Biochemical PharmacologyThis is an RSS file. You can use it to subscribe to this data in your favourite RSS reader, such as GoogleReader, or to display this data on your own website or blog. Subscribe to this data using MyMedWorm.Subscribe to this data using GoogleReader.Subscribe to this data using Bloglines.Subscribe to this data using MyYahoo.

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Synthesis and Pharmacological Characterization of [125I]MRS5127, a High Affinity, Selective Agonist Radioligand for the A3 Adenosine Receptor.Email this article to a colleague. Save this article to My Clippings. Discuss or comment on this article.
A recently reported selective agonist of the human A(3) adenosine receptor (hA(3)AR), MRS5127, (1'R,2'R,3'S,4'R,5'S)-4'-[2-chloro-6-(3-iodobenzylamino)-purine]-2',3'-O-dihydroxy-bicyclo-[3.1.0]hexane, was radioiodinated and characterized pharmacologically. It contains a rigid bicyclic ring system in place of a 5'-truncated ribose moiety, and was selected for radiolabeling due to its nanomolar binding affinity at both human and rat A(3)ARs. The radioiodination of the N(6)-3-iodobenzyl substituent by iododestannylation of a 3-(trimethylstannyl)benzyl precursor was achieved in 73% yield, measured after purification by HPL...
Source: Biochemical Pharmacology - November 13, 2009 Category: Drugs & Pharmacology Authors: Auchampach JA, Gizewski ET, Wan TC, de Castro S, Brown GG, Jacobson KA Tags: Biochem Pharmacol Source Type: journals

Cannabidiol Inhibits Cancer Cell Invasion Via Upregulation Of Tissue Inhibitor Of Matrix Metalloproteinases-1.Email this article to a colleague. Save this article to My Clippings. Discuss or comment on this article.
Although cannabinoids exhibit a broad variety of anticarcinogenic effects, their potential use in cancer therapy is limited by their psychoactive effects. Here we evaluated the impact of cannabidiol, a plant-derived non-psychoactive cannabinoid, on cancer cell invasion. Using Matrigel invasion assays we found a cannabidiol-driven impaired invasion of human cervical cancer (HeLa, C33A) and human lung cancer cells (A549) that was reversed by antagonists to both CB(1) and CB(2) receptors as well as to transient receptor potential vanilloid 1 (TRPV1). The decrease of invasion by cannabidiol appeared concomitantly with upre...
Source: Biochemical Pharmacology - November 12, 2009 Category: Drugs & Pharmacology Authors: Ramer R, Merkord J, Rohde H, Hinz B Tags: Biochem Pharmacol Source Type: journals

Endocrine disruptors and thyroid hormone physiology.Email this article to a colleague. Save this article to My Clippings. Discuss or comment on this article.
Endocrine disruptors are man-made chemicals that can disrupt the synthesis, circulating levels, and peripheral action of hormones. The disruption of sex hormones was subject of intensive research, but thyroid hormone synthesis and signaling are now also recognized as important targets of endocrine disruptors. The neurological development of mammals is largely dependent on normal thyroid hormone homeostasis, and it is likely to be particularly sensitive to disruption of the thyroid axis. Here, we survey the main thyroid-disrupting chemicals, such as polychlorinated biphenyls, perchlorates, and brominated flame retardant...
Source: Biochemical Pharmacology - November 11, 2009 Category: Drugs & Pharmacology Authors: Jugan ML, Levi Y, Blondeau JP Tags: Biochem Pharmacol Source Type: journals

Investigating the Interaction of McN-A-343 with the M(2) Muscarinic Receptor Using its Nitrogen Mustard Derivative.Email this article to a colleague. Save this article to My Clippings. Discuss or comment on this article.
We investigated whether the aziridinium ion formed from a nitrogen mustard derivative (4-[(2-bromoethyl)methyl-amino]-2-butynyl N-(3-chlorophenyl)carbamate; BR384) structurally related to McN-A-343 (4-(trimethyl-amino)-2-butynyl N-(3-chlorophenyl)carbamate) interacts allosterically or orthosterically with the M(2) muscarinic receptor. Chinese hamster ovary cells expressing the human M(2) muscarinic receptor were incubated with the aziridinium ion of BR384 in combination with McN-A-343 or other known orthosteric and allosteric ligands for various incubation times. After removing unreacted ligands, we measured the bindin...
Source: Biochemical Pharmacology - November 11, 2009 Category: Drugs & Pharmacology Authors: Suga H, Ehlert FJ Tags: Biochem Pharmacol Source Type: journals

Identification and characterization of small compound inhibitors of human FATP2.Email this article to a colleague. Save this article to My Clippings. Discuss or comment on this article.
Fatty acid transport proteins (FATPs) are bifunctional proteins, which transport long chain fatty acids into cells and activate very long chain fatty acids by esterification with coenzyme A. In an effort to understand the linkage between cellular fatty acid transport and the pathology associated with excessive accumulation of exogenous fatty acids, we targeted FATP-mediated fatty acid transport in a high throughput screen of more than 100,000 small diverse chemical compounds in yeast expressing human FATP2 (hsFATP2). Compounds were selected for their ability to depress the transport of the fluorescent long chain fatty ...
Source: Biochemical Pharmacology - November 11, 2009 Category: Drugs & Pharmacology Authors: Sandoval A, Chokshi A, Jesch ED, Black PN, Dirusso CC Tags: Biochem Pharmacol Source Type: journals

Induction and intracellular localization of Nur77 dictate fenretinide-induced apoptosis of human liver cancer cells.Email this article to a colleague. Save this article to My Clippings. Discuss or comment on this article.
Fenretinide, a synthetic retinoid, is known to induce apoptosis in various cancer cells. However, the mechanism by which fenretinide induces apoptosis remains unclear. The current study examines the mechanisms of fenretinide-induced apoptosis in human hepatoma cells. The induction of Nur77 and the cytoplasmic distribution of Nur77 induced by fenretinide were positively correlated with the apoptotic effect of fenretinide in HCC cells. The sensitivity of Huh-7 cells was related to Nur77 translocation and targeting mitochondria, whereas the mechanism of resistance for HepG2 cells seemed due to Nur77 accumulating in the nu...
Source: Biochemical Pharmacology - November 10, 2009 Category: Drugs & Pharmacology Authors: Yang H, Bushue N, Bu P, Wan YJ Tags: Biochem Pharmacol Source Type: journals

