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:2.7.10.1 (ERK)
95,504 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Quercetin, the most abundant dietary flavonol, exerts vasodilator, anti-hypertensive, and anti-atherogenic effects and reduces the vascular remodelling associated with elevated blood pressure. Here, we have compared the effects of quercetin in intimal- and medial-type rat vascular smooth muscle cells (VSMC) in culture. After 48 h, quercetin reduced the viability of a polyclonal intimal-type cell line derived from neonatal aorta but not of a medial-type cell line derived from adult aorta. These differential effects were similar in both proliferating and quiescent VSMC. Quercetin also preferentially reduced the viability of intimal-type over medial-type VSMC in primary cultures derived from balloon-injured carotid arteries. The effects of quercetin on cell viability were mainly dependent upon induction of apoptosis, as demonstrated by nuclear condensation and fragmentation, and were unrelated to PPARgamma, pro-oxidant effects or nitric oxide. The expression of MAPKs (ERK, p38, and JNK) and ERK phosphorylation were not different between intimal- and medial-type VSMC. p38 phosphorylation was negligible in both cell types. Medial-type showed a weak JNK phosphorylation while this was markedly increased in intimal-type cells. Quercetin reduced JNK phosphorylation but had no consistent effect on ERK phosphorylation. In conclusion, quercetin preferentially produced apoptosis in intimal-type compared to medial-type VSMC. This might play a role in the anti-atherogenic and anti-hypertensive effects of quercetin.
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PMID:The flavonoid quercetin induces apoptosis and inhibits JNK activation in intimal vascular smooth muscle cells. 1677 73

Hepatocyte growth factor (HGF) is mesenchymal-derived growth factor acting through a transmembrane tyrosine kinase receptor, c-met. HGF has multiple effects on different cells. However, its function in dentinogenesis remains unclear. In this study, the expression of HGF in human dental pulp cells (DPCs) in vitro was studied by immunostaining and RT-PCR. The effect of HGF on DPCs proliferation was determined by MTT, while its effect on cell differentiation was analyzed using ALPase activity, and further confirmed with ALP and DSPP mRNA and protein expression. Immunostaining revealed that HGF was found mainly in the cytoplasm of DPCs. RT-PCR analysis showed that both HGF and c-met were expressed from the DPCs. Exogenous addition of HGF enhanced proliferation and differentiation of DPCs by up-regulating CREB, ELK-1, and PPAR-gamma. U0126, an ERK/MAPK inhibitor, inhibited the effects of HGF on DPCs. It was concluded that HGF stimulated both proliferation and differentiation of DPCs, at least partially through the ERK/MAPK pathway.
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PMID:HGF enhanced proliferation and differentiation of dental pulp cells. 1686 Oct 72

The effect of conjugated linoleic acid (CLA) on pre-existent peritoneal metastasis was examined by mouse peritoneal metastasis models. The cell growth of LL2 mouse cancer cells was suppressed by CLA in a dose-dependent manner. CLA-induced growth inhibition was recovered by the exposure to antisense S-oligodeoxynucleotide for peroxisome proliferator-activated receptor (PPAR)-gamma. C57B6 mice were inoculated with LL2 cells into their peritoneal cavity. Two weeks after inoculation, colonized peritoneal cancer foci (2.2+/-0.4 mm in diameter) were treated with CLA administrated intraperitoneally (200 or 600 pmol/mouse, twice a week). CLA treatment decreased the number of peritoneal tumors: 8.7+/-0.6, 5.7+/-0.6, and 2.3+/-0.6 in untreated, 200 pmol/mouse CLA, and 600 pmol/mouse CLA groups, respectively (P<0.0001). CLA treatment decreased the size of peritoneal tumors: 3.7+/-1.5, 1.3+/-0.5, and 1.0+/-0.4 mm in untreated, 200 pmol/mouse CLA, and 600 pmol/mouse CLA groups, respectively (P<0.0001). In CLA-treated tumors, proliferating cells were decreased (P<0.0001), whereas apoptotic cells were increased (P=0.0010). CLA-treated LL2 tumors showed decrease of PPARgamma and EGFR proteins and increase of BAX protein in comparison with untreated tumors. These findings suggest that CLA possesses anti-tumor capability to peritoneal metastasis.
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PMID:Conjugated linoleic acid reduced metastasized LL2 tumors in mouse peritoneum. 1689 90

