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BMC Chemistry Oct 2023[1,8]-Naphthyridine derivatives have been reported to possess important biological activities and may serve as attractive pharmacophores in the drug discovery process....
[1,8]-Naphthyridine derivatives have been reported to possess important biological activities and may serve as attractive pharmacophores in the drug discovery process. [1,8]-Naphthyridine derivatives (1a-1l) were evaluated for inhibitory potential for isozymes of carbonic anhydrase (CA) and alkaline phosphatase (ALP). CAs have been reported to carry out reversible hydration of CO into HCO, secretion of electrolytes, acid-base regulation, bone resorption, calcification, and biosynthetic reactions. Whereas ALPs hydrolyze monophosphate esters with the release of inorganic phosphate and play an important role in bone mineralization. Both enzymes have been found to be over-expressed and raised functional activities in patients suffering from rheumatoid arthritis. The discovery of dual inhibitors of these enzymes may provide a synergistic effect to cure bone disorders such as rheumatoid arthritis and ankylosing spondylitis. Among the test compounds, the most potent inhibitors for CA-II, CA-IX, and CA-XII were 1e, 1g, and 1a with IC values of 0.44 ± 0.19, 0.11 ± 0.03 and 0.32 ± 0.07 µM, respectively. [1,8]-Naphthyridine derivatives (1a-1l) were approximately 4 folds more potent than standard CA inhibitor acetazolamide. While in the case of ALPs, the most potent compounds for b-TNAP and c-IAP were 1b and 1e with IC values of 0.122 ± 0.06 and 0.107 ± 0.02 µM, respectively. Thus, synthesized derivatives proved to be 100 to 800 times more potent as compared to standard inhibitors of b-TNAP and c-IAP (Levamisole and L-phenyl alanine, respectively). In addition, selectivity and dual inhibition of [1,8]-Naphthyridine derivatives confer precedence over known inhibitors. Molecular docking and molecular simulation studies were also conducted in the present studies to define the type of interactions between potential inhibitors and enzyme active sites.
PubMed: 37880684
DOI: 10.1186/s13065-023-01052-8 -
ACR Open Rheumatology Oct 2023Hypophosphatasia (HPP) is a rare disease characterized by incomplete or defective bone mineralization due to a mutation in the alkaline phosphatase (ALP) gene causing...
OBJECTIVE
Hypophosphatasia (HPP) is a rare disease characterized by incomplete or defective bone mineralization due to a mutation in the alkaline phosphatase (ALP) gene causing low levels of ALP. Disease presentation is heterogeneous and can present as a chronic pain syndrome like fibromyalgia (FM). Our objective was to determine if there are any potential patients with HPP in the group of patients who were diagnosed with FM. Antiresorptive therapy use can trigger atypical femur fractures in patients with HPP.
METHODS
We performed a retrospective chart review of all patients 18 years or older at a single academic center who were diagnosed with FM and had either a low or a normal ALP level. The following characteristics were reviewed: biological sex; age; history of fractures; diagnosis of osteoporosis, osteopenia, osteoarthritis, and chondrocalcinosis; genetic testing; vitamin B6 level testing; and medications.
RESULTS
Six hundred eleven patients with FM were identified. Two hundred had at least one low ALP level, and 57 had at least three consecutively low measurements of ALP, 44% of which had a history of fractures. No patients had vitamin B6 levels checked. None of the patients had previous genetic testing for HPP or underwent testing for zinc or magnesium levels.
CONCLUSION
The percentage of patients with FM who were found to have consistently low ALP levels was 9.3%. None had vitamin B6 level or genetic testing, suggesting that the diagnosis was not suspected. It is important to diagnose HPP given the availability of enzyme replacement therapy to prevent complications from HPP such as fractures. Our data support screening for this condition as a part of the initial workup of FM.
PubMed: 37661663
DOI: 10.1002/acr2.11591 -
Archives of Pathology & Laboratory... May 2024Interpretation of alkaline phosphatase (ALP) activity is essential for the diagnosis of certain diseases. ALP changes during life and may vary between different...
CONTEXT.—
Interpretation of alkaline phosphatase (ALP) activity is essential for the diagnosis of certain diseases. ALP changes during life and may vary between different populations.
OBJECTIVE.—
To establish reference intervals (RIs) and percentile charts for ALP activity in the Spanish population through a multicentric observational study and to compare the RIs to those defined in other countries.
DESIGN.—
A total of 662 350 ALP measurements from individuals ages 0 to 99 years from 9 Spanish tertiary care centers collected between 2020 and 2022 were analyzed. This study is the largest published in the literature to date.
