A Phase 3 Trial of Seladelpar in Primary Biliary Cholangitis.

BACKGROUND: Effective treatments for patients with primary biliary cholangitis are limited. Seladelpar, a peroxisome proliferator-activated receptor delta agonist, has potential benefits. METHODS: 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). RESULTS: 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. CONCLUSIONS: 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.).

Efficacy and Safety of Elafibranor in Primary Biliary Cholangitis.

BACKGROUND: Primary biliary cholangitis is a rare, chronic cholestatic liver disease characterized by the destruction of interlobular bile ducts, leading to cholestasis and liver fibrosis. Whether elafibranor, an oral, dual peroxisome proliferator-activated receptor (PPAR) α and δ agonist, may have benefit as a treatment for primary biliary cholangitis is unknown. METHODS: In this multinational, phase 3, double-blind, placebo-controlled trial, we randomly assigned (in a 2:1 ratio) patients with primary biliary cholangitis who had had an inadequate response to or unacceptable side effects with ursodeoxycholic acid to receive once-daily elafibranor, at a dose of 80 mg, or placebo. The primary end point was a biochemical response (defined as an alkaline phosphatase level of <1.67 times the upper limit of the normal range, with a reduction of ≥15% from baseline, and normal total bilirubin levels) at week 52. Key secondary end points were normalization of the alkaline phosphatase level at week 52 and a change in pruritus intensity from baseline through week 52 and through week 24, as measured on the Worst Itch Numeric Rating Scale (WI-NRS; scores range from 0 [no itch] to 10 [worst itch imaginable]). RESULTS: A total of 161 patients underwent randomization. A biochemical response (the primary end point) was observed in 51% of the patients (55 of 108) who received elafibranor and in 4% (2 of 53) who received placebo, for a difference of 47 percentage points (95% confidence interval [CI], 32 to 57; P<0.001). The alkaline phosphatase level normalized in 15% of the patients in the elafibranor group and in none of the patients in the placebo group at week 52 (difference, 15 percentage points; 95% CI, 6 to 23; P = 0.002). Among patients who had moderate-to-severe pruritus (44 patients in the elafibranor group and 22 in the placebo group), the least-squares mean change from baseline through week 52 on the WI-NRS did not differ significantly between the groups (-1.93 vs. -1.15; difference, -0.78; 95% CI, -1.99 to 0.42; P = 0.20). Adverse events that occurred more frequently with elafibranor than with placebo included abdominal pain, diarrhea, nausea, and vomiting. CONCLUSIONS: Treatment with elafibranor resulted in significantly greater improvements in relevant biochemical indicators of cholestasis than placebo. (Funded by GENFIT and Ipsen; ELATIVE ClinicalTrials.gov number, NCT04526665.).

The Influence of the Preoperative Albumin to Alkaline Phosphatase Ratio on Overall Survival in Post-Radical Surgery for Colorectal Cancer and the Construction of a Nomogram Prediction Model.

PURPOSE: The albumin to alkaline phosphatase ratio (AAPR) is a newly developed blood biomarker that has been reported to have prognostic value in several types of cancers. The aim of this study was to investigate the predictive value of AAPR in overall survival after radical colon cancer surgery in patients with stage I-III colorectal cancer (CRC). METHODS: The clinical data of 221 eligible patients with stage I ∼ III CRC were retrospectively analyzed. A series of survival analyses were performed to assess the prognostic value of AAPR. Univariate and multifactorial Cox analyses were performed to identify independent risk factors. Columnar graph prediction models were further constructed based on independent risk factors such as AAPR, and their predictive properties were validated. RESULTS: The optimal cutoff value of preoperative AAPR for postoperative overall survival (OS) in patients undergoing laparoscopic radical CRC was .495 as shown by univariate and multifactorial Cox regression analysis. The factors of age ≤65 years, Tumor-Node-Metastasis (TNM) stage I-II, tumor grading (high/medium differentiation), CEA ≤5, and AAPR ≥.495 were associated with better OS (P < .05). CONCLUSIONS: Preoperative AAPR level was a good predictor of postoperative survival in patients undergoing laparoscopic radical CRC surgery, and AAPR <.495 was an independent risk factor for decreased postoperative OS.

