Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts:   Target Concepts:
Query: EC:3.1.3.1 (alkaline phosphatase)
 47,916 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

A number of major properties of endothelial cells (EC) at the blood-brain barrier (BBB) have been shown to be astrocyte-dependent. Whether analogous properties at the blood-nerve barrier (BNB) are induced and maintained by Schwann cells has not been investigated. As a preliminary investigation we have undertaken a comparative study of six EC membrane markers at the BBB and BNB and perineurium. Employing immunoblotting and immunocytochemistry the relative distribution between rat brain cortex and sciatic nerve was determined for the glucose transporter (GLUT-1), the transferin receptor (OX-26), the endothelial barrier antigen (EBA) and the OX-47 antigen. Using enzyme cytochemistry the same comparison was made for gamma-glutamyl transpeptidase (GGTP) and alkaline phosphatase. By immunocytochemistry GLUT-1 was uniformly strongly represented in brain EC, nerve EC and perineurium. OX-26 was strongly positive in brain EC but present only in trace quantities in nerve EC and perineurium. EBA similarly showed strong positivity in brain EC and trace amounts in nerve EC but was absent from perineurium. OX-47 was present moderately in brain EC and perineurium but absent from nerve EC. Quantitative immunoblotting of brain and sciatic nerve homogenates showed statistically significant differences in the level of expression of EBA and OX-26 between the two tissues. Enzyme cytochemistry showed that GGTP was strongly positive in brain EC but absent from nerve EC and perineurium. Alkaline phosphatase stained strongly in brain and nerve EC and was absent from perineurium. In summary the six membrane markers were heterogeneously represented in nerve compared with brain. This pattern of distribution in the nerve cannot simply be accounted for by the absence of astrocytes and their inductive influences. Any inductive influences of Schwann cells require investigation.
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PMID:A comparison of blood-brain barrier and blood-nerve barrier endothelial cell markers. 1035 Jan 31

Longitudinal bone growth, and hence stature, are functions of growth plate chondrocyte proliferation and hypertrophy. Insulin-like growth factor 1 (Igf1) is reputed to augment longitudinal bone growth by stimulating growth plate chondrocyte proliferation. In this study, however, we demonstrate that chondrocyte numbers and proliferation are normal in Igf1 null mice despite a 35% reduction in the rate of long bone growth. Igf1 null hypertrophic chondrocytes differentiate normally in terms of expressing specialized proteins such as collagen X and alkaline phosphatase, but are smaller than wild-type at all levels of the hypertrophic zone. The terminal hypertrophic chondrocytes, which form the scaffold on which long bone growth extends, are reduced in linear dimension by 30% in Igf1 null mice, accounting for most of their decreased longitudinal growth. The expression of the insulin-sensitive glucose transporter, GLUT4, is significantly decreased and the insulin-regulated enzyme glycogen synthase kinase 3beta (GSK3) is hypo-phosphorylated in Igf1 null chondrocytes. Glycogen levels were significantly decreased and ribosomal RNA levels were reduced by almost 75% in Igf1 null chondrocytes. These data suggest that Igf1 promotes longitudinal bone growth by 'insulin-like' anabolic actions which augment chondrocyte hypertrophy.
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PMID:Igf1 promotes longitudinal bone growth by insulin-like actions augmenting chondrocyte hypertrophy. 1054 81

The blood-brain barrier (B-BB) protects the free passage of substances into the brain and maintains the homeostasis of the central nervous system. It is commonly accepted that astrocytes surrounding brain endothelial cells influence the B-BB formation and the exhibition of B-BB function of capillaries. To begin the in vitro study on the B-BB, it is essential to obtain a homogenous and sufficient supply of brain endothelial cells as well as astrocytes. We thus immortalized the bovine brain endothelial cell (BBEC) by transfection of the SV40 large T antigen and obtained a single clone, t-BBEC-117, which retained the brain endothelial cell phenotype. Astrocyte in co-culture was found to tighten the intercellular contacts of the immortal cells resulting in a reduced L-glucose permeability, and its conditioned medium (CM) augmented a B-BB phenotype, alkaline phosphatase (ALP) activity. Among known astrocytic factors, only fibroblast growth factor-basic (bFGF) could mimic the actions of astrocytes as measured by L-glucose permeability and ALP activity. Moreover, anti-bFGF antibody canceled 90% of ALP activation by astrocyte CM. Basic FGF, however, failed to induce other B-BB phenotypes such as the expressions of multidrug resistance (mdr) and glucose transporter (GLUT-1) genes. These data suggest that bFGF is one of the most plausible astrocytic factors to induce the B-BB properties of immortal brain endothelial cells together with some unknown factors in the astrocyte CM.
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PMID:Induction of blood-brain barrier properties in immortalized bovine brain endothelial cells by astrocytic factors. 1061 19

