Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts: Gene/Protein Disease Symptom Drug Enzyme Compound   Target Concepts: Gene/Protein Disease Symptom Drug Enzyme Compound

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Query: EC:3.1.3.1 (alkaline phosphatase)
47,916 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Recent evidence suggests that phospholipase A2 (PLA2)-derived lipid mediators may regulate a number of neutrophil responses including degranulation and adhesion. In view of the potential role of PLA2 in stimulus-secretion coupling, we examined the relationship between PLA2 activation and the surface expression of CD11b/CD18 (MAC-1) in human polymorphonuclear leukocytes (hPMNL), including the functional consequences of PLA2 inactivation on MAC-1-dependent adhesion. The selective inhibition of PLA2 by the marine natural products manoalide (MLD) and scalaradial (SLD) blocks [3H]arachidonic acid (AA) release in calcium ionophore A23187-stimulated neutrophils, and also inhibits secretion of specific and azurophilic granule constituents. Additional studies demonstrate that MLD, SLD, and other less potent PLA2 inhibitors such as 4-bromophenacylbromide and nordihydroguiaretic acid inhibit the surface expression of MAC-1 (IC50: MLD, 0.33 microM; SLD, 0.23 microM; 4-bromophenacylbromide, 2.8 microM; NDGA, 3.5 microM) at concentrations similar to those at which they inhibit [3H]AA release. Inhibitors of cyclooxygenase, 5-lipoxygenase, protein kinase C, or calcium channel antagonists have no effect on MAC-1 expression. PLA2 inactivation also prevents MAC-1 up-regulation in hPMNL stimulated with FMLP, IL-8, TNF-alpha, PMA, or platelet activating factor. In FMLP-stimulated hPMNL, under conditions in which no secondary granule constituents are secreted, MAC-1 and alkaline phosphatase up-regulation from intracellular granules is inhibited by MLD and SLD. Functional assays also demonstrate that MLD and SLD block MAC-1-dependent adhesion of activated neutrophils to keyhole limpet hemocyanin at concentrations that block the surface expression of MAC-1. [3H]AA release and MAC-1 expression in MLD and SLD-treated hPMNL could be recovered in the presence of 1 mM hydroxylamine in a time-dependent fashion, consistent with reported data that MLD and SLD inactivate PLA2 through Schiff base formation. In summary, these data emphasize the role of PLA2 as a key regulator of MAC-1 expression in models of neutrophil adhesion.
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PMID:Regulation of CD11b/CD18 expression in human neutrophils by phospholipase A2. 822 53

In this study we examined the effects of continuous calcium channel blocker (CCB) infusion on pancreatic duct-ligated acute pancreatitis (AP) in rabbits. Thirty rabbits were used for this study. Animals in group 1 (n = 10), which served as a control group, underwent dummy operations and received 0.5 microliter/h normal saline via the internal jugular vein. Animals in group 2 (n = 10) with artificially-induced pancreatitis received the same dosage of saline in the same manner. Animals in group 3 (n = 10) with artificially-induced pancreatitis received 180 micrograms/kg/h CCB (Verapamil) via the jugular vein starting from just before pancreatic duct ligation. AP histology score, plasma amylase levels and liver function tests were measured after 48 h. Verapamil infusion did not prevent the rise in plasma amylase levels, nor did it prevent pancreatic inflammation and damage. Serum levels of serum glutamate pyruvate transaminase, serum glutamate oxalacetate transaminase and alkaline phosphatase were significantly elevated in group 2 and significant reductions were seen in the Verapamil treated animals (group 3). The findings in this study imply that a continuous 180 micrograms/kg/h dose Verapamil infusion does not ameliorate the pathogenesis of pancreatitis induced by ligation of pancreatic duct but do not rule out a dose-dependent protective effect. Meanwhile, the lowering of liver function test scores should be considered the beneficial effect of CCBs, and this should be investigated in further studies.
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PMID:Continuous calcium channel blocker infusion in experimentally induced acute pancreatitis: effects on pancreas and liver function. 987 64