Serum alkaline phosphatase can be elevated in patients with hypophosphatasia due to liver disease.

BACKGROUND: Hypophosphatasia (HPP) is a rare inherited disorder caused by pathogenic loss-of-function variants in the ALPL gene, encoding the tissue-nonspecific isoenzym of alkaline phosphatase (ALP; TNSALP). Low serum ALP is the biochemical hallmark of HPP, but it is unknown whether ALP levels can increase due to concurring liver disease, which may lead to a missed diagnose of HPP. We present a patient with genetically confirmed HPP, who showed a transient increase of serum ALP levels due to alcohol-induced hepatitis. CLINICAL REPORT: A 71-year old man was seen at our Bone Center for surveillance of HPP. Serum ALP was always low (23 U/L; reference value: <115 U/L). During follow-up, his serum ALP increased (156 U/L, further rising to 204 U/L), with concomitantly elevated serum gamma-glutamyl transferase and transaminases, and a rise in bone specific ALP (18.7 µg/L; reference value: 5.7-32.9 µg/L). This was attributed to alcohol-induced hepatitis. After refraining from alcohol intake, both serum ALP and bone specific ALP levels returned to initial low levels (30 U/L and 4.3 µg/L respectively). CONCLUSIONS: We demonstrated the history of a 71-year old patient with HPP, presenting during routine follow-up with an elevated serum ALP level up to 204 U/L due to alcohol-induced hepatitis. This case illustrates that the diagnosis of HPP can potentially be missed when ALP levels are normal or elevated due to a concomitant liver disease.

A ratiometric fluorescent probe for simultaneous detection of L-ascorbic acid and alkaline phosphatase activity based on red carbon dots/polydopamine nanocomposite.

Herein, efficient red carbon dots (R-CDs) were synthesized by one-step hydrothermal treatment of N-(4-amino phenyl) acetamide and (2,3-difluoro phenyl) boronic acid. The optimal emission peak of R-CDs was at 602 nm (under 520 nm excitation) and the absolute fluorescence quantum yield of R-CDs was 12.9%. Polydopamine, which was formed by the self-polymerization and cyclization of dopamine in alkaline condition, emitted characteristic fluorescence with peak position of 517 nm (under 420 nm excitation) and affected the fluorescence intensity of R-CDs through inner filter effect. L-Ascorbic acid (AA), which was the hydrolysis product of L-ascorbic acid-2-phosphate trisodium salt under the catalytic reaction of alkaline phosphatase (ALP), effectively prevented the polymerization of dopamine. Combined with the ALP-mediated AA production and the AA-mediated polydopamine generation, the ratiometric fluorescence signal of polydopamine with R-CDs was correlated closely with the concentration of both AA and ALP. Under optimal conditions, the detection limits of AA and ALP were 0.28 µM during linear range of 0.5-30 µM and 0.044 U/L with linear range of 0.05-8 U/L, respectively. This ratiometric fluorescence detection platform can efficiently shield the background interference of sophisticated samples by introducing a self-calibration as reference signal in a multi-excitation mode, which can detect AA and ALP in human serum samples with satisfactory results. Such R-CDs/polydopamine nanocomposite provides a steadfast quantitative information and makes R-CDs be excellent candidate for biosensors via combining target recognition strategy.

Total alkaline phosphatase levels by gestational age in a large sample of pregnant women.