Nematicidal activity of two monoterpenoids and SER-2 tyramine receptor of Caenorhabditis elegans.Email this article to a colleague. Save this article to My Clippings. Discuss or comment on this article.
In vitro cultures of two nematodes (Caenorhabditis elegans and Ascaris suum) were established to study the nematicidal activity of three monoterpenoids (thymol, carvacrol and p-cymene). Toxicity of thymol and carvacrol was found for the two nematodes tested. The study was then aimed to address whether nematode tyramine receptor (TyrR) could interact with the two compounds by using HEK293 mammalian cells transfected with a C. elegans TyrR (ser-2) sequence, in hope of developing a high-throughput cell-based platform for future screening of new antihelminthic compounds. SER-2 expression and functionality in the transfecte...
Source: Biochemical Pharmacology - November 5, 2009 Category: Drugs & Pharmacology Authors: Lei J, Leser M, Enan E Tags: Biochem Pharmacol Source Type: journals

Correlation Of The Time Course Of Development And Decay Of Tolerance To Morphine With Alterations In Sodium Pump Protein Isoform Abundance.Email this article to a colleague. Save this article to My Clippings. Discuss or comment on this article.
This study correlated the time course over which heterologous tolerance develops with changes in the abundance of selected proteins in the guinea-pig longitudinal muscle/myenteric plexus (LM/MP) preparation. Tissues were obtained at various times following a single surgical implantation procedure and heterologous tolerance confirmed by a significant reduction in the sensitivity of the LM/MP to inhibition of neurogenic twitches by morphine, DAMGO, and 2-CADO. Tolerance developed with a delayed onset (significant 2-5 fold reduction in sensitivity by day 4 after pellet implantation) that reached a maximum by 7 days (4-8 fold ...
Source: Biochemical Pharmacology - November 5, 2009 Category: Drugs & Pharmacology Authors: Li P, Maguma HT, Thayne K, Davis B, Taylor DA Tags: Biochem Pharmacol Source Type: journals

Modulation of human placental P-glycoprotein expression and activity by MDR1 gene polymorphisms.Email this article to a colleague. Save this article to My Clippings. Discuss or comment on this article.
The ABC transporter P-glycoprotein is a product of the MDR1 gene and its function in human placenta is to extrude xenobiotics from the tissue thus decreasing fetal exposure. The goal of this investigation was to examine the effect of three polymorphisms in the MDR1 gene on the expression and activity of placental P-gp. In 199 term placentas examined, the C1236T variant was associated with 11% lower P-gp protein expression than wild type, while the C3435T and G2677T/A variants each were associated with a 16% reduction (p<0.05). Homozygotes for the C1236T and C3435T variant allele (TT) were associated with 42% and 47%...
Source: Biochemical Pharmacology - November 5, 2009 Category: Drugs & Pharmacology Authors: Hemauer SJ, Nanovskaya TN, Abdel-Rahman SZ, Patrikeeva SL, Hankins GD, Ahmed MS Tags: Biochem Pharmacol Source Type: journals

Mutations in the human kinesin Eg5 that confer resistance to monastrol and S-Trityl-L-Cysteine in tumor derived cell lines.Email this article to a colleague. Save this article to My Clippings. Discuss or comment on this article.
The kinesin Eg5 plays an essential role in bipolar spindle formation. A variety of structurally diverse inhibitors of the human kinesin Eg5, including monastrol and STLC, share the same binding pocket on Eg5, composed by helix alpha2/loop L5, and helix alpha3 of the Eg5 motor domain. Previous biochemical analysis in the inhibitor binding pocket of Eg5 identified key residues in the inhibitor binding pocket of Eg5 that in the presence of either monastrol or STLC exhibited ATPase activities similar to the untreated wild type Eg5. Here we evaluated the ability of full-length human Eg5 carrying point mutations in the drug ...
Source: Biochemical Pharmacology - November 5, 2009 Category: Drugs & Pharmacology Authors: Tcherniuk S, van Lis R, Kozielski F, Skoufias DA Tags: Biochem Pharmacol Source Type: journals

Ampk-Independent Down-Regulation Of Cflip And Sensitization To Trail-Induced Apoptosis By Ampk Activators.Email this article to a colleague. Save this article to My Clippings. Discuss or comment on this article.
The tumor necrosis factor-related apoptosis-inducing ligand (TRAIL) is a TNF superfamily member that is being considered as a new strategy in anticancer therapy because of its ability to induce apoptosis, alone or in combination with other stimuli, in many cancer cells. AMP-activated protein kinase (AMPK) is an evolutionarily conserved key regulator of cellular energy homeostasis that protects the cell from energy depletion and stress by activating several biochemical pathways that lead to the conservation, as well as generation, of ATP. Here we report that a number of AMPK activators, including the small molecule acti...
Source: Biochemical Pharmacology - November 4, 2009 Category: Drugs & Pharmacology Authors: García-García C, Fumarola C, Navaratnam N, Carling D, López-Rivas A Tags: Biochem Pharmacol Source Type: journals