Troglitazone (Tro) and pioglitazone (Pio) activation of peroxisome proliferator-activated receptor (PPAR)-gamma and PPAR-gamma-independent pathways was studied in cell lines derived from porcine renal tubules. PPAR-gamma-dependent activation of PPAR response element-driven luciferase gene expression was observed with Pio at 1 microM but not Tro at 1 microM. On the other hand, PPAR-gamma-independent P-ERK activation was observed with 5 microM Tro but not with Pio (5-20 microM). In addition, Pio (1-10 microM) increased metabolic acid production and activated AMP-activated protein kinase (AMPK) associated with decreased mitochondrial membrane potential, whereas Tro (1-20 microM) did not. These results are consistent with three pathways through which glitazones may act in effecting metabolic processes (ammoniagenesis and gluconeogenesis) as well as cellular growth: 1) PPAR-gamma-dependent and PPAR-gamma-independent pathways, 2) P-ERK activation, and 3) mitochondrial AMPK activation. The pathways influence cellular acidosis and glucose and glutamine metabolism in a manner favoring reduced plasma glucose in vivo. In addition, significant interactions can be demonstrated that enhance some physiological processes (ammoniagenesis) and suppress others (ligand-mediated PPAR-gamma gene expression). Our findings provide a model both for understanding seemingly opposite biological effects and for enhancing therapeutic potency of these agents.
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PMID:Troglitazone and pioglitazone interactions via PPAR-gamma-independent and -dependent pathways in regulating physiological responses in renal tubule-derived cell lines. 1706 4

Rosiglitazone (Rosi) belongs to the class of thiazolidinediones (TZDs) that are ligands for peroxisome proliferator-activated receptor gamma (PPARgamma). Stimulation of PPARgamma suppresses bone formation and enhances marrow adipogenesis. We hypothesized that activation of PPARgamma down-regulates components of the IGF regulatory system, leading to impaired osteoblast function. Rosi treatment (1 microm) of a marrow stromal cell line (UAMS-33) transfected with empty vector (U-33/c) or with PPARgamma2 (U-33/gamma2) were analyzed by microarray. Rosi reduced IGF-I, IGF-II, IGFBP-4, and the type I and II IGF receptor (IGF1R and IGF2R) expression at 72 h in U-33/gamma2 compared with U-33/c cells (P < 0.01); these findings were confirmed by RT-PCR. Rosi reduced secreted IGF-I from U-33/gamma2 cells by 75% (P < 0.05). Primary marrow stromal cells (MSCs) extracted from adult (8 months) and old (24 months) C57BL/6J (B6) mice were treated with Rosi (1 microm) for 48 h. IGF-I, IGFBP-4, and IGF1R transcripts were reduced in Rosi-treated MSCs compared with vehicle (P < 0.01) and secreted IGF-I was also suppressed (P < 0.05). B6 mice treated with Rosi (20 mg/kg.d) for short duration (i.e. 4 d), and long term (i.e. 7 wk) had reduced serum IGF-I; this was accompanied by markedly suppressed IGF-I transcripts in the liver and peripheral fat of treated animals. To determine whether Rosi affected circulating IGF-I in humans, we measured serum IGF-I, IGFBP-2, and IGFBP-3 at four time points in 50 postmenopausal women randomized to either Rosi (8 mg/d) or placebo. Rosi-treated subjects had significantly lower IGF-I at 8 wk than baseline (-25%, P < 0.05), and at 16 wk their levels were reduced 14% vs. placebo (P = 0.15). We conclude that Rosi suppresses IGF-I expression in bone and liver; these changes could affect skeletal acquisition through endocrine and paracrine pathways.
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PMID:Activation of peroxisome proliferator-activated receptor gamma (PPARgamma) by rosiglitazone suppresses components of the insulin-like growth factor regulatory system in vitro and in vivo. 1712 83

