkaline phosphatase (ALP) is a group of enzymes that catalyze hydrolysis of phosphate esters at an alkaline pH, resulting in the generation of inorganic phosphate.... (Review)
Review
Alkaline phosphatase (ALP) is a group of enzymes that catalyze hydrolysis of phosphate esters at an alkaline pH, resulting in the generation of inorganic phosphate. These enzymes are widely distributed, and their activity is found in various tissues including bone, liver, intestine, and placenta. However, abnormalities in ALP expression and activity have been observed in certain types of cancer. In some cases, elevated serum levels of ALP are observed in patients with liver and bone metastasis. In other cases, increased levels of ALP have been observed in patients with pancreatic and lung cancer. On the other hand, low expression of ALP has also been associated with poor prognosis in patients with certain types of tumors, including colorectal cancer (CRC), breast cancer, and non-small cell lung cancer (NSCLC). In these cases, low ALP activity may be associated with decreased differentiation of cancer cells and increased cancer cell proliferation. Overall, the role of ALP in cancer is complex and context-dependent. This article reviews application progress of ALP in cancer, and we hypothesize that ALP might be a potential tumor biomarker, combined detection of aspartate aminotransferase (AST)/alanine aminotransferase (ALT), bone-specific alkaline phosphatase (BSAP), carbohydrate antigen 19-9 (CA 19-9), lactate dehydrogenase (LDH) and ALP isozymes levels can be used for more accurate diagnosis of a particular tumor. Further research is needed to better understand the mechanisms underlying ALP dysregulation in cancer and to identify potential therapeutic targets.
PubMed: 37969388
DOI: 10.21037/tcr-23-1190 -
Nature Communications Jul 2023Hypophosphatasia (HPP) is a metabolic bone disease that manifests as developmental abnormalities in bone and dental tissues. HPP patients exhibit hypo-mineralization and...
Hypophosphatasia (HPP) is a metabolic bone disease that manifests as developmental abnormalities in bone and dental tissues. HPP patients exhibit hypo-mineralization and osteopenia due to the deficiency or malfunction of tissue non-specific alkaline phosphatase (TNAP), which catalyzes the hydrolysis of phosphate-containing molecules outside the cells, promoting the deposition of hydroxyapatite in the extracellular matrix. Despite the identification of hundreds of pathogenic TNAP mutations, the detailed molecular pathology of HPP remains unclear. Here, to address this issue, we determine the crystal structures of human TNAP at near-atomic resolution and map the major pathogenic mutations onto the structure. Our study reveals an unexpected octameric architecture for TNAP, which is generated by the tetramerization of dimeric TNAPs, potentially stabilizing the TNAPs in the extracellular environments. Moreover, we use cryo-electron microscopy to demonstrate that the TNAP agonist antibody (JTALP001) forms a stable complex with TNAP by binding to the octameric interface. The administration of JTALP001 enhances osteoblast mineralization and promoted recombinant TNAP-rescued mineralization in TNAP knockout osteoblasts. Our findings elucidate the structural pathology of HPP and highlight the therapeutic potential of the TNAP agonist antibody for osteoblast-associated bone disorders.
Topics: Humans; Alkaline Phosphatase; Hypophosphatasia; Cryoelectron Microscopy; Bone and Bones; Osteoblasts
PubMed: 37422472
DOI: 10.1038/s41467-023-39833-3 -
International Journal of Molecular... Jul 2023Estrogen deficiency is a major cause of loss of postmenopausal bone mineral density (BMD). This study aimed to evaluate the effects of equol and resveratrol on bone... (Randomized Controlled Trial)
Randomized Controlled Trial
Estrogen deficiency is a major cause of loss of postmenopausal bone mineral density (BMD). This study aimed to evaluate the effects of equol and resveratrol on bone turnover biomarkers in postmenopausal women. Sixty healthy postmenopausal women were randomly assigned to receive 200 mg fermented soy containing 10 mg equol and 25 mg resveratrol or a placebo for 12 months. Whole-body BMD and bone turnover biomarkers, such as deoxypyridinoline (DPD), tartrate-resistant acid phosphatase 5b (TRACP-5b), osteocalcin, and bone-specific alkaline phosphatase (BAP), were measured at baseline and after 12 months of treatment. At the end of treatment, DPD, osteocalcin, and BAP significantly improved in the active group ( < 0.0001 for all) compared to the placebo group. Conversely, TRACP-5b levels were unaffected by supplementation ( = 0.051). Statistically significant changes in the concentrations of DPD ( < 0.0001), osteocalcin ( = 0.0001), and BAP ( < 0.0001) compared to baseline were also identified. Overall, the intervention significantly increased BMD measured in the whole body ( = 0.0220) compared with the placebo. These data indicate that the combination of equol and resveratrol may positively modulate bone turnover biomarkers and BMD, representing a potential approach to prevent age-related bone loss in postmenopausal women.