Inhibition of soluble epoxide hydrolase enhances the anti-inflammatory effects of aspirin and 5-lipoxygenase activation protein inhibitor in a murine model.Email this article to a colleague. Save this article to My Clippings. Discuss or comment on this article.
Inflammation is a multi-staged process whose expansive phase is thought to be driven by acutely released arachidonic acid (AA) and its metabolites. Inhibition of cyclooxygenase (COX), lipoxygenase (LOX), or soluble epoxide hydrolase (sEH) is known to be anti-inflammatory. Inhibition of sEH stabilizes the cytochrome P450 (CYP450) products epoxyeicosatrienoic acids (EETs). Here we used a non-selective COX inhibitor aspirin, a 5-lipoxygenase activation protein (FLAP) inhibitor MK886, and a sEH inhibitor t-AUCB to selectively modulate the branches of AA metabolism in a lipopolysaccharide (LPS)-challenged murine model. We u...
Source: Biochemical Pharmacology - November 4, 2009 Category: Drugs & Pharmacology Authors: Liu JY, Yang J, Inceoglu B, Qiu H, Ulu A, Hwang SH, Chiamvimonvat N, Hammock BD Tags: Biochem Pharmacol Source Type: journals

UDP-glucose acting at P2Y(14) receptors is a mediator of mast cell degranulation.Email this article to a colleague. Save this article to My Clippings. Discuss or comment on this article.
UDP-glucose (UDPG), a glycosyl donor in the biosynthesis of carbohydrates, is an endogenous agonist of the G protein-coupled P2Y(14) receptor. RBL-2H3 mast cells endogenously express a P2Y(14) receptor at which UDPG mediates degranulation as indicated by beta-hexosaminidase (HEX) release. Both UDPG and a more potent, selective 2-thio-modified UDPG analog, MRS2690 (2-thio-UDPG), caused a substantial calcium transient in RBL-2H3 cells, which was blocked by pertussis toxin, indicating the presence of the G(i)-coupled P2Y(14) receptor, supported also by quantitative detection of abundant mRNA. Expression of the closely rel...
Source: Biochemical Pharmacology - November 4, 2009 Category: Drugs & Pharmacology Authors: Gao ZG, Ding Y, Jacobson KA Tags: Biochem Pharmacol Source Type: journals

Anti-allergic function and regulatory mechanisms of KR62980 in allergen-induced airway inflammation.Email this article to a colleague. Save this article to My Clippings. Discuss or comment on this article.
In conclusion, a novel PPARgamma ligand, KR62980, suppresses in vitro Th2 cell differentiation and attenuates in vivo OVA-induced airway inflammation, suggesting a beneficial role for KR62980 in the treatment of allergic asthma and allergic rhinitis. PMID: 19896472 [PubMed - as supplied by publisher] (Source: Biochemical Pharmacology)
Source: Biochemical Pharmacology - November 4, 2009 Category: Drugs & Pharmacology Authors: Won HY, Min HJ, Ahn JH, Yoo SE, Bae MA, Hong JH, Hwang ES Tags: Biochem Pharmacol Source Type: journals

The PI3K/Akt/FOXO3a/p27(Kip1) signaling contribuTES to Anti-inflammatory Drug-suppressed proliferation of human osteoblasts.Email this article to a colleague. Save this article to My Clippings. Discuss or comment on this article.
In this study, we hypothesized that these drugs might increase p27(Kip1) expression in hOBs by altering the Akt/FOXO signaling. We tested this hypothesis by examining the influences of three anti-inflammatory drugs on the levels and/or activities of Akt, FOXO and p27(Kip1) as well as the relationship between these factors and proliferation of hOBs. We tested the effects of indomethacin (10(-5) and 10(-4)M), celecoxib (10(-6) and 10(-5)M), and dexamethasone (10(-7) and 10(-6)M) using PI3K inhibitor, LY294002 (10(-5)M) as the basis of comparison. The three drugs suppressed the canonical level of phosphorylated Akt in hOBs. T...
Source: Biochemical Pharmacology - October 30, 2009 Category: Drugs & Pharmacology Authors: Li CJ, Chang JK, Chou CH, Wang GJ, Ho ML Tags: Biochem Pharmacol Source Type: journals

2-Methoxyestradiol induces endoreduplication through the induction of mitochondrial oxidative stress and the activation of MAPKs signaling pathways.Email this article to a colleague. Save this article to My Clippings. Discuss or comment on this article.
We report here that 2ME2 induces G2/M phase cell cycle arrest followed by endoreduplication of the well-differentiated HK-1 cells. The increase in chromosome number was confirmed by cytogenetic study. Analysis of stress signaling pathways revealed the phosphorylation activation of ERK, JNK and p38 MAPKs at various times after 2ME2 treatment. Pre-treatment of 2ME2-treated HK-1 cells with JNK inhibitor (SP600125), ERK inhibitor (PD98059) and p38 MAPKs inhibitor (SB203580) resulted in the reduction of endoreduplicating cells. Furthermore, the increase in the phosphorylation of JNK was accompanied with the increased in reactiv...
Source: Biochemical Pharmacology - October 30, 2009 Category: Drugs & Pharmacology Authors: Ting CM, Lee YM, Wong CK, Wong AS, Lung HL, Lung ML, Lo KW, Wong RN, Mak NK Tags: Biochem Pharmacol Source Type: journals

Involvement of miR-326 in chemotherapy resistance of breast cancer through modulating expression of multidrug resistance-associated protein 1.Email this article to a colleague. Save this article to My Clippings. Discuss or comment on this article.
Multidrug resistance-associated protein (MRP-1/ABCC1) transports a wide range of therapeutic agents and may play a critical role in the development of multidrug resistance (MDR) in tumor cells. However, the regulation of MRP-1 remains controversial. To explore whether miRNAs are involved in the regulation of MRP-1 expression and modulate the sensitivity of tumor cells to chemotherapeutic agents, we analyzed miRNA expression levels in VP-16-resistant MDR cell line, MCF-7/VP, in comparison with its parent cell line, MCF-7, using a miRNA microarray. MCF-7/VP overexpressed MRP-1 mRNA and protein not MDR-1 and BCRP. MiR-326...
Source: Biochemical Pharmacology - October 30, 2009 Category: Drugs & Pharmacology Authors: Liang Z, Wu H, Xia J, Li Y, Zhang Y, Huang K, Wagar N, Yoon Y, Cho HT, Scala S, Shim H Tags: Biochem Pharmacol Source Type: journals