INTRODUCTION: Total alkaline phosphatase (tALP) levels rise physiologically in maternal serum during pregnancy, and excessively so in certain conditions. However, current reference values are dated, nonlinear, and based on small samples. Factors related to variation in tALP remain unexplained. Thus, our goals in this study were to establish a physiological development curve for tALP within low-risk pregnancies and to evaluate the factors influencing tALP values. METHODS: This was a single-center, retrospective, observational study. All patients who delivered a live singleton infant at our center from January 1, 2011 to May 31, 2019, and had a tALP assay during pregnancy, were included regardless of the gestational age at which the assay was conducted. RESULTS: A total of 2415 pregnancies were included. Median tALP decreased during the first trimester, it increased slightly during the second trimester, and then increased sharply during the third trimester. Factors associated with a significant increase in tALP were chronic histiocytic intervillositis, cholestasis, multiple pregnancies, liver disease, preeclampsia, smoking, and low weight for gestational age. Conversely, gestational diabetes was associated with a discrete decrease in tALP. DISCUSSION: Our large sample allowed establishment of tALP reference curves based on gestational age. To interpret these results more thoroughly, factors that influence tALP rates should be further scrutinized.

Association between serum alkaline phosphatase and cardiovascular events in patients with atrial fibrillation.

High alkaline phosphatase (ALP) levels are reported to be associated with an increased risk of cardiovascular events in patients with chronic kidney disease (CKD). Given the pathological link with CKD, a similar relationship may exist in patients with atrial fibrillation (AF). We retrospectively evaluated 1,719 patients with AF and normal hepatic function who were registered in the Shinken Database between November 2011 and March 2017. Study patients were divided into three groups according to ALP value tertiles with cut-offs of 175 and 227 IU/L (normal range: 95-350 IU/L). Each group's incidence rate was recorded, and the risks of cardiovascular events and each component for patients in the middle and high ALP tertiles were compared with those in the low tertile and evaluated using Cox regression models. The additional predictive value of the high ALP tertile over the existing risk scores for the components of cardiovascular events was evaluated via receiver operating characteristic (ROC) curve analysis. During the median follow-up of 731 days (IQR: 444-1095 days), 137 cardiovascular events occurred, with incidence rates of 2.94%, 3.44%, and 6.19%/person-year for the low, middle, and high ALP tertiles, respectively. Of these cardiovascular events, heart failure had the highest incidence rates (1.34%, 1.89%, and 4.29%/person-year for the low, middle, and high ALP tertiles, respectively) and the incidence rates of the other components of cardiovascular event were similar in each ALP groups. Multivariate Cox regression analysis yielded hazard ratios of 1.22 (95% confidence interval [CI] 0.70-1.96) and 1.62 (95% CI 1.06-2.48) for cardiovascular events and 1.66 (95% CI 0.87-3.15) and 2.50 (95% CI 1.39-4.48) for heart failure admission in the middle and high ALP tertiles, respectively. By ROC curve analysis for heart failure admission showed that the high ALP tertile lacked significant additive predictive value over the existing risk scores. High serum ALP levels, even those in the normal range, were significantly associated with an increased risk of cardiovascular events, especially heart failure admission in patients with AF.

Changes in bone turnover markers in adolescents with gastroesophageal reflux disease treated with lansoprazole.

Background: Proton pump inhibitors (PPIs) have been suggested to lead to bone resorption, while the effects of PPIs on the bone mineral metabolism in children has received only limited attention in literature to date. The present study investigates whether lansoprazole alters bone turnover markers in adolescents with gastroesophageal reflux disease (GERD). Patients and methods: Included in the study were adolescents aged 16-18 with GERD and a healthy volunteers group. The GERD patient group was treated with lansoprazole 30 mg once daily for eight weeks. The serum calcium, phosphorus, magnesium, alkaline phosphatase (ALP), parathormone (PTH), 25 (OH) vitamin D, osteocalcin and urinary calcium, creatinine, deoxypyridinoline (DPD), collagen type-1 crosslinked C-telopeptide (CTX) and collagen type-1 crosslinked N-telopeptide (NTX) of both groups were studied before and after the end of the treatment. Results: A comparison of the 30 patients with GERD and the 30 volunteers revealed no significant difference in the serum calcium, phosphorus, magnesium, ALP, urinary calcium/creatinine ratio, 25 (OH) vitamin D and PTH levels measured before and after the lansoprazole treatment, while the osteocalcin, DPD, CTX and NTX values were found to be higher after treatment when compared to those at pre- treatment. Conclusions: The results of this study reveal that eight weeks of treatment with 30 mg lansoprazole daily increased the bone turnover markers of CTX, NTX, DPD and osteocalcin in adolescents aged 16-18.

