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:3.4.21.4 (trypsin)
42,187 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Peroxisomes increase in size and number in responsive animals ranging from mammals to marine mussels and fish species when treated with certain compounds named peroxisome proliferators. This phenomenon, known as peroxisome proliferation, is mediated by nuclear receptors termed peroxisome proliferator-activated receptors (PPARs). Three PPAR subtypes have been described (alpha, beta, and gamma) and in mammals PPARalpha is mainly expressed in tissues that catabolize fatty acids, PPARbeta is ubiquitously distributed, and PPARgamma is mainly expressed in the adipose tissue and immune system. The aim of this study was to analyze the tissue distribution of different PPAR subtypes in zebrafish Danio rerio using commercially available antibodies against PPARalpha, PPARbeta, and PPARgamma. In western blots, specific bands were detected at about 58 kDa for PPARalpha and PPARbeta. For PPARgamma the band was detected at 56 kDa. Similar results were obtained in mouse liver homogenates used as positive control, indicating the specificity of the antibodies. Immunohistochemistry was performed in paraformaldehyde-fixed tissue using either microwave or microwave plus trypsin pretreatment for antigen retrieval. In zebrafish, PPARalpha was expressed mainly in liver parenchymal cells, proximal tubules of kidney, enterocytes, and pancreas. PPARbeta showed a widespread distribution and was expressed in the liver, proximal and distal tubules and glomeruli of the kidney, pancreas, enterocytes and smooth muscle of the intestine, skin epithelium, lymphocytes, and male and female gonads. PPARgamma expression was weak in pancreatic cells, intestine, and gonads for both pretreatments. Most of the signal detected was cytoplasmic; only in the cases of PPARalpha and PPARbeta was some nuclear labeling detected in the liver. In mouse tissues, the distribution of PPAR subtypes was similar to that described previously for rats. Our results demonstrate that all three distinct PPAR subtypes are present in zebrafish. The tissue and cellular distribution of PPAR subtypes in zebrafish resembled partly that described before in mammals. Further studies are needed to decipher the functions of PPAR subtypes in zebrafish and other aquatic organisms and particularly their role in regulation of metabolic responses to xenobiotic exposure.
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PMID:Expression of peroxisome proliferator-activated receptors in zebrafish (Danio rerio). 1227 59

Mast-cell products can stimulate fibroblast proliferation, implying that these cells are key players in fibrosis. One mast-cell product, the serine protease tryptase, is known to activate protease-activated receptor 2 (PAR2) and cause proliferation of fibroblasts. We found that recombinant tryptase, human mast-cell (HMC-1) supernatant, which contains tryptase, and the PAR2-activating peptide SLIGKV exert fibroproliferative actions in human fibroblasts. Here we report insights into this action, which after activation of PAR2 leads to increased expression of cyclooxygenase 2 (COX2), a key enzyme in the biosynthesis of prostaglandins, and consequently to enhanced prostaglandin synthesis. Subsequent cell proliferation is mediated by the prostaglandin 15-deoxy-Delta(12,14)-prostaglandin J(2), which acts via the nuclear peroxisome proliferator-activated receptor gamma (PPARgamma). Fibroblast proliferation induced by tryptase and PAR2 agonist peptide can be blocked by antagonists of COX2 and PPARgamma, implying that the proliferative effect of tryptase is PAR2-initiated but depends on COX2, 15-deoxy-Delta(12,14)-prostaglandin J(2), and PPARgamma. This previously uncharacterized pathway could be of relevance for human fibrotic diseases. For instance, increased numbers of activated mast cells are correlated with fibrosis in testes of infertile men. In these cases all components of the signaling pathway of tryptase were detected as well as expression of COX2. Therefore, our study describes as-yet-unknown interactions between mast cells and fibroblasts, which could be relevant for human fibrotic diseases.
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PMID:Proliferative action of mast-cell tryptase is mediated by PAR2, COX2, prostaglandins, and PPARgamma : Possible relevance to human fibrotic disorders. 1239 76