Characterization of endogenous calcium responses in neuronal cell lines.Email this article to a colleague. Save this article to My Clippings. Discuss or comment on this article.
This study revealed a remarkable diversity of endogenous Ca(2+) responses in these cell lines, with one or more cell lines responding to addition of trypsin, bradykinin, ATP, nicotine, acetylcholine, histamine and neurotensin. Subtype specificity of these responses was inferred from agonist potency and the effect of receptor subtype specific antagonist. Surprisingly, HEK293 and SH-SY5Y cells responded to the largest number of agonists with potential roles in neuronal signaling. These findings have implications for the heterologous expression of neuronal receptors and ion channels in these cell lines, and highlight the pote...
Source: Biochemical Pharmacology - October 30, 2009 Category: Drugs & Pharmacology Authors: Vetter I, Lewis RJ Tags: Biochem Pharmacol Source Type: journals

Reverse Phase Protein Array Identifies Novel Anti-invasion Mechanisms of YC-1.Email this article to a colleague. Save this article to My Clippings. Discuss or comment on this article.
YC-1 has recently been demonstrated to have potent anti-invasion and anti-metastatic activity in several cancer models, in addition to its anti-proliferation activity. However, the mechanism underlying its anti-invasion/anti-metastatic activity is largely unknown. Nasopharyngeal carcinoma (NPC) is a highly metastatic head and neck cancer in Southeast Asia. Here, we demonstrated that YC-1 inhibited invasiveness and proliferation of NPC cells, with the latter being accompanied by PARP cleavage, S-phase arrest and activation of Chk1/Chk2. We aimed at identifying novel anti-invasion mechanisms of YC-1 in NPC by a functiona...
Source: Biochemical Pharmacology - October 29, 2009 Category: Drugs & Pharmacology Authors: Hong B, Lui VW, Hui EP, Lu Y, Leung HS, Wong EY, Cheng SH, Ng MH, Mills GB, Chan AT Tags: Biochem Pharmacol Source Type: journals

Capacity of type I and II ligands to confer to estrogen receptor alpha an appropriate conformation for the recruitment of coactivators containing a LxxLL motif - Relationship with the regulation of receptor level and ERE-dependent transcription in MCF-7 cells.Email this article to a colleague. Save this article to My Clippings. Discuss or comment on this article.
Estrogen receptor alpha (ERalpha) belongs to the superfamily of nuclear receptors and as such acts as a ligand-modulated transcription factor. Ligands elicit in ERalpha conformational changes leading to the recruitment of coactivators required for the transactivation of target genes via cognate response elements. In many cells, activated ERalpha also undergoes downregulation by proteolysis mediated by the ubiquitin/proteasome system. Although these various molecular processes have been well characterized, little is known as to which extent they are interrelated. In the present study, we used a panel of type I (estradio...
Source: Biochemical Pharmacology - October 28, 2009 Category: Drugs & Pharmacology Authors: Bourgoin-Voillard S, Gallo D, Laïos I, Cleeren A, Bali LE, Jacquot Y, Nonclercq D, Laurent G, Tabet JC, Leclercq G Tags: Biochem Pharmacol Source Type: journals

Angiotensin-Induced Egf Receptor Transactivation Inhibits Insulin Signalling In C9 Hepatic Cells.Email this article to a colleague. Save this article to My Clippings. Discuss or comment on this article.
To investigate the potential interactions between the angiotensin II (Ang II) and insulin signaling systems, regulation of IRS-1 phosphorylation and insulin-induced Akt activation by Ang II were examined in clone 9 (C9) hepatocytes. In these cells, Ang II specifically inhibited activation of insulin-induced Akt Thr(308) and its immediate downstream substrate GSK-3alpha/beta in a time-dependent fashion, with approximately 70% reduction at 15minutes. These inhibitory actions were associated with increased IRS-1 phosphorylation of Ser(636)/Ser(639) that was prevented by selective blockade of EGFR tyrosine kinase activity ...
Source: Biochemical Pharmacology - October 28, 2009 Category: Drugs & Pharmacology Authors: Arellano-Plancarte A, Hernandez-Aranda J, Catt KJ, Olivares-Reyes JA Tags: Biochem Pharmacol Source Type: journals

Development of tolerance in D3 dopamine receptor signaling is accompanied by distinct changes in receptor conformation.Email this article to a colleague. Save this article to My Clippings. Discuss or comment on this article.
The D3 but not D2 dopamine receptors exhibit a tolerance property in which agonist-induced D3 receptor response progressively decreases upon repeated agonist stimulation. We have previously shown that the D3 receptor tolerance property is not mediated by receptor internalization, persistent agonist binding or a decrease in receptor binding affinity. In this paper, we test the hypothesis that alterations in D3 receptor conformation underlie the tolerance property. Structural models of wild type and mutant human D3 receptors were generated using the beta adrenergic receptor crystal structure as a template. These models s...
Source: Biochemical Pharmacology - October 28, 2009 Category: Drugs & Pharmacology Authors: Westrich L, Gil-Mast S, Kortagere S, Kuzhikandathil EV Tags: Biochem Pharmacol Source Type: journals

IL-8 production by macrophages is synergistically enhanced when cigarette smoke is combined with TNF-(Email this article to a colleague. Save this article to My Clippings. Discuss or comment on this article.
In conclusion, CSM exposure of macrophages up-regulates the expression and the production of IL-8 via reactive oxygen species and NF-(B activation. Moreover, CSM dramatically enhances the production of IL-8 in combination with TNF-(. Based upon the strong synergistic action, a combination therapy directed against ROS and TNF-( could be a new approach to stop the progression in lung damage during emphysema. PMID: 19874800 [PubMed - as supplied by publisher] (Source: Biochemical Pharmacology)
Source: Biochemical Pharmacology - October 26, 2009 Category: Drugs & Pharmacology Authors: Sarir H, Mortaz E, Janse WT, Givi ME, Nijkamp FP, Folkerts G Tags: Biochem Pharmacol Source Type: journals