Metabolic acidosis is almost invariably a consequence of advanced renal failure, although its severity can vary widely. To evaluate the determinants of the severity of metabolic acidosis, with special interest in determining if there is any difference in the prevalence and severity of metabolic acidosis between patients with and without diabetes, 113 predialysis patients with renal failure were studied. Criteria for inclusion onto the study were: creatinine clearance (Ccr)/1.73 m2 less than 30 mL/min, no alkali therapy within the previous 30 days, and the absence of respiratory diseases. Forty-eight patients had diabetes (33 patients with diabetic nephropathy). The following data were analyzed: demographics; cause of renal failure; hematocrit; serum urea, creatinine, uric acid, albumin, glucose, hemoglobin A1c, bicarbonate, sodium, potassium, chloride, calcium, phosphorus, and alkaline phosphatase levels; anion gap; urinary protein excretion; Ccr/1.73 m2; half of the sum of creatinine and urea clearances (Ccr-Cu); protein-equivalent nitrogen appearance (PNA); and whether the patients received diuretics (75 patients), angiotensin-converting enzyme inhibitors (54 patients), and/or calcium channel blockers (55 patients). After the exclusion of eight patients because of hypochloremia (three patients with and five patients without diabetes), mean serum bicarbonate levels were significantly greater in patients with diabetes than in the rest of the patients (20.7 +/- 2.3 v 18.2 +/- 2. 3 mmol/L; P = 0.0001). The mean anion gap (mmol/L) was also significantly less in patients with than without diabetes (19.70 +/- 3.65 v 22.35 +/- 3.64; P = 0.003). Eleven of 105 patients had serum bicarbonate levels of 23 mmol/L or greater (9 patients with and 2 patients without diabetes). Pure elevated anion gap followed by mixed (high anion gap and hyperchloremia) were the most common types of metabolic acidosis observed in both groups. There were no differences in PNA, diuretic treatment, or vomiting history between patients with and without diabetes. By multiple logistic regression analysis, the best determinants for a serum bicarbonate level greater than 19 mmol/L were: the diagnosis of diabetic nephropathy (odds ratio, 0.107; P = 0.0002), Ccr-Cu (odds ratio, 0.824; P = 0. 014), and age (odds ratio, 0.966; P = 0.046). In conclusion, patients with diabetes with advanced renal failure showed a less severe metabolic acidosis, which cannot be explained by gastrointestinal hydrogen ion losses, drugs, or reduced protein catabolic rate. Patients with diabetes may have a more efficient extrarenal generation of bicarbonate than end-stage renal failure patients without diabetes.
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PMID:Metabolic acidosis in advanced renal failure: differences between diabetic and nondiabetic patients. 1021 45

Several studies have suggested that high blood pressure is associated with the risk of bone loss. Since various antihypertensive drugs are in wide use for the treatment of hypertension, it is important to investigate the influences of these drugs on bone metabolism. Osteoblasts play a pivotal role in the regulation of bone formation. During differentiation, they sequentially express type I collagen, alkaline phosphatase (ALP), other bone matrix proteins, and finally undergo mineral deposition. In this study, we examined the effects of various antihypertensive drugs on the function of osteoblast using clonal MC3T3-E1 cells. Drugs examined include dihydropyridine-type calcium channel blockers (benidipine, amlodipine, and nifedipine), angiotensin-converting enzyme (ACE) inhibitors (captopril, lisinopril, and enalapril), and angiotensin II receptor type1 (AT1) antagonists (TCV-116 and KW-3433). None of the ACE inhibitors or AT1 antagonists affected ALP activity or cellular DNA content significantly. In contrast, benidipine, amlodipine, and nifedipine increased ALP activity when used in amounts 1 pM, 100 nM, and 100 nM, respectively. Benidipine blocked calcium influx through the L-type voltage dependent calcium channel of MC3T3-E1 more potently than amlodipine or nifedipine. These calcium channel blockers did not change collagen accumulation. Benidipine significantly increased in vitro mineralization at a concentration of 1 nM and higher, while amlodipine did so at 1 microM and nifedipine did not. Comparison of the effective concentration of each calcium channel blocker in our study with the reported maximum serum concentration of each drug suggests that benidipine, but not amlodipine or nifedipine, promotes mineral deposition in human.
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PMID:Effects of various antihypertensive drugs on the function of osteoblast. 1141 49