The Relationship between the SUVmax Value Obtained in Ga-68 PSMA PET/CT and Lactate Dehydrogenase and Alkaline Phosphatase in Prostate Cancer

Objectives: ALP and LDH are serum markers of prognostic importance in prostate cancer patients. PET/CT imaging with Ga-68 PSMA has played an important role in prostate cancer imaging in recent years. Our aim in this study was to evaluate the relationship and prognostic significance between SUVmax values obtained with Ga-68 PSMA PET/CT and LDH and ALP levels in prostate cancer patients. Methods: We retrospectively evaluated 61 prostate cancer patients who had Ga-68 PSMA PET/CT imaging and who did not have a prostatectomy between 2019 and 2020. PSA, ALP and LDH levels were measured in all patients before or after imaging within a maximum of 28 days. Results: The median age of the patients included in this study was 73 (range: 57–89) and all 61 patients were prostatic adenocarcinoma. 50 (82%) of the patients had distant metastasis in Ga-68 PSMA PET/CT. There was a significant positive correlation between serum LDH and PSA levels. There was a positive correlation between serum ALP and PSA levels. A negative correlation was found between ALP levels and prostate SUVmax. Conclusions: While negative correlation was found between SUVmax and ALP levels, no correlation was found between LDH levels and SUVmax. High ALP levels were found to be related to metastasis rates and severity and high serum PSA levels (AU)

Objetivos: ALP y LDH son marcadores séricos deimportancia pronóstica en pacientes con cáncer de próstata.Las imágenes de PET/CT con Ga-68 PSMA han jugado unpapel importante en las imágenes de cáncer de próstata enlos últimos años. Nuestro objetivo en este estudio fue evaluar la relación y la importancia pronóstica entre los valores de SUVmax obtenidos con Ga-68 PSMA PET/CT ylos niveles de LDH y ALP en pacientes con cáncer de próstata.Métodos: Evaluamos retrospectivamente a 61 pacientes con cáncer de próstata que se sometieron a imágenes de PET/CT con Ga-68 PSMA y que no se sometierona prostatectomía entre 2019 y 2020. Los niveles de PSA,ALP y LDH se midieron en todos los pacientes antes o después de la obtención de imágenes en un plazo máximo de28 días.Resultados: La mediana de edad de los pacientes incluidos en este estudio fue de 73 (rango: 57–89) y los 61pacientes eran adenocarcinoma de próstata. 50 (82%) delos pacientes tenían metástasis a distancia en Ga-68 PSMAPET/CT. Hubo una correlación positiva significativa entrelos niveles séricos de LDH y PSA. Hubo una correlaciónpositiva entre los niveles séricos de ALP y PSA. Se encontró una correlación negativa entre los niveles de ALP y elSUVmáx prostático.Conclusiones: Si bien se encontró una correlaciónnegativa entre los niveles de SUVmáx y ALP, no se encontró correlación entre los niveles de LDH y el SUVmáx. Seencontró que los niveles altos de ALP estaban relacionadoscon las tasas de metástasis y la gravedad y los niveles altosde PSA en suero. (AU)

Liver function markers predict cardiovascular and renal outcomes in the CANVAS Program.