The glucose transporter of Escherichia coli couples translocation with phosphorylation of glucose. The IICB(Glc) subunit spans the membrane eight times. Split, circularly permuted and cyclized forms of IICB(Glc) are described. The split variant was 30 times more active when the two proteins were encoded by a dicistronic mRNA than by two genes. The stability and activity of circularly permuted forms was improved when they were expressed as fusion proteins with alkaline phosphatase. Cyclized IICB(Glc) and IIA(Glc) were produced in vivo by RecA intein-mediated trans-splicing. Purified, cyclized IIA(Glc) and IICB(Glc) had 100% and 30% of wild-type glucose phosphotransferase activity, respectively. Cyclized IIA(Glc) displayed increased stability against temperature and GuHCl-induced unfolding.
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PMID:Carbohydrate transporters of the bacterial phosphoenolpyruvate: sugar phosphotransferase system (PTS). 1153 41

Space flight-induced bone loss has been attributed to a decrease in osteoblast function, without a significant change in bone resorption. To determine the effect of microgravity (MG) on bone, we used the Rotary Cell Culture System [developed by the National Aeronautics and Space Administration (NASA)] to model MG. Cultured mouse calvariae demonstrated a 3-fold decrease in alkaline phosphatase (ALP) activity and failed to mineralize after 7 d of MG. ALP and osteocalcin gene expression were also decreased. To determine the effects of MG on osteoblastogenesis, we cultured human mesenchymal stem cells (hMSC) on plastic microcarriers, and osteogenic differentiation was induced immediately before the initiation of modeled MG. A marked suppression of hMSC differentiation into osteoblasts was observed because the cells failed to express ALP, collagen 1, and osteonectin. The expression of runt-related transcription factor 2 was also inhibited. Interestingly, we found that peroxisome proliferator-activated receptor gamma (PPARgamma2), which is known to be important for adipocyte differentiation, adipsin, leptin, and glucose transporter-4 are highly expressed in response to MG. These changes were not corrected after 35 d of readaptation to normal gravity. In addition, MG decreased ERK- and increased p38-phosphorylation. These pathways are known to regulate the activity of runt-related transcription factor 2 and PPARgamma2, respectively. Taken together, our findings indicate that modeled MG inhibits the osteoblastic differentiation of hMSC and induces the development of an adipocytic lineage phenotype. This work will increase understanding and aid in the prevention of bone loss, not only in MG but also potentially in age-and disuse-related osteoporosis.
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PMID:Modeled microgravity inhibits osteogenic differentiation of human mesenchymal stem cells and increases adipogenesis. 1474 52

A male newborn infant was recognized having Fanconi-Bickel syndrome (FBS) in the neonatal period. The presenting clinical findings were hyperglycemia and polyuria detected during an episode of acute enteritis. Physical examination was normal, biochemical analyses were suggestive of FBS: glycosuria, proteinuria, phosphaturia, generalized aminoaciduria, and increased levels of urinary beta 2-microglobulin, serum glucose and serum alkaline phosphatase. The molecular genetic analysis showed homozygosity for mutations within the gene of the glucose transporter 2 (Glut 2), 1213 C>T. The patient demonstrated improved clinical and metabolic status following institution of diet with frequent small meals and galactose-free-milk as well as pharmacological treatment with phosphate and vitamin alpha-OH-D3. In conclusion, infants showing hyperglycemia and polyuria may be considered having FBS also in the neonatal period. Early institution of adequate caloric intake and replacement of electrolytes and vitamin D may avoid or reduce metabolic complications.
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PMID:The Fanconi-Bickel syndrome: a case of neonatal onset. 1511 30

Hypoxia-inducible factor 1 (HIF-1) is the central mediator of cellular responses to low oxygen and has recently become an important therapeutic target for solid tumor therapy. Inhibition of HIF-1 is expected to result in the attenuation of hypoxia-inducible genes, which are vital to many aspects of tumor biology, including adaptative responses for survival under anaerobic conditions. To identify small molecules inhibiting the HIF-1 pathway, we did a biological screen on a 10,000-membered natural product-like combinatorial library. The compounds of the library, which share a 2,2-dimethylbenzopyran structural motif, were tested for their ability to inhibit the hypoxic activation of an alkaline phosphatase reporter gene under the control of hypoxia-responsive elements in human glioma cells. This effort led to the discovery of 103D5R, a novel small-molecule inhibitor of HIF-1alpha. 103D5R markedly decreased HIF-1alpha protein levels induced by hypoxia or cobaltous ions in a dose- and time-dependent manner, whereas minimally affecting global cellular protein expression levels, including that of control proteins such as HIF-1beta, IkappaBalpha, and beta-actin. The inhibitory activity of 103D5R against HIF-1alpha was clearly shown under normoxia and hypoxia in cells derived from different cancer types, including glioma, prostate, and breast cancers. This inhibition prevented the activation of HIF-1 target genes under hypoxia such as vascular endothelial growth factor (VEGF) and glucose transporter-1 (Glut-1). Investigations into the molecular mechanism showed that 103D5R strongly reduced HIF-1alpha protein synthesis, whereas HIF-1alpha mRNA levels and HIF-1alpha degradation were not affected. 103D5R inhibited the phosphorylation of Akt, Erk1/2, and stress-activated protein kinase/c-jun-NH(2)-kinase, without changing the total levels of these proteins. Further studies on the mechanism of action of 103D5R will likely provide new insights into its validity/applicability for the pharmacologic targeting of HIF-1alpha for therapeutic purposes.
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PMID:Identification of a novel small-molecule inhibitor of the hypoxia-inducible factor 1 pathway. 1569 5