RESULTS.—
Continuous percentile charts for ALP according to sex and age were established which can be used as RIs. Higher levels are reached during the first weeks of life. In puberty, a differential evolution is observed in both sexes, reaching a peak at 10 to 13 years of age in boys and remaining stable in girls at this age. Significant differences were also observed in adults, higher in men between ages 20 and 49 years and between ages 50 and 79 years in women, as reported in some countries.
CONCLUSIONS.—
ALP activity follows an age- and sex-dependent fluctuation with geographic differences. It is important to have appropriate reference values for each population in order to allow for a correct diagnostic interpretation and early diagnosis of diseases related to ALP abnormalities.
PubMed: 38797525
DOI: 10.5858/arpa.2023-0335-OA -
Current Oncology (Toronto, Ont.) Jul 2023Osteosarcoma is a highly aggressive malignant bone tumor that affects mainly adolescents and young adults. We analyzed serum biomarkers for their prognostic significance...
BACKGROUND
Osteosarcoma is a highly aggressive malignant bone tumor that affects mainly adolescents and young adults. We analyzed serum biomarkers for their prognostic significance in children with osteosarcoma.
METHODS
In this retrospective study, we investigated the prognostic factors in 210 children who were treated for appendicular osteosarcoma, including patient age and sex, tumor site and size (≥8 cm or <8 cm), presence of metastasis, chemotherapy-induced tumor necrosis, serum levels of alkaline phosphatase (AP), C-reactive protein, serum hemoglobin, lactate dehydrogenase, erythrocyte sedimentation rate (ESR), leukocyte counts, platelet count, and neutrophil-lymphocyte ratio.
RESULTS
A multivariate Cox regression model showed that high level of AP [HR of 1.73; 95% CI, 1.02 to 2.94], poor chemotherapy-induced tumor necrosis [HR of 2.40; 95% CI, 1.41 to 4.08] and presence of metastases at presentation [HR of 3.71; 95% CI, 2.19 to 6.29] were associated with poor prognosis at 5 years ( < 0.05). Inadequate surgical margins [HR 11.28; 95% CI, 1.37 to 92.79] and high levels of ESR [HR 3.58; 95% CI, 1.29 to 9.98] showed a greater risk of local recurrence at 5 years follow-up ( < 0.05).
CONCLUSIONS
AP and ESR can identify osteosarcoma-diagnosed children with a greater risk of death and local recurrence, respectively.
Topics: Adolescent; Young Adult; Humans; Child; Prognosis; Retrospective Studies; Osteosarcoma; Extremities; Bone Neoplasms; Biomarkers; Necrosis; Antineoplastic Agents
PubMed: 37504371
DOI: 10.3390/curroncol30070511 -
Renal Failure Dec 2023Patients with chronic kidney disease, especially those undergoing hemodialysis (HD), have a higher risk of fragility fractures. However, the magnitude of the problem and...
BACKGROUND
Patients with chronic kidney disease, especially those undergoing hemodialysis (HD), have a higher risk of fragility fractures. However, the magnitude of the problem and risk factors associated with fracture incidence have not been well studied in the Kingdom of Saudi Arabia.
METHODS
This multicenter retrospective study involved HD centers in Jeddah from 2015 to 2021. This study included all adult HD patients. Patient demographics, medication usage, and clinical and biochemical parameters were collected from the registry records.
RESULTS
The study included 328 patients on HD, with a mean age of 53 years. The median duration of HD was 47 months. Osteoporosis was found in 9% of the patients, and 8% had a previous parathyroidectomy. Over the observation period, fractures occurred in 32 patients, with an incidence rate of 20 case/1000 end stage kidney disease patients-year. Patients with fractures had a higher rate of osteoporosis, underwent more parathyroidectomy, had longer HD vintage, and higher bone-specific alkaline phosphatase (BSAP) levels. BSAP was the most significant predictor of fracture incidence in the regression analysis. Using a BSAP cutoff value of 96.6 µg/L, the sensitivity and specificity to predict fractures were 81.8% and 49%, respectively.
CONCLUSION
The main risk factors for incident fractures were osteoporosis, previous parathyroidectomy, longer HD vintage, and higher BSAP level. A higher BSAP score was the most significant predictor of incident fractures. This may highlight the importance of monitoring bone turnover markers and the negative impact of high bone turnover on patient health.
Topics: Adult; Humans; Middle Aged; Alkaline Phosphatase; Fractures, Bone; Incidence; Osteoporosis; Renal Dialysis; Retrospective Studies
PubMed: 37345711
DOI: 10.1080/0886022X.2023.2224456 -
Acta Paediatrica (Oslo, Norway : 1992) Dec 2023Individuals with spinal muscular atrophy (SMA) are at risk of developing skeletal problems. This study investigated bone mineral density (BMD), bone turnover markers and...