Topics: Humans; Female; Postmenopause; Equol; Resveratrol; Tartrate-Resistant Acid Phosphatase; Osteocalcin; Bone Density; Alkaline Phosphatase; Biomarkers; Bone Remodeling; Osteoporosis, Postmenopausal
PubMed: 37569440
DOI: 10.3390/ijms241512063 -
Frontiers in Endocrinology 2023There are few population studies on the associations of serum alkaline phosphatase (AlkP) with all-cause and cardiovascular mortality. We aimed to investigate the...
BACKGROUND AND AIMS
There are few population studies on the associations of serum alkaline phosphatase (AlkP) with all-cause and cardiovascular mortality. We aimed to investigate the relevancy of serum AlkP with all-cause and cardiovascular mortality in the general population.
METHODS AND RESULTS
Our research included 34,147 adults in the National Health and Nutrition Examination Survey (NHANES) from 1999 to 2014. Cox proportional hazards regression models were used to assess the associations of serum AlkP with all-cause and cardiovascular mortality. Mediation analysis was used to analyze mechanisms that might link serum AlkP to all-cause and cardiovascular mortality. After 139.7 ± 57.8 months of follow-up, 5413 participants experienced all-cause death and 1820 participants experienced cardiovascular death. Mortality rates per 1000 person-years from various diseases increased with increasing serum concentrations of AlkP, especially all-cause death, cerebrovascular disease and cardiovascular death. High serum AlkP level significantly increased all-cause and cardiovascular mortality. After multivariate adjustment, the highest AlkP group had the highest risk to experience all-cause (hazard ratio [HR] = 1.30, < 0.001) and cardiovascular mortality (HR = 1.39, < 0.001) than the lowest AlkP group. γ-glutamyl transpeptidase (GGT) (13.33% and 15.79%), followed by Vitamin D (8.33% and 7.14%) and C-reactive protein (CRP) (7.69% and 10.35%) were identified as possible major mediators.
CONCLUSION
Higher AlkP concentrations were associated with higher all-cause and cardiovascular mortality, largely related to mediated factors such as GGT, Vitamin D, and CRP. These findings suggest that lower serum AlkP level may reduce all-cause and cardiovascular mortality in general population.
Topics: Adult; Humans; Alkaline Phosphatase; Nutrition Surveys; Cardiovascular Diseases; Risk Factors; Vitamin D
PubMed: 37867513
DOI: 10.3389/fendo.2023.1217369 -
Osteoporosis and Sarcopenia Dec 2023Hypophosphatasia (HPP), also called Rathbun disease, is a rare genetic disorder that is caused by the loss-of-function mutation in the gene encoding tissue non-specific... (Review)
Review
Hypophosphatasia (HPP), also called Rathbun disease, is a rare genetic disorder that is caused by the loss-of-function mutation in the gene encoding tissue non-specific alkaline phosphatase. Doctor Rathbun first described the case of a 3-week-old infant who presented with severe osteopenia, rickets, and multiple radiographic fractures, and died shortly after of epileptic seizure and respiratory distress. The term "hypophosphatasia" was coined as the patients' alkaline phosphatase levels were significantly low. Since then, our understanding of HPP has evolved, and now we appreciate causative genetic mutation and the broad spectrum of clinical presentation depending on the age of onset, severity, and skeletal involvement: perinatal, infantile, childhood, adult and odontohypophosphatasia. The new development of enzyme replacement with asfostase alfa has saved the lives of severe form of hypophosphatasia. However, it is still unclear and remains challenging how to manage adult HPP that often presents with mild and non-specific symptoms such as muscle pain, joint stiffness, fatigue, anxiety, or low bone mass, which are common in the general population and not necessarily attributed to HPP. In this review, we will present 3 unique cases of adult HPP and discuss the pathophysiology, clinical presentation particularly neuromuscular and neurocognitive symptoms and management of adult HPP.
PubMed: 38374822
DOI: 10.1016/j.afos.2023.12.003