BACKGROUND: Raised liver function tests (LFTs) have been correlated with multiple metabolic abnormalities and variably associated with cardiorenal outcomes. We sought to systematically test the relationship between LFT levels within the accepted range and major cardiorenal outcomes in a large clinical trial in type 2 diabetes, and the possible impact of placebo-controlled canagliflozin treatment. METHODS: We measured serum alanine aminotransferase (ALT), aspartic aminotransferase (AST), gamma-glutamyl transferase (γGT), alkaline phosphatase (ALP), and bilirubin concentrations in 10,142 patients, at baseline and repeatedly over follow-up. The relation of LFTs to first hospitalized heart failure (HHF), cardiovascular (CV) and all-cause mortality, and progression of renal impairment was investigated using multivariate proportional-hazards models. RESULTS: In univariate association, ALT was reciprocally predictive, and ALP was positively predictive, of all adjudicated outcomes; γGT also was directly associated with CV-but not renal-outcomes. In multivariate models including all 5 LFTs and 19 potential clinical confounders, ALT was independently associated with lower, and γGT with higher, CV outcomes risk. Canagliflozin treatment significantly reduced ALT, AST, and γGT over time. In a fully adjusted model including updated LFT levels and treatment, γGT was independently associated with CV and all-cause mortality, ALP with renal dysfunction progression, and canagliflozin treatment with significant reduction in HHF and renal risk. CONCLUSIONS: Higher γGT levels are top LFT markers of risk of HHF and death in patients with diabetes and high CV risk, while ALT are protective. Canagliflozin lowers the risk of HHF and renal damage independently of LFTs and potential confounders.

The correlation between serum total alkaline phosphatase and bone mineral density in young adults.

BACKGROUND: Elevated total alkaline phosphatase (T-ALP) levels are usually indicative of enhanced osteoblastic activity and bone conversion status and are thus considered as a key factor needed for fresh bone mineralization and synthesis. To date, there is no consistent conclusion on the association between the serum T-ALP levels and bone mineral density (BMD). Therefore, the present study focused on exploring the association of serum T-ALP with lumbar BMD among young adults. METHODS: The present cross-sectional study included 6,331 subjects included in the National Health and Nutrition Examination Survey (NHANES) during 2011-2016. The participants aged 20-40 years included 3,349 males and 2,982 females. Serum T-ALP was our main variable, lumbar BMD was our outcome variable, and additional variables were the possible impact modifiers. The relations were analysed by the trend study, weighted multiple linear regression models, smooth curve fitting, and stratified analyses. RESULTS: In a completely corrected multiple regression model, a negative association between serum T-ALP and lumbar BMD was discovered (ß = -0.0007, 95% CI: -0.0009- -0.0005, P < 0.000001). After converting the continuous variable serum T-ALP into the categorical one, the significant negative association was still observed (P < 0.001), and in the subgroup and smooth curve fitting analyses, this negative correlation remained significant, too. CONCLUSIONS: Our study results indicated that serum T-ALP was negatively associated with lumbar BMD among young adults. Serum T-ALP measurement in the near future might become an effective biomarker to diagnose and treat osteoporosis on time.

Comparison of two methods measuring serum alkaline phosphatase in neonates.

BACKGROUND: Serum alkaline phosphatase (ALP) is a useful bone turnover marker to diagnose metabolic bone disease in preterm infants. In Japan, serum ALP levels were generally measured using the Japan Society of Clinical Chemistry (JSCC) method. It is problematic that ALP levels measured using the JSCC method tend to be higher in people with blood types B and O regardless of the disease. For international standardization, since 2020, the International Federation of Clinical Chemistry and Laboratory Medicine (IFCC) method has been used as a reference method for ALP measurement instead of the JSCC method. However, no report has investigated the correlation between these two methods in neonates. We therefore aimed to compare the JSCC and IFCC methods and demonstrate a conversion formula in neonates. METHODS: In this retrospective study, we used a total of 402 samples in 49 preterm and 38 term infants. Serum ALP levels were measured using the JSCC and IFCC methods. RESULTS: Alkaline phosphatase measured using the JSCC method strongly correlated with that measured using the IFCC method in all blood types in preterm and term infants (P < 0.01 for all). CONCLUSIONS: We found that the serum ALP levels measured using the IFCC method could be calculated as 0.34 times the ALP levels measured using the JSCC method in preterm and term infants with any blood type: ALP levels (IFCC method) = 0.34 × ALP levels (JSCC method).

Role of Wnt-signaling inhibitors DKK-1 and sclerostin in bone fragility associated with Turner syndrome.