Epithelial tumors of the thyroid are cytogenetically well-investigated tumors. So far, the main cytogenetic subgroups, characterized by trisomy 7 and by rearrangements of either 19q13 or 2p21, respectively, have been described. Recently, we have been able to describe the involvement of a novel gene called THADA in benign thyroid lesions with 2p21 rearrangements. Other fusion genes found in thyroid lesions are RET/PTC and PAX8/PPAR(gamma). The latter occurs in follicular thyroid carcinomas with a t(2;3)(q13;p25). Here we present molecular-cytogenetic and cytogenetic investigations on a follicular thyroid adenoma with a t(2;20;3)(p21;q11.2; p25). In this case, an intronic sequence of PPAR(gamma) is fused to exon 28 of THADA. We used BAC clones containing the genomic sequence of PPARgamma for fluorescence in situ hybridization to confirm the localization of the breakpoint within intron 2 of PPAR(gamma) . Our findings suggest that the close surrounding of PPAR(gamma) is a breakpoint hot spot region, leading to recurrent alterations of this gene in thyroid tumors of follicular origin including carcinomas as well as adenomas with or without involvement of PAX8.
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PMID:Evidence for a 3p25 breakpoint hot spot region in thyroid tumors of follicular origin. 1712 35

Carcinomas of the thyroid comprise a heterogeneous group of neoplasms with distinctive clinical and pathological characteristics. Over the past 15 years, the application of molecular technologies to the study of these neoplasms has elucidated critical genetic pathways associated with the development of specific thyroid tumor types. In papillary thyroid carcinoma (PTC), genetic events involve RET and TRK (rearrangements) and BRAF and RAS (mutations), although RAS mutations are uncommon except in the follicular variant of PTC. These genetic alterations, which rarely overlap in the same tumor, result in signaling abnormalities in the mitogen-activated protein kinase pathway. In contrast, genetic alterations in follicular carcinomas include PAX8-PPARgamma translocations and RAS mutations while mutations of CTNNB1 and p53 have been implicated in the development and progression of poorly differentiated and undifferentiated (anaplastic) thyroid carcinomas. Germline mutations of RET are responsible for the development of heritable forms of medullary thyroid carcinoma (MTC) while somatic mutations of this oncogene are found in a significant proportion of sporadic MTCs. The results of these studies not only have provided additional approaches to thyroid tumor classification, but also have stimulated the development of novel approaches to tumor diagnosis and additional parameters for prognostic assessment and potential biologic therapeutic strategies.
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PMID:Pathology and genetics of thyroid carcinoma. 1713 11

The diagnosis of well differentiated carcinoma (i.e papillary carcinoma and follicular carcinoma) represents one of the most challenging issue in thyroid pathology. Aim of the present review is to discuss new perspective and old problems in this topic. Three main subjects are developed, corresponding to: 1) the role of fine needle aspiration versus frozen section examination in pre- or peri- operative diagnosis; 2) the management of small papillary tumour; 3) pathological classification of those tumours indeterminate for papillary or follicular nature. There is general agreement that fine needle aspiration represent the best pre-operative diagnostic tool for thyroid nodules; foremost limits are represented by "not diagnostic" and 'follicular lesion, NOS". The former should be repeated or, if suspicious for papillary lesion, improved with intra-operative apposition cytology; the latter should be deferred to histology with frozen section evaluation reserved to those institution with daily practice on this issue. The management of papillary micro-carcinoma (i.e. papillary carcinoma smaller than 1 cm.) in the setting of an otherwise benign thyroid disease is a matter of debate, since several clinicians suggest to consider these as incidental findings thus avoiding additional treatment. Recently this attitude has been supported by the proposal to regard these lesion as "tumour" and not carcinoma: available data on follow up seems to sustain and favour this approach. There exist a group of well differentiated tumours of the thyroid lacking the criteria to be diagnosed either as papillary (i.e. nuclear grooves, nuclear pseudo-inclusion and nuclear clearing) or follicular (i.e. capsular or vascular invasion) carcinoma; for these lesion, whose behaviour (nodal or blood metastasis) can not be predicted, it has been suggested the term of well differentiated tumour of uncertain malignant potential. Finally it has to be mentioned the possible role of molecular biology in the diagnosis of well differentiated thyroid carcinoma; indeed markers such as RET/PTC or PAX8/PPARgamma, which to date have been employed mainly in basic research, might represent useful diagnostic (and therapeutic) tools in the future.
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PMID:[Well differentiated thyroid carcinoma: new perspectives and old dilemmas]. 1713 34

