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)

The cellular mechanism by which TNF-alpha inhibits osteoblastic differentiation induced by BMPs was investigated using mouse myoblast C2C12 cells expressing functional BMP receptors and Smad signaling molecules except ALK-6. Osteoblast transformation in response to BMP-2 was morphologically suppressed by TNF-alpha. Expression of biological markers for osteoblasts including Runx2 and osteocalcin, alkaline phosphatase activity, and parathyroid hormone (PTH) responsiveness shown by PTH-induced cAMP production were readily activated by BMP-2, -4, -6, and -7. The BMP-induced osteoblastic phenotype was dose-dependently inhibited by TNF-alpha. BMP-induced Smad1,5,8 phosphorylation of C2C12 cells was suppressed by TNF-alpha signaling. In addition, cDNA array analysis showed an increased expression of inhibitory Smad6 by TNF-alpha. MAP kinase analysis showed that ERK1/ERK2 and SAPK/JNK phosphorylation were selectively activated by TNF-alpha regardless of the presence of BMP ligands. BMPs had no effect on expression levels of TNF type 1 and 2 receptors. Notably, inhibition of SAPK/JNK restored TNF-alpha effects on BMP-induced osteoblast differentiation demonstrated by Id-1-promoter activity as well as Runx2 and osteocalcin mRNA levels. Collectively, TNF-alpha elicits BMP-induced osteogenic inhibition by suppressing BMP-Smad signaling pathway, at least in part, through SAPK/JNK activation and Smad6 upregulation.
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PMID:TNF-alpha inhibits BMP-induced osteoblast differentiation through activating SAPK/JNK signaling. 1739 98

Many plant-derived substances have estrogenic activities. Due to their ability to bind the estrogen receptor, these compounds have the potential to counteract the deleterious effects of estrogen deficiency on bone. In this study, the effects of apigenin on the function of osteoblastic MC3T3-E1 cells and the production of local factors in osteoblasts were investigated. Apigenin (0.01 microM) significantly increased the growth of MC3T3-E1 cells and caused a significant elevation of alkaline phosphatase (ALP) activity and collagen content in the cells (P < 0.05). The effect of apigenin in increasing ALP activity and collagen content was completely prevented by the presence of 10(-6) M cycloheximide and 10-6 M tamoxifen, suggesting that apigenin's effect results from a newly synthesized protein component and might be partly involved in estrogen action. Locally derived mediators in bone play a crucial role in the regulation of bone remodeling, i.e., bone formation and bone resorption processes. The effect of apigenin on the TNF-alpha-induced production of IL-6 and nitric oxide (NO) in osteoblasts was examined. Treatment with apigenin (10 microM) decreased the TNF-alpha-induced production of IL-6 and NO in osteoblasts. Taken together, these results suggest that apigenin may represent new pharmacological tools for the treatment of osteoporosis.
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PMID:Apigenin increases osteoblastic differentiation and inhibits tumor necrosis factor-alpha-induced production of interleukin-6 and nitric oxide in osteoblastic MC3T3-E1 cells. 1741 99

Pentoxifylline (POF) is a new candidate for the treatment of nonalcoholic steatohepatitis (NASH). Its effects on the cytokine production in patients with NASH are not completely understood. This study was designed to investigate the effect of POF on TNF-alpha production by peripheral blood mononuclear cells (PBMC) in patients with NASH. After preliminary experiments in healthy control subjects to determine the range of POF concentration to be used in NASH patients, PBMCs from patients with NASH (n = 13) were cultured in the presence of lipopolysaccharide (LPS, 100 ng/ml) and various concentrations of POF for 24 hr. Concentrations of TNF-alpha in culture supernatants were measured by ELISA and the transcriptional activity was determined by RT-PCR. As dictated by the results of our preliminary study in PBMC from healthy control subjects, we treated LPS stimulated PBMCs from NASH patients with 10, 100, and 500 microg/ml of POF. Stimulation of PBMCs from NASH patients with LPS resulted in a strong up-regulation of TNF-alpha production from median 355.9 (interquartile range, 206.7-463.5) pg/ml to 1,670 pg/ml (interquartile range, 1,121-2,414) pg/ml. In this LPS-stimulated culture system, POF caused a dose-dependent suppression of TNF-alpha levels (P < 0.001, ANOVA on ranks for repeated measures). TNF-alpha levels in culture supernatants decreased to 870.3 (range, 598.3-2,077) pg/ml with 10 microg/ml of POF treatment, and to levels similar to those obtained in baseline unstimulated cultures (133.4 (range, 95.8-1518.5) pg/ml) at 100 microg/ml. At 500 microg/ml, POF suppressed TNF-alpha production to levels significantly lower than that obtained in unstimulated (baseline) culture supernatants (76.3 (range, 33-94.5) pg/ml; P = 0.001). The mRNA expression was consistent with the effects on protein concentration. Demographic characteristics of the patients, laboratory results, such as AST, ALT, alkaline phosphatase, GGT, and triglyceride levels, and the liver histology did not seem to influence the in vitro TNF-alpha response of the PBMCs from NASH patients. POF can significantly decrease the LPS-stimulated TNF-alpha production by PBMCs in NASH patients. Our results support the notion that POF might be a good candidate for the treatment of NASH.
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PMID:Effects of pentoxifylline on TNF-alpha production by peripheral blood mononuclear cells in patients with nonalcoholic steatohepatitis. 1743 95