PURPOSE: Girls affected with Turner syndrome (TS) present with low bone mineral density (BMD) and osteopenia/osteoporosis. Thus, they have an increased risk to develop fractures compared to normal population. The aim of this study was to deepen the pathophysiology of skeletal fragility in TS subjects by evaluating the serum levels of Dickkopf-1 (DKK-1) and sclerostin, main regulators of bone mass, as well as the percentage of circulating osteoblast precursors (OCPs). METHODS: Thirty-four TS girls and 24 controls were recruited. All subjects underwent anthropometric measures (height, weight, body mass index-BMI). A peripheral venous blood sample was collected to determine serum levels of active intact parathyroid hormone (PTH), 25-OH vitamin D, calcium, phosphorus, bone alkaline phosphatase (bALP), osteocalcin, sclerostin, DKK-1, RANKL and OPG. OCPs were detected by flow cytometry. In TS subjects bone mineralization was measured at lumbar spine by dual energy X-ray absorptiometry (DXA). RESULTS: bALP, 25-OH Vitamin D, and osteocalcin levels were significant lower in TS subjects than in the controls. Statistically significant higher levels of sclerostin, DKK-1 and RANKL were measured in patients compared with the controls. The percentage of OCPs did not show significant differences between patients and controls. Sclerostin and DKK-1 levels were related with anthropometric parameters, bone metabolism markers, HRT, rhGH therapy, RANKL and lumbar BMAD-Z-score. CONCLUSION: TS patients showed higher levels of sclerostin and DKK-1 than controls which can be related to HRT, and to reduced bone formation markers as well as the increased bone resorption activity.

Prevalence of Low Serum Alkaline Phosphatase and Hypophosphatasia in Adult Patients with Atypical Femur Fractures.

Hypophosphatasia (HPP) is a rare genetic disorder characterized by low serum alkaline phosphatase (ALP), its manifestations may include atypical femoral fractures (AFF). However, the prevalence of low serum ALP and HPP in patients with AFF remains unknown. We retrospectively analyzed ALP levels and clinical manifestations compatible with HPP in 72 adult patients with confirmed AFF by chart review. ALP values were compared with those of a control group of patients with prior proximal femoral fracture during antiresorptive treatment (n = 20). Among the AFF patients, 18 (25%) had at least one serum ALP value ≤ 40 IU/L, although in all but one case, at least one ALP value > 40 IU/L was also detected at another time point. Most low ALP values were associated with antiresorptive treatment (P = 0.049) and lowest levels of ALP did not differ between the AFF and the control groups (P = 0.129). However, low ALP values among AFF patients were associated with a higher rate of bilateral AFF (50% vs 22%, P = 0.025), metatarsal fracture (33% vs 7%, P = 0.006), and with trends for more frequent use of glucocorticoid (22% vs 8%, P = 0.089) and proton pump inhibitor (61% vs 44%, P = 0.220). In one AFF patient with low ALP and clinical suspicion of HPP, a rare pathogenic heterozygous variant of the ALPL gene was identified. In conclusion, low ALP values are common among subjects with AFF and mainly related to concomitant antiresorptive medication. Hence, low serum ALP has low specificity for HPP among AFF patients.

Icariin attenuates thioacetamide­induced bone loss via the RANKL­p38/ERK­NFAT signaling pathway.