Targets and effectors of the cellular response to aurora kinase inhibitor mk-0457 (vx-680) in imatinib sensitive and resistant chronic myelogenous leukemia.Email this article to a colleague. Save this article to My Clippings. Discuss or comment on this article.
TARGETS AND EFFECTORS OF THE CELLULAR RESPONSE TO AURORA KINASE INHIBITOR MK-0457 (VX-680) IN IMATINIB SENSITIVE AND RESISTANT CHRONIC MYELOGENOUS LEUKEMIA. Biochem Pharmacol. 2009 Oct 26; Authors: Donato NJ, Feng D, Sun H, Giannola D, Peterson LF, Talpaz M MK-0457 inhibits aurora, BCR-ABL and other kinases and may be clinically active in imatinib resistant leukemia. To define mediators of MK-0457 responsiveness, kinase inhibitory profiles were examined in multiple cell models of imatinib sensitive and resistant disease. Aurora and BCR-ABL kinase inhibition were consistently measured at 20 - 100nM and 2 - 10muM...
Source: Biochemical Pharmacology - October 26, 2009 Category: Drugs & Pharmacology Authors: Donato NJ, Feng D, Sun H, Giannola D, Peterson LF, Talpaz M Tags: Biochem Pharmacol Source Type: journals

Effects of cisplatin on matrix metalloproteinase-2 in transformed thyroid cells.Email this article to a colleague. Save this article to My Clippings. Discuss or comment on this article.
In conclusion, the decrease of MMP-2 secretion after cisPt was allowed by PKB/AKT and counteracted by PKC-zeta; the cisPt-provoked inhibition of MMP-2 secretion ended in reduction of cell migration. PMID: 19874802 [PubMed - as supplied by publisher] (Source: Biochemical Pharmacology)
Source: Biochemical Pharmacology - October 26, 2009 Category: Drugs & Pharmacology Authors: Urso L, Muscella A, Calabriso N, Vetrugno C, Jimenéz E, Montiel M, Marsigliante S Tags: Biochem Pharmacol Source Type: journals

3,3'-Diindolylmethane Attenuates Experimental Arthritis and Osteoclastogenesis.Email this article to a colleague. Save this article to My Clippings. Discuss or comment on this article.
This study aimed to investigate the therapeutic efficacies of DIM on experimental arthritis. The effects of DIM on experimental arthritis were examined on a rat model of adjuvant-induced arthritis (AIA), with daily AIA paw swelling observation and histological / radiographic analysis. To elucidate the possible mechanisms of its action, serum cytokine levels as well as the expression of receptor activator for nuclear factor kappa B ligand (RANKL) in infected tissues were subsequently analyzed. The impact of DIM on osteoclastogenesis was further investigated on a mouse model of endotoxin-induced bone resorption (EIBR) and in...
Source: Biochemical Pharmacology - October 22, 2009 Category: Drugs & Pharmacology Authors: Dong L, Xia S, Gao F, Chen J, Zhang J Tags: Biochem Pharmacol Source Type: journals

Inhibition of hepatic Carnitine Palmitoyl-Transferase I (CPT IA) by Valproyl-CoA as a possible mechanism of Valproate-induced steatosis.Email this article to a colleague. Save this article to My Clippings. Discuss or comment on this article.
CONCLUSIONS: The interference of VP-CoA with CPT IA, a pivotal enzyme in mitochondrial fatty acid beta-oxidation, may be a crucial mechanism in the drug-induced hepatotoxicity and the weight gain frequently observed in patients under VPA therapy. PMID: 19854160 [PubMed - as supplied by publisher] (Source: Biochemical Pharmacology)
Source: Biochemical Pharmacology - October 22, 2009 Category: Drugs & Pharmacology Authors: Aires CC, Ijlst L, Stet F, Prip-Buus C, Almeida IT, Duran M, Wanders RJ, Silva MF Tags: Biochem Pharmacol Source Type: journals

Transcriptional and post-transcriptional regulation of iNOS expression in human chondrocytes.Email this article to a colleague. Save this article to My Clippings. Discuss or comment on this article.
Chondrocytes are important for the development and maintenance of articular cartilage. However, both in osteoarthritis (OA) and rheumatoid arthritis (RA) chondrocytes are involved in the process of cartilage degradation and synthesize important immunomodulatory mediators, including nitric oxide (NO) generated by the inducible NO synthase (iNOS). To uncover the role of iNOS in the pathomechanisms of OA and RA, we analyzed the regulation of iNOS expression using immortalized human chondrocytes as a reproducible model. In C-28/I2 chondrocytes, iNOS expression was associated with the expression of the chondrocyte phenotype...
Source: Biochemical Pharmacology - October 22, 2009 Category: Drugs & Pharmacology Authors: Schmidt N, Pautz A, Art J, Rauschkolb P, Jung M, Erkel G, Goldring MB, Kleinert H Tags: Biochem Pharmacol Source Type: journals

Discovery And Evaluation Of Escherichia Coli Nitroreductases That Activate The Anti-Cancer Prodrug Cb1954.Email this article to a colleague. Save this article to My Clippings. Discuss or comment on this article.
Gene-directed enzyme prodrug therapy (GDEPT) aims to achieve highly selective tumor cell kill through use of tumor-tropic gene delivery vectors coupled with systemic administration of otherwise inert prodrugs. Nitroaromatic prodrugs such as CB1954 hold promise for GDEPT as they are readily reduced to potent DNA alkylating agents by bacterial nitroreductase enzymes (NTRs). Transfection with the nfsB gene from Escherichia coli can increase the sensitivity of tumor cells to CB1954 by greater than 1000-fold. However, poor catalytic efficiency limits the activation of CB1954 by NfsB at clinically relevant doses. A lack of f...
Source: Biochemical Pharmacology - October 20, 2009 Category: Drugs & Pharmacology Authors: Prosser GA, Copp JN, Syddall SP, Williams EM, Smaill JB, Wilson WR, Patterson AV, Ackerley DF Tags: Biochem Pharmacol Source Type: journals