Multiorgan dysfunction ensuing from severe heatstroke includes hypotension, hepatic and renal failure, hypercoagulable state, activated inflammation, and cerebral ischemia and injury. We attempted to assess whether human umbilical cord blood-derived CD34+ cell therapy improves survival during experimental heatstroke by attenuating multiorgan dysfunction. Anesthetized rats, immediately after the onset of heatstroke, were divided into 2 major groups and given CD34- or CD34+ cells (1 x 10(5)-5 x 10(5)/mL/kg body weight) i.v. They were exposed to ambient temperature of 43 degrees C to induce heatstroke. Another group of rats were exposed to room temperature (26 degrees C) and used as normothermic controls. Hypotension, hepatic and renal failure (evidenced by increased serum urea nitrogen, creatinine, aspartate aminotransferase, alanine aminotransferase, and alkaline phosphatase levels in plasma), hypercoagulable state (evidenced by increased prothrombin time, activated partial thromboplastin time, and D-dimer, and decreased platelet count and protein C in plasma), activated inflammation (evidence by increased TNF-alpha levels in serum), and cerebral dysfunction (evidenced by intracranial hypertension, cerebral hypoperfusion and hypoxia, and cerebral ischemia and injury) were monitored. When the CD34- cell-treated or untreated rats underwent heat stress, their survival time values were found to be 19 to 23 min. Resuscitation with CD34+ cells significantly improved survival time (duration, 63-291 min). As compared with normothermic controls, all CD34- cell-treated heatstroke animals displayed hypotension, hepatic and renal failure, hypercoagulable state, activated inflammation, and cerebral ischemia and injury. However, CD34+ cell therapy significantly caused attenuation of all the above-mentioned heatstroke reactions. In addition, the levels of IL-10 in plasma and glial cell line-derived neurotrophic factors in brain were all significantly increased after CD34+ cell therapy during heatstroke. Our data indicate that CD34+ cell therapy may resuscitate persons who had a heatstroke by reducing multiorgan dysfunction or failure.
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PMID:Human umbilical cord blood-derived CD34+ cells cause attenuation of multiorgan dysfunction during experimental heatstroke. 1750 7

We tested the power of tumor necrosis factor (TNF)-alpha and/or leptin in predicting the degree of liver involvement in children with nonalcoholic fatty liver disease (NAFLD). We measured serum levels of TNF-alpha and leptin and computed NAFLD activity score (NAS) (NAS >or= 5, diagnostic of nonalcoholic steatohepatitis [NASH]) in 72 consecutive biopsy-proven NAFLD cases (training and validation sets, 36 cases each). Univariate analysis evaluated variables significantly associated with a diagnostic NAS. Receiver operating characteristic (ROC) curve analysis assessed the diagnostic value of selected variables in predicting a NAS of 5 or more.TNF-alpha (P < .0001), leptin (P = .001); triglycerides (P = .013), and alkaline phosphatase (P = .046) levels were significantly associated with a NAS of 5 or more. TNF-alpha and leptin levels predicted the risk of NAS of 5 or more. ROC analyses defined cutoff values for TNF-alpha, leptin, and risk score. They identified 90%, 83%, and 83% of the cases, respectively, with a NAS of 5 or more (true-positive cases) from the validation set.TNF-alpha alone or combined with leptin in a simple risk score can accurately predict a NAS of 5 or more. TNF-alpha seems to be a specific laboratory marker of NASH.
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PMID:Correlation of serum TNF-alpha levels and histologic liver injury scores in pediatric nonalcoholic fatty liver disease. 1750 93