There is an increasing incidence of destructive bone disease caused by osteoclast proliferation. This is characterized by reduced bone mass and imbalance of bone homeostasis. Icariin (ICA), a flavonoid compound isolated from Epimedium, has anti­osteoporosis activity and inhibits the formation of osteoclasts and bone resorption. The purpose of the present study was to investigate the protective effect of ICA on osteoclastic differentiation induced by thioacetamide (TAA) and its possible mechanism in Sprague Dawley (SD) rats. In the present study, SD rats were intraperitoneally injected with TAA (300 mg/kg) for the bone loss model, treated with ICA (600 mg/kg, intragastric gavage) in the ICA group and TAA+ICA group for treatment of bone loss for 6 weeks. Indexes associated with bone metabolism, such as alkaline phosphatase, N­terminal telopeptide of type­I collagen (NTX­I), calcium (Ca), phosphorus (P) and magnesium (Mg) in the serum, were detected. Osteoclast differentiation of femoral tissues was detected by hematoxylin and eosin and tartrate­resistant acid phosphatase staining. The femoral bone mass was evaluated using a three­point bending test and micro computed tomography. Western blotting was used to detect the expression levels of osteoclast­related proteins in each group. In the rats treated with TAA, the serum concentrations of Ca, P and Mg were decreased, the serum concentration of NTX­I was increased, osteoclast differentiation of the femur was increased, femur bone stress and bone mass were decreased and the bone loss and osteoclast formation were reduced after ICA treatment. In addition, ICA inhibited the protein expression of receptor activator of nuclear factor κ­Β ligand (RANKL), receptor activator of nuclear factor κ­B (RANK), p38, ERK, c­Fos and nuclear factor of activated T cells 1 (NFATc1) in the femur of rats treated with TAA. The results suggested that ICA may inhibit osteoclast differentiation by downregulating the RANKL­p38/ERK­NFAT signaling pathway and prevent TAA­induced bone loss. The results are helpful to understand the mechanism of osteoclast differentiation induced by TAA, as well as the antiresorptive activity and molecular mechanism of ICA, and to provide new ideas for the treatment of osteolytic diseases.

Fluorescent assay of alkaline phosphatase activity via atom transfer radical polymerization.

A novel fluorescence assay is proposed through activators regenerated by electron transfer atom transfer radical polymerization (ARGET ATRP) strategy for alkaline phosphatase (ALP) activity detection. First of all, 2-bromo-2-methylpropionic acid (BMP) was employed as the initiator to modify on the surface of the magnetic nanoparticle (Fe3O4-MNP) by amide bonding. Then, ascorbic acid (AA) produced by ALP catalyzed the phosphate group removal from L-ascorbic acid 2-phosphate sesquimagnesium salt hydrate (AAPS), which underwent a redox reaction with Cu(II) and the product Cu(I) triggered the ARGET ATRP reaction. Finally, a strong fluorescent signal could be detected at 514 nm due to numerous fluorescent monomers being grafted to the Fe3O4-MNPs surface (Ex = 490 nm, Em = 514 nm). Under optimal experimental conditions, the linear range of this fluorometric assay for ALP activity was 1-80 mU mL-1, and the detection limit was 0.68 mU mL-1. The method exhibited excellent selectivity and satisfactory results were obtained in the inhibition rate and human serum experiments. Therefore, this ALP activity detection strategy has great potential for clinically relevant disease detection and drug screening. A novel fluorescence strategy for alkaline phosphatase activity detection based on the dephosphorylation property of alkaline phosphatase and ARGET ATRP reaction.

The association between elevated lipid profile and liver enzymes: a study on Bangladeshi adults.

Dyslipidemia, a major contributor to cardiovascular diseases, is rapidly increasing in Asian countries including Bangladesh. In addition to the cardiovascular system, abnormal lipid levels are also known to cause complications in renal and hepatic systems. The data regarding dyslipidemia and its relationship with liver enzymes are scarce for the Bangladeshi population. Therefore, this study was conducted to estimate the prevalence of dyslipidemia and determine the relationship between lipid profile and liver enzymes in Bangladeshi adults. A total of 405 participants (318 males and 87 females) were enrolled in the study. Serum levels of TG, TC, LDL, HDL and liver enzymes including ALT, AST, GGT and ALP were analyzed using standard methods. Dyslipidemia and liver function tests abnormalities were defined according to the international standard guidelines. The association between elevated lipid profile markers and liver enzyme abnormalities was assessed by logistic regression analysis. Overall, the prevalence of elevated TG, TC, LDL and low HDL were 30.9%, 23.7%, 26.2% and 78.8%, respectively. On the other hand, the prevalence of elevated liver enzymes ALT, AST, GGT and ALP were 18.8%, 21.6%, 12.9% and 21.9%, respectively. Dyslipidemia and liver enzyme abnormalities were higher in diabetic and hypertensive participants than in the healthy participants. About 61% of participants with dyslipidemia had at least one or more elevated liver enzymes. In regression analysis, an independent association was observed between serum GGT and all lipid components. In conclusion, a high prevalence of dyslipidemia and liver enzyme abnormalities were observed among the study participants. Of the four liver enzymes, the serum levels of GGT showed an independent association with all lipid components. Moreover, this study indicates that subjects with dyslipidemia often have a higher chance of having liver diseases than subjects with no dyslipidemia. However, large-scale prospective studies are needed to understand the underlying mechanisms of lipid-induced hepatic dysfunction in the Bangladeshi population.