During their differentiation, osteoblasts sequentially express type I collagen, alkaline phosphatase (ALP), and osteocalcin, and then undergo mineral deposition. Among dihydropyridine-type calcium channel blockers, only benidipine stimulated ALP activity of osteoblastic cells derived from neonatal mouse calvaria. To identify the molecular target of benidipine and elucidate the mechanism of action of the drug in osteoblasts, the mouse osteoblastic cell line MC3T3-E1 was used. Benidipine prompted ALP activity and ALP transcription induced by ascorbic acid, and mineral deposition by ascorbic acid and b-glycerophosphate. Benidipine, however, did not change collagen accumulation. MC3T3-E1 cells expressed the L-type Ca channel a1C subunit throughout the differentiation process, and Ca influx by potassium ions and Bay K 8644, an agonist, was strongly attenuated by benidipine. Each one of three structurally different classes of Ca channel blockers, nifedipine, verapamil, and diltiazem stimulated ALP activity, although at much higher concentrations of ca. 100 nM than benidipine, 1 pM. These results suggest that benidipine directly exerts its effect on osteoblasts and promotes osteoblast differentiation after the step of collagen accumulation by blocking the L-type Ca channel. Since benidipine blocked Ca influx more potently than the three other Ca channel blockers, the unique and potent osteoblast differentiating ability of benidipine may be due to its high affinity for Ca channel together with its high membrane retaining ability, as has been previously reported.
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PMID:A potent 1,4-dihydropyridine L-type calcium channel blocker, benidipine, promotes osteoblast differentiation. 1190 5

In this study. we investigate the potential for manipulating bone cell mechanotransducers in tissue engineering. Membrane ion channels such as voltage operated calcium channels (VOCC) have been shown to be a critical component of the bone cell transduction pathway with agonists and inhibitors of this pathway having profound effects on the load signal. By encapsulating a calcium channel agonist with slow release within a poly(L-lactide) (PLLA) scaffold, we can generate a 'mechano-active' scaffold for use in skeletal tissue engineering. PLLA scaffolds with and without a calcium channel agonist, BAY K8644, were seeded with primary human bone cells or the human MG63 bone cell line and cultured for 13 weeks followed by mechanical stimulation with a four-point bending model. Our results show that addition of the agonist for slow release is sufficient to enhance the load-related responses in bone cells within the scaffolds. Specifically, collagen type I expression and the ratio of alkaline phosphatase to protein are elevated in response to cyclical mechanical stimulation of approximately 1000 microstr which is then further enhanced in the mechano-active' scaffolds. As the agonists only act when the calcium channels are open by attenuating the calcium flux, the stimulation is specifically targeted to scaffolds subjected to load either in vitro or ultimately in vivo. Our results suggest that manipulating the VOCC and attenuating the opening of the calcium channels may be an effective technique to amplify matrix production via mechanical stimulation which may be applied to bone tissue engineering and potentially engineering of other load-bearing connective tissues.
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PMID:Development of a 'mechano-active' scaffold for tissue engineering. 1196 52

This study describes the antihypertensive, antispasmodic, bronchodilator and hepatoprotective activities of the aqueous-methanolic extract of Carum copticum Benth. seeds (CSE) to rationalize some of its traditional uses. CSE (3-100 mg/kg) caused a dose-dependent fall in arterial blood pressure in anaesthetized rats. In isolated rabbit aorta and jejunum preparations, CSE (0.1-3.0 mg/ml) caused an inhibitory effect on the K+-induced contractions. The calcium channel blocking (CCB) effect was confirmed when CSE shifted the Ca2+ dose-response curves (DRCs) to right similar to verapamil. In isolated guinea-pig tracheal preparations, it caused inhibition of carbachol and K+-induced bronchoconstriction at 0.1-1.0 mg/ml as well as shifted the dose-response curves (DRCs) of carbachol and histamine to the right with suppression of maximum response suggestive of non-specific bronchodilator effect mediated possibly through CCB. Pretreatment of rats with CSE (500 mg/kg orally for 2 days at 12 h intervals) prevented paracetamol (640 mg/kg) and CCl4 (150 ml/kg)-induced rise in serum alkaline phosphatase (ALP) and aminotransferases (AST and ALT). The same dose of CSE was able to prevent the CCl4-induced prolongation in pentobarbital-induced sleeping time in mice confirming its hepatoprotectivity. These results indicate the presence of calcium antagonist(s) in Carum copticum seeds and thus provides sound mechanistic basis for some of their folkloric uses.
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PMID:Studies on the antihypertensive, antispasmodic, bronchodilator and hepatoprotective activities of the Carum copticum seed extract. 1576 73