K-7174, a GATA-specific inhibitor, is a putative anti-inflammatory agent that attenuates effects of inflammatory cytokines in certain cell types. However, molecular mechanisms involved have not been elucidated. We found that, in glomerular podocytes, induction of monocyte chemoattractant protein 1 (MCP-1) and inducible nitric oxide synthase (iNOS) by TNF-alpha was abrogated by K-7174. It was correlated with unexpected induction of unfolded protein response (UPR) evidenced by: (1) induction of endogenous indicators 78 kDa glucose-regulated protein and CCAAT/enhancer-binding protein-homologous protein, and (2) suppression of an exogenous indicator, endoplasmic reticulum stress-repressive alkaline phosphatase. In podocytes, induction of UPR by either tunicamycin, thapsigargin, A23187 or AB5 subtilase cytotoxin completely reproduced the suppressive effect of K-7174. Furthermore, K-7174-elicited UPR abrogated induction of MCP-1 and iNOS not only by TNF-alpha but also by medium conditioned by activated macrophages. These results suggested a novel, UPR-dependent mechanism underlying the anti-inflammatory potential of K-7174.
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PMID:Suppression of cytokine response by GATA inhibitor K-7174 via unfolded protein response. 1760 1

Obstructive sleep apnea (OSA) causes chronic intermittent hypoxia (CIH) during sleep. OSA is associated with nonalcoholic steatohepatitis (NASH) in obese individuals and may contribute to progression of nonalcoholic fatty liver disease from steatosis to NASH. The purpose of this study was to examine whether CIH induces inflammatory changes in the liver in mice with diet-induced hepatic steatosis. C57BL/6J mice (n = 8) on a high-fat, high-cholesterol diet were exposed to CIH for 6 mo and were compared with mice on the same diet exposed to intermittent air (control; n = 8). CIH caused liver injury with an increase in serum ALT (461 +/- 58 U/l vs. 103 +/- 16 U/l in the control group; P < 0.01) and AST (637 +/- 37 U/l vs. 175 +/- 13 U/l in the control group; P < 0.001), whereas alkaline phosphatase and total bilirubin levels were unchanged. Histology revealed hepatic steatosis in both groups, with mild accentuation of fat staining in the zone 3 hepatocytes in mice exposed to CIH. Animals exposed to CIH exhibited lobular inflammation and fibrosis in the liver, which were not evident in control mice. CIH caused significant increases in lipid peroxidation in serum and liver tissue; significant increases in hepatic levels of myeloperoxidase and proinflammatory cytokines IL-1beta, IL-6, and CXC chemokine MIP-2; a trend toward an increase in TNF-alpha; and an increase in alpha1(I)-collagen mRNA. We conclude that CIH induces lipid peroxidation and inflammation in the livers of mice on a high-fat, high-cholesterol diet.
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PMID:Chronic intermittent hypoxia causes hepatitis in a mouse model of diet-induced fatty liver. 1800 63

We compared the secretion of vascular endothelial growth factor (VEGF) by chondrocytes isolated from cartilage of patients with osteoarthritis (OA) and maintained in monolayer or in three-dimensional culture. Chondrocytes, immediately after isolation, or after one passage in monolayer culture (subculture), were seeded in monolayer or pelleted in micromasses. Cells cultured differently were immunoassayed for the secretion of VEGF in basal conditions or after stimulation with IL-17, TNF-alpha or B IL-17+TNF-alpha. Chondrocytes cultured in micromasses secreted lower levels of VEGF in comparison with those in monolayer culture. In micromass cultures TNF-alpha was more stimulating than IL-17 and their combined effect was additional. On the basis of alkaline phosphatase/cathespin B activities, primary cultures in micromass, characterized by low VEGF secretion, represented the best condition for maximal cell differentiation. Our results suggest that the culture of chondrocytes in micromasses represents a good condition to study the physiology of these cells to a maximum degree when micromasses are obtained with freshly isolated chondrocytes.
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PMID:VEGF production by osteoarthritic chondrocytes cultured in micromass and stimulated by IL-17 and TNF-alpha. 1788 99