Hydrogel-Involved Colorimetric Platforms Based on Layered Double Oxide Nanozymes for Point-of-Care Detection of Liver-Related Biomarkers.

Monitoring the liver status in a convenient and low-cost way is significant for obtaining a warning about drug-indued liver diseases promptly. Herein, we designed a novel colorimetric point-of-care (POC) platform for the determination of three liver-related biomarkers─aspartate transaminase (AST), alanine transaminase (ALT), and alkaline phosphatase (ALP). This platform integrated agarose hydrogels into a portable device, where hydrogels were loaded with nanozymes and different reaction substances for triggering specific reactions and generating colorimetric signals. Typically, Au-decorated CoAl-layered double oxide (Au/LDO) was for the first time developed as the nanozyme with peroxidase (POD) mimic activity, which can accelerate the oxidation of colorless 3,3',5,5'-tetramethylbenzidine (TMB) to blue oxTMB with the coexistence of hydrogen peroxide (H2O2). The detection mechanism of AST and ALT is based on the fact that they can cause individual cascade reactions to generate H2O2, and H2O2 further activates the Au/LDO nanozyme to catalyze the chromogenic reaction of TMB. As for ALP, it can catalytically hydrolyze l-ascorbic acid-2-phosphate to ascorbic acid. The latter then discolored the oxTMB that was produced with the assistance of Au/LDO. Teaming up with a smartphone, the color information of hydrogels can be converted to hue values, which allow quantitative analysis of ALT, AST, and ALP with detection limits of 15, 10, and 5 U/L, respectively. Moreover, the simple and cost-effective platform was successfully applied for the simultaneous determination of the three analytes in human plasma. Additionally, since the hydrogel is disposable and can be replaced by new ones loaded with different reaction regents, the platform is expected to serve the POC testing of various chem/bio targets.

Prognostic Value of ALP and LDH in Periampullary Carcinoma Patients Undergoing Surgery.

OBJECTIVE: Conversion of normal cells to cancer cells is often accompanied by abnormal synthesis of serum enzymes. Both alkaline phosphatase (ALP) and lactate dehydrogenase (LDH) have been reported to have prognostic value in a variety of malignancies. The aim of this study was to investigate the effect of preoperative serum ALP and LDH levels on the prognosis of patients with periampullary carcinoma who underwent pancreatoduodenectomy (PD). METHODS: According to the preoperative ALP or LDH values, 856 cancer patients receiving PD treatment from January 2001 to January 2019 were divided into high-ALP group and low-ALP group or high-LDH group and low-LDH group. Statistical analysis was carried out to study the differences between the high-ALP and low-ALP groups or the high-LDH and low-LDH groups. Furthermore, the possibility of preoperative ALP or LDH as prognostic factor of periampullary carcinoma was investigated. RESULTS: In both the high-ALP and the high-LDH groups, the prognosis of patients with periampullary carcinoma who underwent PD was worse than that of the low-ALP and low- LDH group. Even through risk factor analysis, it was found that preoperative ALP and LDH could be independent prognostic factor for patients with periampullary carcinoma who underwent PD. CONCLUSION: Preoperative ALP or LDH is an independent risk factor for periampullary carcinoma.