Gametocytes, the sexual stages of malaria parasites (Plasmodium spp.) that are transmissible to mosquitoes, have been the focus of much recent research as potential targets for novel drug and vaccine therapies. However, little is known about the host clearance of gametocyte-infected erythrocytes (GEs). Using a number of experimental strategies, we found that the scavenger receptor CD36 mediates the uptake of nonopsonized erythrocytes infected with stage I and IIA gametocytes of Plasmodium falciparum by monocytes and culture-derived macrophages (Mphis). Light microscopy and immunofluorescence assays revealed that stage I and IIA gametocytes were readily internalized by monocytes and Mphis. Pretreating monocytes and Mphis with a monoclonal antibody that blocked CD36 resulted in a significant reduction in phagocytosis, as did treating GEs with low concentrations of trypsin to remove P. falciparum erythrocyte membrane protein 1 (PfEMP-1), a parasite ligand for CD36. Pretreating monocytes and Mphis with peroxisome proliferator-activated receptor gamma-retinoid X receptor agonists, which specifically upregulate CD36, resulted in a significant increase in the phagocytosis of GEs. Murine CD36 on mouse Mphis also mediated the phagocytosis of P. falciparum stage I and IIA gametocytes, as determined by receptor blockade with anti-murine CD36 monoclonal antibodies and the lack of uptake by CD36-null Mphis. These results indicate that phagocytosis of stage I and IIA gametocytes by monocytes and Mphis appears to be mediated to a large extent by the interaction of PfEMP-1 and CD36, suggesting that CD36 may play a role in innate clearance of these early sexual stages.
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PMID:CD36-mediated nonopsonic phagocytosis of erythrocytes infected with stage I and IIA gametocytes of Plasmodium falciparum. 1249 89

Peroxisome proliferator-activated receptor (PPAR) gamma is a ligand-inducible transcription factor mediating glucose and lipid metabolism. Prior studies showed that YM440 ameliorated hyperglycemia in diabetic mice without affecting body fat weight or PPARgamma transactivation. In this study we have examined further the effects of YM440 on PPARgamma binding, transactivation and conformational change. YM440, pioglitazone and rosiglitazone displaced [3H]rosiglitazone from PPARgamma with K(i) values of 4.0, 3.1, and 0.20 microM, indicating that YM440 was comparable to pioglitazone and 20-fold less potent than rosiglitazone. Although pioglitazone and rosiglitazone increased both PPARgamma transactivation in cells expressing human full-length PPARgamma2 or GAL4-PPARgamma and mRNA expression of PPARgamma responsive genes in 3T3-L1 cells, YM440 had weak effects on PPARgamma transactivation and mRNA expression being 550- to 790-fold and 36- to 110-fold less active than rosiglitazone, respectively. YM440 and rosiglitazone induced interaction between PPARgamma and the transcriptional cofactor, p300 or SRC-1, but YM440 was 151- and 1091-fold less potent than rosiglitazone, respectively. The weak transcriptional activity of YM440 was not due to poor cell permeability. Limited trypsin digestion of the full-length human PPARgamma2 with YM440 or rosiglitazone showed distinct patterns of digestion, suggesting a difference in the conformational change of PPARgamma. When db/db mice were treated with YM440 (100mg/kg) for 28 days, YM440 increased hepatic glucokinase expression but not adipose tissue FABP and UCP1 expression, indicating a tissue selective expression of PPARgamma-related genes. Unique properties regarding the binding-transactivation of PPARgamma by YM440 may lead to the hypoglycemic activity without affecting body fat weight in diabetic mice.
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PMID:Differential effects of YM440 a hypoglycemic agent on binding to a peroxisome proliferator-activated receptor gamma and its transactivation. 1262 77

The estrogen receptor-related receptor gamma (ERR gamma/ERR3/NR3B3) is the newest member of the ERR subfamily that also includes ERR alpha and ERR beta. All three isoforms share a high degree of amino acid identity especially in the DNA binding domain. ERR gamma is a constitutively active transcriptional activator that regulates reporter elements driven by steroidogenic factor 1 response element (SF-1RE) and estrogen response element. However, it has the highest potency on a derivative of SF-1RE present in the small heterodimer partner gene promoter called sft4 and unlike ERR alpha and -beta, it fails to activate a palindromic thyroid hormone response element. To investigate the mechanism behind this response element-specific differential transcriptional activity of ERR gamma, the interactions of ERR gamma and the aforementioned response elements was monitored. EMSA and chromatin immunoprecipitation assays demonstrated that ERR gamma binds to sft4, SF-1RE, and palindromic thyroid hormone response element albeit with different degrees of affinity, but causes hyperacetylation of sft4 and SF-1RE templates only. Limited proteolysis assays showed that ERR gamma, bound to different elements, shows differential trypsin sensitivity. A search for novel coregulators of ERR gamma led to the identification of receptor interacting protein 140 as a potent corepressor and peroxisome proliferator-activated receptor gamma coactivator 1 as a potent coactivator of ERR gamma. DNA-dependent pull-down and transient transfection assays demonstrated that, on different DNA elements, ERR gamma exhibits differential cofactor interactions, which in turn dictate its transcriptional activity. Because ERR gamma shows a similar tissue distribution as peroxisome proliferator-activated receptor gamma coactivator 1 and receptor interacting protein 140, these two coregulators may act as key components of ERR gamma-mediated transcription.
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PMID:Deoxyribonucleic acid response element-dependent regulation of transcription by orphan nuclear receptor estrogen receptor-related receptor gamma. 1464 97