Reaction of human albumin with aspirin in vitro: mass spectrometric identification of acetylated lysines 199, 402, 519, and 545.Email this article to a colleague. Save this article to My Clippings. Discuss or comment on this article.
The aspirin esterase activity of human plasma is due to butyrylcholinesterase and albumin. Our goal was to identify the amino acid residues involved in the aspirin esterase activity of albumin. Fatty acid free human albumin and human plasma were treated with aspirin for 5min to 24h. Acetylated residues were identified by LC/MS/MS and MALDI-TOF/TOF mass spectrometry of tryptic peptides. Treatment with 0.3mM aspirin resulted in acetylation of Lys-199, Lys-402, Lys-519, and Lys-545. Treatment with 20mM aspirin resulted in acetylation of 26 lysines. There was no acetylation of Tyr-411, under any conditions. Acetylated lysi...
Source: Biochemical Pharmacology - October 13, 2009 Category: Drugs & Pharmacology Authors: Liyasova MS, Schopfer LM, Lockridge O Tags: Biochem Pharmacol Source Type: journals

Proteasome inhibition up-regulates inflammatory gene transcription induced by an atypical pathway of NF-kappaB activation.Email this article to a colleague. Save this article to My Clippings. Discuss or comment on this article.
Proteasome inhibition has become synonymous with inhibition of NF-kappaB activity. However, hyperactive NF-kappaB responses often accompany physiological conditions marked by proteasomal defects, i.e. advancing age, geriatric diseases, and bortezomib resistance. These paradoxical NF-kappaB responses are likely to be impervious to proteasomal defects because they stem from atypical NF-kappaB signaling induced by upstream mechanisms which are proteasome-independent. While this atypical pathway does not require proteasome for NF-kappaB nuclear translocation, a role for proteasome in regulating nuclear NF-kappaB remains un...
Source: Biochemical Pharmacology - October 12, 2009 Category: Drugs & Pharmacology Authors: Cullen SJ, Ponnappan S, Ponnappan U Tags: Biochem Pharmacol Source Type: journals

Good Night and Good Luck: Norepinephrine in Sleep Pharmacology.Email this article to a colleague. Save this article to My Clippings. Discuss or comment on this article.
Sleep is a crucial biological process is regulated through complex interactions between multiple brain regions and neuromodulators. As sleep disorders can have deleterious impacts on health and quality of life, a wide variety of pharmacotherapies have been developed to treat conditions of excessive wakefulness and excessive sleepiness. The neurotransmitter norepinephrine (NE), through its involvement in the ascending arousal system, impacts the efficacy of many wake- and sleep-promoting medications. Wake-promoting drugs such as amphetamine and modafinil increase extracellular levels of NE, enhancing transmission along ...
Source: Biochemical Pharmacology - October 11, 2009 Category: Drugs & Pharmacology Authors: Mitchell HA, Weinshenker D Tags: Biochem Pharmacol Source Type: journals

Genistein and daidzein prevent low potassium-dependent apoptosis of cerebellar granule cells.Email this article to a colleague. Save this article to My Clippings. Discuss or comment on this article.
We have investigated the ability of certain dietary flavonoids, known to exert beneficial effects on the central nervous system, to affect neuronal apoptosis. We used cerebellar granule cells undergoing apoptosis due to potassium deprivation in a serum-free medium in either the absence or presence of the flavonoids genistein and daidzein, which are present in soy, and of catechin and epicatechin, which are present in cocoa. These compounds were used in a blood dietary concentration range. We found that genistein and daidzein, but not catechin and epicatechin, prevented apoptosis, with cell survival measured 24h after t...
Source: Biochemical Pharmacology - October 8, 2009 Category: Drugs & Pharmacology Authors: Atlante A, Bobba A, Paventi G, Pizzuto R, Passarella S Tags: Biochem Pharmacol Source Type: journals

Mouse OCTN2 is directly regulated by peroxisome proliferator-activated receptor alpha (PPARalpha) via a PPRE located in the first intron.Email this article to a colleague. Save this article to My Clippings. Discuss or comment on this article.
In conclusion, the present study shows that mouse OCTN2 is a direct target gene of PPARalpha and that transcriptional up-regulation of OCTN2 by PPARalpha is likely mediated via PPRE1 in its first intron. PMID: 19819229 [PubMed - as supplied by publisher] (Source: Biochemical Pharmacology)
Source: Biochemical Pharmacology - October 7, 2009 Category: Drugs & Pharmacology Authors: Wen G, Ringseis R, Eder K Tags: Biochem Pharmacol Source Type: journals

Mevalonate pathway intermediates downregulate zoledronic acid- induced isopentenyl pyrophosphate and ATP analog formation in human breast cancer cells.Email this article to a colleague. Save this article to My Clippings. Discuss or comment on this article.
This study represents a novel insight into the mechanism of action of MVP intermediates on the regulation of MVP after FPPS inhibition. The data implies that in addition to the previously reported effects on rescuing protein prenylation, MVP intermediates can preserve cell activity by inhibiting the accumulation of IPP/ApppI via HMGR downregulation. This supports the hypothesis that IPP/ApppI formation is a significant mechanism in the anticancer action of ZOL. PMID: 19819230 [PubMed - as supplied by publisher] (Source: Biochemical Pharmacology)
Source: Biochemical Pharmacology - October 7, 2009 Category: Drugs & Pharmacology Authors: Räikkönen J, Mönkkönen H, Auriola S, Mönkkönen J Tags: Biochem Pharmacol Source Type: journals