AIM
Individuals with spinal muscular atrophy (SMA) are at risk of developing skeletal problems. This study investigated bone mineral density (BMD), bone turnover markers and motor function in children and adolescents with SMA type 2 and type 3 over a two-year period. The effect of nusinersen was studied in a subgroup.
METHODS
Single-centre study, including 20 patients, 2-18 years, of whom ten patients received nusinersen treatment. BMD was measured by dual-energy X-ray absorptiometry.
RESULTS
All patients had low BMD levels at baseline; mean Z-score -2.3 for total body less head (TBLH) and -2.9 for total hip left (THL). Significant correlations were found both at baseline and for the follow-up change for motor function and Z-scores (TBLH and THL). For the whole study group, reduced bone formation and unchanged bone resorption, assessed by bone-specific alkaline phosphatase (BALP) (p = 0.0006, ES = -0.83) and C-terminal cross-linking telopeptide of type I collagen (CTX), respectively, were found over the study period. However, BALP decreased less in the nusinersen treatment group, which suggests a positive development on bone mass in these patients.
CONCLUSION
Bone health evaluation is important in follow-up programmes for SMA patients. Further investigations are warranted for individuals on survival motor neuron-targeted treatments.
Topics: Child; Adolescent; Humans; Bone Density; Alkaline Phosphatase; Prospective Studies; Spinal Muscular Atrophies of Childhood; Bone Remodeling; Bone Diseases, Metabolic; Collagen Type I
PubMed: 37712193
DOI: 10.1111/apa.16974 -
International Journal of Molecular... Jun 2023Over the last few years, intense research efforts have been made to anticipate or improve the diagnosis of Alzheimer's disease by detecting blood biomarkers. However,...
Over the last few years, intense research efforts have been made to anticipate or improve the diagnosis of Alzheimer's disease by detecting blood biomarkers. However, the most promising blood biomarkers identified to date have some limitations, most of them related to the techniques required for their detection. Hence, new blood biomarkers should be identified to improve the diagnosis of AD, better discriminate between AD and mild cognitive impairment (MCI) and identify cognitively unimpaired (CU) older individuals at risk for progression to AD. Our previous studies demonstrated that both the purinergic receptor P2X7 and the tissue-nonspecific alkaline phosphatase ectoenzyme (TNAP) are upregulated in the brains of AD patients. Since both proteins are also present in plasma, we investigated whether plasma P2X7R and TNAP are altered in MCI and AD patients and, if so, their potential role as AD biomarkers. We found that AD but not MCI patients present increased plasma P2X7R levels. Nevertheless, TNAP plasma activity was increased in MCI patients and decreased in the AD group. ROC curve analysis indicated that measuring both parameters has a reasonable discriminating capability to diagnose MCI and AD conditions. In addition to confirming that individuals progressing to MCI have increased TNAP activity in plasma, longitudinal studies also revealed that CU individuals have lower plasma TNAP activity than stable controls. Thus, we propose that P2X7 and TNAP could serve as new plasma biomarkers for MCI and AD.
Topics: Humans; Alzheimer Disease; Alkaline Phosphatase; Biomarkers; Cognitive Dysfunction; Longitudinal Studies; Amyloid beta-Peptides; Disease Progression; tau Proteins
PubMed: 37446074
DOI: 10.3390/ijms241310897 -
World Journal of Hepatology Sep 2023Surrogate endpoints are needed to estimate clinical outcomes in primary sclerosing cholangitis (PSC). Serum alkaline phosphatase was among the first markers studied, but... (Review)
Review
Surrogate endpoints are needed to estimate clinical outcomes in primary sclerosing cholangitis (PSC). Serum alkaline phosphatase was among the first markers studied, but there is substantial variability in alkaline phosphatase levels during the natural history of PSC without intervention. The Mayo risk score incorporates noninvasive variables and has served as a surrogate endpoint for survival for more than two decades. Newer models have better test performance than the Mayo risk score, including the primary sclerosing risk estimate tool (PREsTo) model and UK-PSC score that estimate hepatic decompensation and transplant free survival, respectively. The c-statistics for transplant-free survival for the Mayo risk model and the long-term UK-PSC model are 0.68 and 0.85, respectively. The c-statistics for hepatic decompensation for the Mayo risk model and PREsTo model are 0.85 and 0.90, respectively. The Amsterdam-Oxford model included patients with large duct and small duct PSC and patients with PSC-autoimmune hepatitis overlap and had a c-statistic of 0.68 for transplant-free survival. Other noninvasive tests that warrant further validation include magnetic resonance imaging, elastography and the enhanced liver fibrosis score. Prognostic models, noninvasive tests or a combination of these surrogate endpoints may not only serve to be useful in clinical trials of investigational agents, but also serve to inform our patients about their prognosis.