FK614 is a structurally novel class of peroxisome proliferator-activated receptor gamma (PPARgamma) agonist, with the mechanism of its insulin-sensitizing action most likely due to activation of PPARgamma. In this study, properties of FK614 for PPARgamma binding, ability to induce conformational change, and coactivator recruitment were investigated. FK614, rosiglitazone, and pioglitazone competed specific binding of [3H]rosiglitazone to PPARgamma with Ki values of 11 nM, 47 nM, and 1.3 microM, respectively. Limited trypsin digestion of PPARgamma with FK614 or rosiglitazone produced distinct patterns of digested polypeptides, suggesting that FK614 directly binds to PPARgamma but induces specific alterations in receptor conformation. FK614 induced interaction of PPARgamma with nuclear receptor coactivator CBP but of lower magnitude than rosiglitazone and pioglitazone. The estimated Kd values of FK614-, rosiglitazone-, and pioglitazone-PPARgamma complex to CBP peptide were 1.8, 0.64, and 0.72 microM, respectively, indicating FK614-PPARgamma complex exhibits a lower affinity for CBP peptide compared to other agonist-PPARgamma complexes. When tested the effect of FK614 on CBP recruitment induced by 9(S)-hydroxyoctadecadienoic acid, an endogenous ligand, FK614 negatively modulated PPARgamma activation. The unique properties of FK614 may underlie the molecular basis of ligand-dependent transcriptional modulation mediated by PPARgamma.
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PMID:Unique properties of coactivator recruitment caused by differential binding of FK614, an anti-diabetic agent, to peroxisome proliferator-activated receptor gamma. 1650 39

Peroxisome proliferator-activated receptor gamma (PPARgamma) has been reported to play an important role to regulate adiposity and insulin sensitivity. It is not clear whether antagonism of PPARgamma using a synthetic ligand has significant effects on adipose tissue weight and glucose metabolism in vivo. The aim of this study is to examine the effects of a synthetic PPARgamma antagonist (GW9662) on adiposity and glycemic control in high-fat (HF) diet-fed mice. First the properties of GW9662 as a PPARgamma antagonist were estimated in vitro. GW9662 displaced [(3)H]rosiglitazone from PPARgamma with K(i) values of 13nM, indicating that the affinity of GW9662 for PPARgamma was higher than that of rosiglitazone (110nM). GW9662 had no effect on PPARgamma transactivation in cells expressing human PPARgamma. Treatment of 3T3-L1 preadipocytes with GW9662 did not increase aP2 expression or [(14)C]acetic acid uptake. GW9662 did not recruit transcriptional cofactors to PPARgamma. Limited trypsin digestion of the human PPARgamma/GW9662 complex showed patterns of digestion distinct from those of rosiglitazone. This suggests that the binding characteristics between GW9662 and PPARgamma are different from those of rosiglitazone. Treatment of HF diet-fed mice with GW9662 revealed that this compound prevented HF diet-induced obesity without affecting food intake. GW9662 suppressed any increase in the amount of visceral adipose tissue, but it did not change HF diet-induced glucose intolerance. These data indicate that antagonism of PPARgamma using a synthetic ligand suppresses the increased adiposity observed in HF diet-induced obesity, and that a PPARgamma antagonist could possibly be developed as an anti-obesity drug.
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PMID:Antagonism of peroxisome proliferator-activated receptor gamma prevents high-fat diet-induced obesity in vivo. 1669 51