Heteronemin, a spongean sesterterpene, inhibits TNFalpha-induced NF-kappaB activation through proteasome inhibition and induces apoptotic cell death.Email this article to a colleague. Save this article to My Clippings. Discuss or comment on this article.
In this study, we investigated the biological effects of heteronemin, a marine sesterterpene isolated from the sponge Hyrtios sp. on chronic myelogenous leukemia cells. To gain further insight into the molecular mechanisms triggered by this compound, we initially performed DNA microarray profiling and determined which genes respond to heteronemin stimulation in TNFalpha-treated cells and which genes display an interaction effect between heteronemin and TNFalpha. Within the differentially regulated genes, we found that heteronemin was affecting cellular processes including cell cycle, apoptosis, mitogen-activated protein ki...
Source: Biochemical Pharmacology - October 4, 2009 Category: Drugs & Pharmacology Authors: Schumacher M, Cerella C, Eifes S, Chateauvieux S, Morceau F, Jaspars M, Dicato M, Diederich M Tags: Biochem Pharmacol Source Type: journals

Measuring levels of proteins by various technologies: can we learn more by measuring turnover?Email this article to a colleague. Save this article to My Clippings. Discuss or comment on this article.
In routine experiments, scientists measure the levels of various substances such as proteins after various treatments. Detection of a change in levels suggests an impact of treatment on that particular protein. However, we sometimes forget the importance of turnover in this process. Proteins have half-lives that may change in response to treatments (which is in fact why levels may change), and an examination of half-lives may yield better clues as to how treatment affects the protein. After an exploration of the quantitative aspects of protein turnover, several interesting conclusions may be drawn. 1.) Even though leve...
Source: Biochemical Pharmacology - October 4, 2009 Category: Drugs & Pharmacology Authors: Kuhar MJ Tags: Biochem Pharmacol Source Type: journals

Chain Termination and Inhibition of Mammalian Poly(A) Polymerase by modified ATP analogues.Email this article to a colleague. Save this article to My Clippings. Discuss or comment on this article.
In conclusion, modified ATP analogues may exert their biological effects through polyadenylation inhibition, and thus may provide an RNA-directed mechanism of action for 8-Cl-Ado and 8-amino-Ado. PMID: 19814999 [PubMed - as supplied by publisher] (Source: Biochemical Pharmacology)
Source: Biochemical Pharmacology - October 4, 2009 Category: Drugs & Pharmacology Authors: Chen LS, Du-Cuny L, Vethantham V, Hawke DH, Manley JL, Zhang S, Gandhi V Tags: Biochem Pharmacol Source Type: journals

Chronic inhibition of farnesyl pyrophosphate synthase attenuates cardiac hypertrophy and fibrosis in spontaneously hypertensive rats.Email this article to a colleague. Save this article to My Clippings. Discuss or comment on this article.
In conclusion, chronic treatment with an FPPS inhibitor attenuates the development of cardiac hypertrophy and fibrosis, and the suppression of ERK1/2 phosphorylation and TGF-beta1 expression with inhibition of RhoA activation may be an important mechanism. PMID: 19800872 [PubMed - as supplied by publisher] (Source: Biochemical Pharmacology)
Source: Biochemical Pharmacology - September 30, 2009 Category: Drugs & Pharmacology Authors: Li L, Chen GP, Yang Y, Ye Y, Yao L, Hu SJ Tags: Biochem Pharmacol Source Type: journals

A novel anti-neuroinflammatory pyridylimidazole compound kr-31360.Email this article to a colleague. Save this article to My Clippings. Discuss or comment on this article.
Excessive microglial activation with overexpression of proinflammatory cytokines and oxidative stress products is linked to the progression of several neurodegenerative diseases; therefore, suppression of microglial activation is a potential therapeutic approach against these diseases. Since nitric oxide (NO) is one of the major inflammatory mediators that are produced by activated microglia, inhibitory effects of novel synthetic compounds on microglial NO production were investigated. From the mouse microglia cell-based assays, an imidazo [4,5-b] pyridine compound KR-31360 was identified as an inhibitor of microglial ...
Source: Biochemical Pharmacology - September 29, 2009 Category: Drugs & Pharmacology Authors: Ock J, Kim S, Yi KY, Kim NJ, Han HS, Cho JY, Suk K Tags: Biochem Pharmacol Source Type: journals

Lithium ameliorates altered glycogen synthase kinase-3 and behavior in a mouse model of Fragile X Syndrome.Email this article to a colleague. Save this article to My Clippings. Discuss or comment on this article.
This study examined the effects on glycogen synthase kinase-3 (GSK3) of treatment with a metabotropic glutamate receptor (mGluR) antagonist, MPEP, and the GSK3 inhibitor, lithium, in C57Bl/6 Fmr1 knockout mice. Increased mGluR signaling may contribute to the pathology of FXS, and the mGluR5 antagonist MPEP increased inhibitory serine-phosphorylation of brain GSK3 selectively in Fmr1 knockout mice but not in wild-type mice. Inhibitory serine-phosphorylation of GSK3 was lower in Fmr1 knockout, than wild-type, mouse brain regions and was increased by acute or chronic lithium treatment, which also increased hippocampal brain-d...
Source: Biochemical Pharmacology - September 28, 2009 Category: Drugs & Pharmacology Authors: Yuskaitis CJ, Mines MA, King MK, Sweatt JD, Miller CA, Jope RS Tags: Biochem Pharmacol Source Type: journals

New caspase-independent but ROS-dependent apoptosis pathways are targeted in melanoma cells by an iron-containing cytosine analogue.Email this article to a colleague. Save this article to My Clippings. Discuss or comment on this article.
Chemotherapy resistance and related defects in apoptotic signaling are crucial for the high mortality of melanoma. Effective drugs are lacking, also due to the fact that apoptosis regulation in this tumor is essentially not understood. The cytosine analogue ferropoptoside (N69), which contains an iron carbonyl complex, resulted in strong induction of apoptosis in melanoma cells starting already after 2h, whereas cytotoxicity remained at a low level. Surprisingly, there was no indication for any caspase activation at early times, although cytochrome c was released from mitochondria. Indicative for new proapoptotic pathw...
Source: Biochemical Pharmacology - September 28, 2009 Category: Drugs & Pharmacology Authors: Franke JC, Plötz M, Prokop A, Geilen CC, Schmalz HG, Eberle J Tags: Biochem Pharmacol Source Type: journals