Papillary and follicular carcinomas, commonly referred to as follicular cell-derived differentiated thyroid carcinomas (DTC), account for 90% of all thyroid carcinomas. The prognosis of DTC is generally good, depending on the biologic behavior of the tumor and on the appropriate initial treatment which includes total thyroidectomy and ablation by radioiodine-131. However, a considerable number of patients, approximately 30%, as shown after 30 years of follow-up, have recurrent disease. It is thus of utmost importance to evaluate the prognostic factors, as derived from retrospective studies, and identify high risk patients. Age of more than 45 years or less than 25 years is a particularly strong independent prognostic factor; on the contrary gender is a poor prognostic factor. Histological type of the cancer especially tall cancer cells and columnar cancer cells, as well as increased vascular invasion of the tumor, lymph-node and distant metastases, are all considered as risk factors that can lead to poor prognosis. Combined prognostic factors have been used to form scoring systems (SS) such as AGES, MACIS, AMES, EORTC and TNM for a more precise description of high or low risk patients. However, prognostic significance of the SS is limited, since they do not take into consideration the clinical status or the treatment procedure during the course of the disease. Molecular factors such as rearrangements of genes RET/PTC, RAS mutations and fusion of, paired box and 8/peroxisome proliferator-activated receptor gamma (PAX8/PPARgamma) are also involved in thyroid cancer prognosis, while some others: human Pituitary- Tumor Transforming Gene (e.g. MIB-1, hPTTG) have been reported as additional prognostic factors. In this review we describe the risk and the prognostic factors of DTC as related to management and the outcome of DTC.
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PMID:Risk and prognostic factors for differentiated thyroid cancer. 1881 68

Oncostatin M (OSM) is a multifunctional cytokine of the interleukin-6 family and has been implicated in embryonic development, differentiation, inflammation, and regeneration of liver and bone. In the present study, we demonstrated that treatment of human adipose mesenchymal stem cells (hADSCs) with OSM-attenuated adipogenic differentiation, as indicated by decreased accumulation of intracellular lipid droplets and down-regulated expression of adipocytic markers, such as lipoprotein lipase and PPARgamma. However, OSM treatment stimulated osteogenic differentiation, as demonstrated by the increase in matrix mineralization and expression levels of osteogenic differentiation markers, including alkaline phosphatase, Runx2, and osteocalcin. OSM treatment induced activation of JAK2, JAK3, and ERK in hADSCs, and pre-treatment of hADSCs with the JAK2 inhibitor, AG490, significantly restored the OSM-induced inhibition of adipogenic differentiation. Whereas, the JAK3 inhibitor, WHI-P131, and the MEK inhibitor, U0126, had no effects on the anti-adipogenic activity of OSM. On the other hand, the pro-osteogenic activity of OSM was prevented by treatment of the cells with WHI-P131 or U0126, but not with AG490. These results indicate that distinct signaling pathways, including JAK2, JAK3, and MEK-ERK, play specific roles in the OSM-induced anti-adipogenic and pro-osteogenic differentiation of hADSCs.
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PMID:Oncostatin M promotes osteogenesis and suppresses adipogenic differentiation of human adipose tissue-derived mesenchymal stem cells. 1722 68


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