The bulk of glucose that is filtered by the renal glomerulus is reabsorbed by the glucose transporters of the proximal convoluted tubular epithelium. However, it has been difficult to investigate this in diseases such as type 2 diabetes because of the inability to isolate primary renal cells from patients without a renal biopsy. We report here a method for the immunomagnetic isolation and novel primary culture of human exfoliated proximal tubular epithelial cells (HEPTECs) from fresh urine. The primary isolates are highly enriched and differentiated and express characteristic proximal tubular phenotypic markers. They continue to express the proximal tubular markers CD13/aminopeptidase-N, sodium glucose cotransporter (SGLT) 2, and alkaline phosphatase through up to six subsequent subcultures in a similar way to human proximal cells isolated from renal biopsies. In a hyperglycemic environment, HEPTECs isolated from patients with type 2 diabetes expressed significantly more SGLT2 and the facilitative glucose transporter GLUT2 than cells from healthy individuals. We also demonstrated a markedly increased renal glucose uptake in HEPTECs isolated from patients with type 2 diabetes compared with healthy control subjects. Our findings indicate for the first time in a human cellular model that increased renal glucose transporter expression and activity is associated with type 2 diabetes.
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PMID:Glucose transporters in human renal proximal tubular cells isolated from the urine of patients with non-insulin-dependent diabetes. 1630 58

The view that ascorbic acid indirectly benefits osteoclastogenesis through expression of receptor activator of nuclear factor-kappaB (NF-kappaB) ligand (RANKL) by osteoblasts is prevailing. In this study, we have examined the direct effect of ascorbic acid on osteoclastogenesis in cultured mouse osteoclasts differentiated from bone marrow precursors. The absence of alkaline phosphatase and osteoblastic marker genes validated the usefulness of isolation procedures. Sustained exposure to ascorbic acid, but not to dehydroascorbic acid, significantly reduced the number of multinucleated cells positive to tartrate-resistant acid phosphatase (TRAP) staining. In cultured osteoclasts, mRNA expression was seen for glucose transporter-1 involved in membrane transport of dehydroascorbic acid, but not for sodium-dependent vitamin C transporters-1 and -2 that are both responsible for the transport of ascorbic acid. The inhibition by ascorbic acid was completely prevented by catalase, while ascorbic acid or hydrogen peroxide drastically increased the number of cells stained with propidium iodide and the generation of reactive oxygen species, in addition to inducing mitochondrial membrane depolarization in cultured osteoclasts. In pre-osteoclastic cell line RAW264.7 cells, ascorbic acid similarly inhibited the formation of TRAP-positive multinucleated cells, with a significant decrease in RANKL-induced NF-kappaB transactivation. Moreover, co-culture with osteoblastic MC3T3-E1 cells significantly prevented the ascorbic acid-induced decrease in the number of TRAP-positive multinucleated cells in RAW264.7 cells. These results suggest that ascorbic acid may play a dual repulsive role in osteoclastogenesis toward bone remodeling through the direct cytotoxicity mediated by oxidative stress to osteoclasts, in addition to the indirect trophism mediated by RANKL from osteoblasts.
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PMID:Osteoblast protects osteoclast devoid of sodium-dependent vitamin C transporters from oxidative cytotoxicity of ascorbic acid. 1769 58

Furocoumarins are a group of natural products with many biological activities. Clinical evidences have demonstrated the important contribution of furocoumarins to the toxicity of some foods and herbs. In order to assess liver and kidney toxicity of furocoumarins, male mice were orally administrated with psoralen, isopsoralen, imperatorin, isoimperatorin and xanthotoxin at 20 and 40 mg/kg once daily for 28 days, respectively. No changes of food or water intake were observed in furocoumarins-treated mice. Only 40 mg/kg isopsoralen reduced body weight. 40 mg/kg furocoumarins altered serum activities of alanine transaminase, aspartate aminotransferase, alkaline phosphatase, and/or levels of albumin, showing hepatotoxicity. Furthermore, furocoumarins increased activity and protein expression of hepatic microsomal cytochrome P450 (CYP450) 3A11. CYP 2E1 activity and protein expression were suppressed by psoralen and isopsoralen and increased by xanthotoxin. Renal protein levels of organic cation/carnitine transporters (OCT1, OCT2 and OCTN2) and organic anion transporter 3 were increased by most furocoumarins. Renal urate transporter 1, glucose transporter 9 and multidrug resistance protein 4 were influenced by furocoumarins. These findings suggest that furocoumarins may interfere in metabolism, excretion and bioavailability of endogenous and exogenous compounds to impair liver and kidney functions mediated by affecting hepatic CYP450 and renal organic ion transport system.
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PMID:Furocoumarins affect hepatic cytochrome P450 and renal organic ion transporters in mice. 2217


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