PubMed: 37900215
DOI: 10.4254/wjh.v15.i9.1013 -
International Journal of Clinical... 2023Skeletal maturity assessment involves radiographic analysis and visual inspection of developing bone and their initial appearance or sequential ossification and related...
INTRODUCTION
Skeletal maturity assessment involves radiographic analysis and visual inspection of developing bone and their initial appearance or sequential ossification and related changes in size and shape along with the expression of various biomarkers in body fluids.
AIM
To investigate the correlation of biomarkers such as salivary alkaline phosphatase (S-ALP) and salivary total protein (STP) with skeletal maturity assessment and growth prediction in growing children.
MATERIALS AND METHODS
A total of 8-15-year-old 150 healthy children were divided into five groups depending upon radiographic stage maturity of the middle phalanx of the left hand's third finger according to the Hagg and Taranger method. Radiographs were taken using intraoral periapical (IOPA) radiographic films.
RESULTS
Salivary alkaline phosphatase (S-ALP) activity in the MP3 G group was significantly higher than MP3 F group and MP3 I group. Total protein levels in MP3 F were significantly lower than in MP3 G. The mean value of S-ALP (33541.45 IU/L) and that of STP (2.77 mg/mL) was observed to be highest in the MP3 G group (G3) group.
CONCLUSION
Salivary total protein (STP) and S-ALP may be used as an additional diagnostic tool to assess skeletal maturation and optimize growth prediction during myofunctional orthodontic treatment.
CLINICAL SIGNIFICANCE
Skeletal maturity assessment plays a significant role in orthodontic diagnosis, treatment planning, and stability of orthodontic treatment. Radiographic parameters involve radiographic exposure; hence in this study noninvasive biomarkers such as S-ALP and STP have been evaluated for skeletal maturity assessment and growth prediction.
HOW TO CITE THIS ARTICLE
Abhangi KK, Choudhari SR, Butala PB, Salivary Total Protein and Alkaline Phosphatase Activity as Biomarkers for Skeletal Maturity and Growth Prediction in Healthy Children: An Study. Int J Clin Pediatr Dent 2023;16(4):603-607.
PubMed: 37731811
DOI: 10.5005/jp-journals-10005-2629 -
Scientific Reports Dec 2023Sarcopenia is a disease characterized by decreased muscle mass and strength, affecting 20-70% of patients with cirrhosis, and is associated with poor prognosis,...
Sarcopenia is a disease characterized by decreased muscle mass and strength, affecting 20-70% of patients with cirrhosis, and is associated with poor prognosis, complications, and high mortality. At present, the epidemiological investigation of sarcopenia in patients with liver cirrhosis is relatively limited, and because of the differences in population characteristics, regions, diagnostic criteria and diagnostic tools, the prevalence of sarcopenia in various studies varies greatly. The definition of sarcopenia in this study adopted the criteria of the Asian Working Group on Sarcopenia (AWGS 2019), including muscle mass and muscle strength / physical performance. A total of 271 patients with liver cirrhosis were included in this cross-sectional study to explore the influencing factors of sarcopenia in patients with liver cirrhosis. The prevalence of sarcopenia was 27.7%, 27.3% in male and 28.4% in female. The results of binary logistic regression analysis showed that age, physical activity, BMI, mid-upper arm muscle circumference, hepatic encephalopathy, nutritional status, alkaline phosphatase, albumin and total cholesterol were significantly correlated with the occurrence of sarcopenia in patients with liver cirrhosis. After adjusting for the potential influencing factors, it was found that the correlation between age and sarcopenia was weakened (OR = 0.870, 95% CI 0.338-2.239). The current findings show that sarcopenia is common in patients with cirrhosis and is independently associated with age, physical activity, BMI, nutritional status, and albumin, and serum alkaline phosphatase and total cholesterol are associated with the development of sarcopenia. Regular exercise may help maintain the grip strength of patients with cirrhosis and delay the deterioration of liver function.
Topics: Humans; Male; Female; Sarcopenia; Cross-Sectional Studies; Case-Control Studies; Alkaline Phosphatase; Liver Cirrhosis; Risk Factors; Muscle, Skeletal; Fibrosis; Hand Strength; Albumins; Cholesterol
PubMed: 38071233
DOI: 10.1038/s41598-023-48955-z