Estrogen-related receptor alpha (ERRalpha) modulates estrogen receptor (ER)-mediated activity and is participating in the energy homeostasis by regulation of downstream target genes. The ERRalpha gene itself is proposed to be regulated by peroxisome proliferator-activated receptor gamma coactivator (PGC-1alpha) through an autoregulatory loop under physiological stimulation. We have previously shown that the close family member ERRgamma is a positive regulator of ERRalpha gene expression. ERRalpha and ERRgamma are coexpressed in metabolically active tissues such as heart, kidney and muscle, yet the physiological role of ERRgamma and its relationship with ERRalpha in gene regulation are currently unknown. The present study examined the interplay of ERRgamma and ERRalpha in regulation of ERRalpha gene expression. Using real-time PCR analyses we found that ERRgamma, like the ERRalpha and PGC-1alpha is induced in mouse liver during fasting. Overexpression of ERRgamma in the HEC-1B cells robustly stimulated the multi-hormone response element (MHRE) of the ERRalpha gene promoter and this activity was repressed by increasing expression of ERRalpha. The two ERRs bind MHRE simultaneously in electrophoretic mobility shift assay (EMSA) and they were detected as multimeric complexes in cells by coimmunoprecipitation. Although ERRalpha and ERRgamma share high sequence identity, they differ in biochemical and molecular characteristics as examined by trypsin digestion, reporter activation and coactivator interaction and utilization. Using chromatin immunoprecipitation (ChIP) assay, we showed that ectopic expression of both ERRalpha and ERRgamma modifies chromatin structure at the MHRE region while ectopic expression of PGC-1alpha in HEC-1B cells promotes ERRgamma but not ERRalpha occupancy at the MHRE region of the ERRalpha gene promoter and enhances the recruitment of coactivator SRC1. These data suggested that ERRalpha and ERRgamma regulate ERRalpha gene expression with different molecular mechanisms.
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PMID:Interplay between estrogen-related receptor alpha (ERRalpha) and gamma (ERRgamma) on the regulation of ERRalpha gene expression. 1715 80

Alcohol exposure is known to sensitize acinar cells to various insults but the pathophysiological mechanisms of alcoholic pancreatitis remain unknown. Alcohol abuse has been shown to mediate an anti-inflammatory response and periods of immune suppression seem to be associated with organ injury and mortality. The purpose of this study was to determine the mechanisms by which alcohol exerts transcriptional activities in the rat pancreas and how alcohol alters the inflammatory response. Using the Lieber-DeCarli alcohol/control diet, rats that were fed with alcohol over 14 weeks demonstrated a decrease of inflammatory cells in pancreatic tissue compared to controls. The anti-inflammatory effects of alcohol were confirmed by decreased expression of pro-inflammatory cytokines including TNFalpha, IL-1beta, IL-18, TGFbeta, and MCP-1. In addition, alcohol significantly increased the activity of PPARgamma, which is a known anti-inflammatory transcription factor, while pro-inflammatory factors including AP-2 and EGR-1 were significantly suppressed. NFkappaB binding showed a tendency towards a reduction. Electron microscopy studies revealed enlarged and injured mitochondria and lysosomes, accompanied by peri-cellular fibrosis. Furthermore, alcohol exposure increased the activities of trypsin and cathepsin B, both known to be critical in initiating acinar cell injury and pancreatitis. Despite the known alcohol-mediated acinar cell and mitochondrial injury, the mitochondrial-mediated apoptotic pathway was attenuated. These data demonstrate that the pancreas exposed to alcohol maintains an anti-inflammatory state by activating PPARgamma. Intracellular mitochondrial and lysosomal damage after chronic alcohol exposure induces premature activation of digestive enzymes and establishment of peri-cellular fibrosis in the absence of inflammation.
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PMID:Immune-compromised state in the rat pancreas after chronic alcohol exposure: the role of peroxisome proliferator-activated receptor gamma. 1793 47

To examine if overexpression of certain chemokines and proinflammatory cytokines in response to oxidized low-density lipoprotein could be involved in the onset and development of tendon xanthomas (TX), we quantified IL-1beta, TNF-alpha, and IL-8 and compared gene expression of PPAR-gamma, NF-kappaBIA, IL-8, IL-1beta, CXCL3, tryptase, and TNF-alpha in macrophages of familial hypercholesterolemia subjects with and without TX stimulated with oxidized low-density lipoprotein at 1, 3, 6, and 18 h of incubation. We propose that chemokines belonging to the CXC family could play an important role in the etiology of TX, with CXCL3 being a possible biological marker of onset and development of TX.
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PMID:Overexpression of the CXCL3 gene in response to oxidized low-density lipoprotein is associated with the presence of tendon xanthomas in familial hypercholesterolemia. 1944 42


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