Rheumatoid arthritis (RA) is frequently complicated by peri-articular and generalized osteoporosis due to increased bone resorption by activated osteoclasts. Pro-inflammatory cytokines, such as TNF-alpha, interleukin 1 (IL1), and interleukin 6 (IL6) are thought, among other factors, to be directly responsible for this extra-articular complication of RA. Glucocorticoids (GCS) commonly prescribed in RA due to their strong anti-inflammatory effect are also well known for causing secondary osteoporosis during a prolonged use. An influence of low-dose GCS therapy (8.7 mg per day) on a bone turnover in female RA patients with or without previous history of GCS treatment was investigated by measuring bone mineral content (BMC), bone mineral density (BMD), and various biochemical markers of inflammation and bone metabolism in comparison to results obtained from: (1) RA patients who have not been treated with GCS and (2) the control group of healthy individuals. Sixty-two female patients with established active RA and 178 healthy individuals from the control group have been investigated. The RA patients were divided into three groups: 21 treated with GCS before the trial--these patients have continued GCS therapy using low doses during the observation; 21 with low-dose GCS therapy launched at the beginning of the trial; and 20 left without GCS treatment. All patients have been assessed twice: at the beginning and after 12 months of observation. BMC and BMD have been measured in all patients in a distal part of forearm. Additionally, several different biochemical markers of osteoporosis and inflammation have been determined. We did not notice any increase in bone metabolism between RA patients receiving GCS therapy for the first time and those treated without GCS after 12 months of observation. Results of BMC, BMD osteocalcin level, total and bone alkaline phosphatase, carboxy-terminal collagen cross links, carboxy-terminal propeptides of type 1 collagen, deoxypyridynoline, and calcium/creatinine ratio were comparable in both groups at the end of the study. There was a significant decrease of the level of IL-6 in patients who had GCS therapy launched at the beginning of observation (p<0.01). However, levels of C-reactive protein (CRP) and alpha1-acid-glycoprotein (AGP) have not changed; the level of ESR dropped significantly (p<0.05) in this group. In contrast, in the group of patients with the previous history of prolonged GCS treatment receiving low doses of GCS during the trial, statistically significant increase of CRP and AGP could be observed (p<0.05) along with further significant worsening of the primary low BMD (p<0.05). Based on the obtained data, we came to the conclusion that anti-inflammatory effect of the low-dose GCS therapy in RA patients without previous history of their use may balance their direct negative effect on BMC and BMD. In this group of RA patients, benefits resulting from the 12-month GCS therapy prevail over adverse effects, even if calcium with vitamin D3 supplementation, biphosphonians, or estrogens have not been introduced. On the other hand, low-dose GCS therapy could have no benefit for RA patients with the previous history of their prolonged use, as a rise of markers of inflammation and bone turnover, resulting in the further bone loss, has been observed.
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PMID:Does low-dose and short-term glucocorticoids treatment increase the risk of osteoporosis in rheumatoid arthritis female patients? 1790 41

Drug-induced liver injury (DILI) encompasses a spectrum of clinical disease ranging from mild biochemical abnormalities to acute liver failure. The majority of adverse liver reactions are idiosyncratic, occurring in most instances 5-90 days after the causative medication was last taken. The diagnosis of DILI is clinical, based on history, probability of the suspect medication as a cause of liver injury and exclusion of other hepatic disease. DILI can be hepatocellular (predominant rise in alanine transaminase), cholestatic (predominant rise in alkaline phosphatase) or mixed liver injury. An elevated bilirubin level more than twice the upper limit of normal in patients with hepatocellular liver injury implies severe DILI, with a mortality of approximately 10% and with an incidence rate of 0.7-1.3 per 100,000. Although acute liver failure is rare, 13-17% of all acute liver failure cases are attributed to idiosyncratic drug reactions. Response to drug withdrawal may be delayed up to 1 year with cholestatic liver injury with occasional subsequent progressive cholestasis known as the vanishing bile duct syndrome. Overall, chronic disease may occur in up to 6% even if the offending drug is withdrawn. Antibiotics and NSAIDs are the most common cause of DILI. Statins rarely cause significant liver injury whereas antiretroviral therapy is associated with hepatotoxicity in 10% of treated patients. Multiple mechanisms of DILI have been implicated, including TNF-alpha-activated apoptosis, inhibition of mitochondrial function and neoantigen formation. Risk factors for DILI include age, sex and genetic polymorphisms of drug-metabolising enzymes such as cytochrome P450. In patients with human immunodeficiency virus, the presence of chronic viral hepatitis increases the risk of antiretroviral therapy hepatotoxicity. Over the next decade, the combination of accurate case ascertainment of DILI via clinical networks and the application of genomics and proteomics will hopefully lead to accurate prediction of risk of DILI, so that pharmacotherapy can be optimised with avoidance of adverse hepatic events.
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PMID:Idiosyncratic drug-induced liver injury: an overview. 1796 56


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