Protective efficacy of diltiazem (a calcium channel blocker) has been studied against cadmium chloride (CdCl2) induced hematological and biochemical alterations in Swiss albino mice. CdCl2 (5 mg/kg b.wt.; i.p.) with or without prior treatment of diltiazem (100 mg/kg b. wt.; i.p.) was given to six-week old mice. Significant increase in the number of bone marrow cells as well as hematological parameters was observed in diltiazem pretreated CdCl2 intoxicated animals. A significant increase in lipid peroxidation (LPO) and acid phosphatase (ACP) level, and decrease in glutathione (GSH) and alkaline phosphatase (ALP) level in blood as well as liver were measured in CdCl2 intoxicated mice, while such values were near normal in DTZ pretreated animals. Furthermore, a significant increase in erythropoeitin (EPO) level was observed in diltiazem (DTZ) pretreated CdCl2 intoxicated animals as compared to CdCl2 alone treated animals. Thus, Diltiazem administration before cadmium intoxication protects bone marrow and hematological constituents in mice.
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PMID:Protective effect of diltiazem (a calcium channel blocker) against cadmium-induced toxicity in mice. 1819 34

In bone, osteoblasts and chondrocytes synthesize matrix vesicles (MVs) that interact with collagen to initiate calcification. MVs have been identified in human calcified arteries but are poorly characterized. The objective of this study is to determine the role of annexins and fetuin-A in MV formation and activity during calcification in bovine vascular smooth muscle cells (BVSMCs). BVSMCs were treated with control or calcification (high phosphorus) media, and cellular MVs were isolated by collagenase digestion and secreted MVs were isolated from cultured media by ultracentrifugation. The results showed that alkaline phosphatase (ALP) activity was significantly increased in MVs from calcified BVSMCs compared with noncalcified BVSMCs, as was annexin II and VI content and (45)Ca uptake. We also determined that MVs from calcifying BVSMCs could mineralize type I collagen but not type II collagen in the absence of cells in a dose- and time-dependent manner. Blockade of annexin calcium channel activity by K201 significantly decreased ALP activity and reduced the ability of the MVs to subsequently calcify on collagen, whether the K201 was added during or after MV formation. Furthermore, cellular MVs had significantly increased ability to calcify on collagen compared with secreted MVs, likely because of their increased ALP activity and annexin II content but low fetuin-A content. In conclusion, our results suggest that mineralization in VSMCs requires both active MVs and an interaction of the MVs with type I collagen, and both steps require annexin activity.
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PMID:Annexin-mediated matrix vesicle calcification in vascular smooth muscle cells. 1859 35

Drug-related hepatotoxicity is now the leading cause of acute liver failure in the United States, especially among patients who have no prior liver disease. Nicardipine is the only IV calcium channel blocker available for the short-term treatment of hypertension with a considerably good safety profile. We report a case of nicardipine-induced hepatitis. A patient with history of hypertension was admitted because of right middle cerebral artery infarction. Computed tomography of the brain showed evolving stroke. The patient went for cerebral angiography and stent placement, and during the procedure he had cerebral hemorrhage. He was transferred to neurosurgery. After surgery, he was started on hypertonic saline, mannitol for cerebral edema, and nicardipine drip for blood pressure control. On the fourth day after operation, he started to have fever with progressive elevation of liver enzymes [Aspartate amino transferase (AST) 450, Alanine amino transferase (ALT) 356, and alkaline phosphatase 299]. Serum bilirubin was 0.6. He did not receive blood transfusion. No medical history of hepatitis or liver disease was reported. Other medications included metoprolol and heparin. White blood cell count was 13,000. Chest x-ray did not show evidence of consolidation. Urine analysis was unremarkable. Cultures were negative. Acute hepatitis panel was negative. Cerebrospinal fluid examination was normal. Liver enzymes were trending up gradually with normal protein and bilirubin. Computed tomography of the abdomen was unremarkable. The patient's medications were reviewed. It was noticed that the patient started to have fever and elevated liver enzymes after administration of nicardipine drip. It was postulated that nicardipine may be the culprit of acute hepatitis. Nicardipine drip was stopped, and the patient was started on labetalol. Fever started to resolve, and liver enzymes started trending down toward normal. The patient remained afebrile after that.
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PMID:Nicardipine-induced acute hepatitis in an intensive care unit patient. 1909 42


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