Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: EC:2.7.7.49 (reverse transcriptase)
 31,746 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

In the present study, the role of endothelin-1 (ET-1) on alterations of hepatic and renal metallothionein (MT) and trace metals (Zn, Cu, and Fe) were investigated in streptozotocin (STZ)-induced diabetic rats. Diabetic rats, age- and sex-matched controls, as well as control and diabetic animals on a dual ETA/ETB receptor blocker, bosentan, were investigated after 6 months of follow-up. MT was measured by cadmium-heme assay. Metals were measured by atomic absorption spectrometer. ET-1 mRNA was analyzed by reverse transcriptase-polymerase chain reaction (RT-PCR) technique. Hepatic and renal ET-1 mRNA was increased in diabetic rats as compared to control rats, along with an increase in both hepatic and renal MT proteins. The increased hepatic MT protein level was associated with decreases in hepatic Cu and Fe, whereas increased renal MT was associated with increases in renal Cu and Fe accumulation. Zn levels were unaltered in both organs in diabetic rats. Bosentan treatment partially prevented the increase in MT levels in both liver and kidney, along with reduced serum creatinine and increased urinary creatinine levels. Further bosentan treatment corrected the increased Cu and Fe levels in the kidney in diabetic rats, but reduced hepatic Cu and Fe levels. No significant effects of bosentan treatment on nondiabetic rats were observed. The data suggest that the possible effects of ET antagonism in diabetes may be mediated via changes in MT and trace metals.
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PMID:Endothelin-1-mediated alteration of metallothionein and trace metals in the liver and kidneys of chronically diabetic rats. 1245 61

Endothelin (ET)-1 is an autocrine/paracrine growth factor or an antiapoptotic factor in human cancers, and blockade of ET-1 receptors can sensitize human tumor cells to apoptosis. The role of the ET-1 axis in the proliferation and/or apoptosis of melanoma cells and in their response to the alkylating agent, dacarbazine (DTIC), used in clinical treatment of human melanoma were investigated in five human melanoma cell lines obtained form surgical resection specimens. Melanoma cells expressed the messenger RNAs (mRNAs) for the components of the ET-1 axis. ET-1 binding was mediated by ET(B) but was inhomogeneous among melanoma cells. Exogenous ET-1 did not induce human melanoma cell proliferation. Bosentan, a dual ET(A/B)-receptor antagonist, decreased melanoma cell viability and DNA synthesis and induced melanoma cell apoptosis in defined human melanoma cells. Bosentan potentiated Fas ligand-induced apoptosis only in one melanoma cell line. Variants of ET(B)were determined using reverse transcriptase (RT) polymerase chain reaction (PCR) and primers spanning the whole sequence of the ET(B)gene. ET(B)variants were demonstrated only in one of the five cell lines, corresponding to the absence of ET-1 binding by these cells. Bosentan did not inhibit the effects of alkylating agents, and the effects of bosentan and alkylating agents were additive in melanoma cells. In conclusion, exogenous ET-1 is not a growth factor for human melanoma cells, but blockade of ET receptors decreases proliferation, induces apoptosis, and potentiates the effects of anticancer agents in defined melanoma cells, suggesting that combination therapy of ET-receptor antagonists with alkylating agents may improve their efficacy.
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PMID:Targeting the endothelin axis in human melanoma: combination of endothelin receptor antagonism and alkylating agents. 1674 Oct 59

Bacterial infections induce exacerbations in chronic lung diseases, e.g., chronic obstructive pulmonary disease (COPD), by enhancing airway inflammation. Exacerbations are frequently associated with right heart decompensation and accelerate disease progression. Endothelin receptor antagonists (ERAs) might have therapeutic potential as pulmonary vasodilators and anti-inflammatory agents, but utility in exacerbations of chronic lung diseases is unknown. We hypothesized that cytokine releases induced by lipopolysaccharide (LPS), the major bacterial trigger of inflammation, are reduced by ERAs in pulmonary vascular smooth muscle cells (PVSMCs). Ex vivo cultivated human PVSMCs were preincubated with the endothelin-A-receptor selective inhibitor ambrisentan, with the endothelin-B-receptor selective inhibitor BQ788 [sodium (2R)-2-{[(2S)-2-({[(2R,6S)-2,6-dimethyl-1-piperidinyl]carbonyl}amino)-4,4-dimethylpentanoyl][1-(methoxycarbonyl)-d-tryptophyl]amino}hexanoate], or with the dual blocker bosentan before stimulation with smooth LPS (S-LPS), rough LPS (Re-LPS), or a mixture of long and short forms (M-LPS). Expression of cytokines and LPS receptors (TLR4, CD14) were analyzed via enzyme-linked immunosorbent assay (ELISA) and/or quantitative reverse transcriptase polymerase chain reaction (qRT-PCR). All LPS forms induced interleukin (IL)-6-, IL-8-, and granulocyte macrophage-colony stimulating factor (GM-CSF) release. Bosentan and BQ788 inhibited M-LPS-induced release of all cytokines and soluble CD14 (sCD14) but not TLR4 expression. Ambrisentan blocked M-LPS-induced IL-6 release but not IL-8, GM-CSF, or LPS receptors. IL-8 release induced by S-LPS, which requires CD14 to activate TLR4, was blocked by bosentan and BQ788. IL-8 release induced by Re-LPS, which does not require CD14 to activate TLR4, was insensitive to both bosentan and BQ788. In conclusion, PVSMCs contribute to inflammation in bacteria-induced exacerbations of chronic lung diseases. Inhibition of the endothelin-B receptor suppresses cytokine release induced by long/smooth LPS attributable to sCD14 downregulation. ERAs, particularly when targeting the endothelin-B receptor, might have therapeutic utility in exacerbations of chronic lung diseases.
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PMID:Endothelin receptor antagonists attenuate the inflammatory response of human pulmonary vascular smooth muscle cells to bacterial endotoxin. 2372 Apr 57