Suppression of ERCC1 and Rad51 expression through ERK1/2 inactivation is essential in emodin-mediated cytotoxicity in human non-small cell lung cancer cells.Email this article to a colleague. Save this article to My Clippings. Discuss or comment on this article.
Emodin, a tyrosine kinase inhibitor, is a natural anthraquinone derivative found in the roots and rhizomes of numerous plants. Emodin exhibits anticancer effects against a variety of cancer cells, including lung cancer cells. ERCC1 and Rad51 proteins are essential for nucleotide excision repair and homologous recombination, respectively. Furthermore, ERCC1 and Rad51 overexpression induces resistance to DNA-damaging agents that promote DNA double-strand breaks. Accordingly, the aim of this study was to determine the role of ERCC1 and Rad51 in emodin-mediated cytotoxicity in human non-small cell lung cancer (NSCLC) cells...
Source: Biochemical Pharmacology - September 28, 2009 Category: Drugs & Pharmacology Authors: Ko JC, Su YJ, Lin ST, Jhan JY, Ciou SC, Cheng CM, Lin YW Tags: Biochem Pharmacol Source Type: journals

DNA damage response to the Mdm2 inhibitor Nutlin-3.Email this article to a colleague. Save this article to My Clippings. Discuss or comment on this article.
Mdm2 inhibitors represent a promising class of p53 activating compounds that may be useful in cancer treatment and prevention. However, the consequences of pharmacological p53 activation are not entirely clear. We observed that Nutlin-3 triggered a DNA damage response in azoxymethane-induced mouse AJ02-NM(0) colon cancer cells, characterized by the phosphorylation of H2AX (at Ser-139) and p53 (at Ser-15). The DNA damage response was highest in cells showing robust p53 stabilization, it could be triggered by the active but not the inactive Nutlin-3 enantiomer, and it was also activated by another pharmacological Mdm2 in...
Source: Biochemical Pharmacology - September 25, 2009 Category: Drugs & Pharmacology Authors: Verma R, Rigatti MJ, Belinsky GS, Godman CA, Giardina C Tags: Biochem Pharmacol Source Type: journals

Predicting gemcitabine transport and toxicity in human pancreatic cancer cell lines with the positron emission tomography tracer 3'-deoxy-3'-fluorothymidine.Email this article to a colleague. Save this article to My Clippings. Discuss or comment on this article.
The abundance of human equilibrative nucleoside transporter 1 (hENT1) has recently been shown to be a predictive marker of benefit from gemcitabine therapy in patients with pancreatic cancer. Since hENT1 is also important for uptake of the positron emission tomography (PET) tracer 3'-deoxy-3'-fluorothymidine (FLT) in various cultured human cell lines, this study was undertaken to determine if FLT uptake predicts gemcitabine uptake and/or toxicity in a panel of human pancreatic cancer cell lines (Capan-2, AsPC-1, BxPC-3, PL45, MIA PaCa-2, and PANC-1). Capan-2 cells displayed the lowest levels of 1) extracellular nitrobe...
Source: Biochemical Pharmacology - September 25, 2009 Category: Drugs & Pharmacology Authors: Paproski RJ, Young JD, Cass CE Tags: Biochem Pharmacol Source Type: journals

Cytotoxicity, cellular uptake, glutathione and DNA interactions of an antitumor large-ring Pt(II) chelate complex incorporating the cis-1,4-diaminocyclohexane carrier ligand.Email this article to a colleague. Save this article to My Clippings. Discuss or comment on this article.
Earlier studies have described promising antitumor activity of a large-ring chelate complex [PtCl(2)(cis-1,4-DACH)] (DACH = diaminocyclohexane). Encouraging antitumor activity of this analogue of cisplatin prompted us to perform studies focused on the mechanistic basis of pharmacological effects of this complex. Four early steps in the mechanism of biological activity of cisplatin have been delineated: cell entry, reactions with sulfur-containing compounds, platinum-DNA binding along with processing platinated DNA by proteins (enzymes) and DNA repair. Here, we describe comparative experiments (involving also cisplatin)...
Source: Biochemical Pharmacology - September 23, 2009 Category: Drugs & Pharmacology Authors: Kasparkova J, Suchankova T, Halamikova A, Zerzankova L, Vrana O, Margiotta N, Natile G, Brabec V Tags: Biochem Pharmacol Source Type: journals

Human DEAD-box protein 3 has multiple functions in gene regulation and cell cycle control and is a prime target for viral manipulation.Email this article to a colleague. Save this article to My Clippings. Discuss or comment on this article.
The human DEAD-box RNA helicase DDX3 has been implicated to play a role in the whole repertoire of processes regulating gene expression, including transcription, splicing, mRNA export and translation. It has also been suggested to be involved in cell cycle control and the regulation of apoptosis. In addition, DDX3 was recently shown to be part of innate immune signalling pathways and to contribute to the induction of anti-viral mediators, such as type I interferon. Interestingly, DDX3 appears to be a prime target for viral manipulation: at least four different viruses, namely Hepatitis C virus (HCV), Hepatitis B virus ...
Source: Biochemical Pharmacology - September 23, 2009 Category: Drugs & Pharmacology Authors: Schröder M Tags: Biochem Pharmacol Source Type: journals

Statins inhibit aminoglycoside accumulation and cytotoxicity to renal proximal tubule cells.Email this article to a colleague. Save this article to My Clippings. Discuss or comment on this article.
Nephrotoxicity due to renal proximal tubule accumulation of aminoglycoside (AG) antibiotics, such as gentamicin, represents a major clinical problem. Receptor-mediated endocytosis via the multi-ligand receptor megalin is thought to be a key mechanism in the cellular uptake of AGs and nephrotoxicity. This process can be modulated by the intracellular concentration of isoprenoid pyrophosphates derived from the processing of mevalonate by 3-hydroxy-3-methylglutaryl-CoA (HMG-CoA) reductase. Post-translation modifications by isoprenoid pyrophosphates are necessary for GTP-binding protein function. Given that statins inhibit...
Source: Biochemical Pharmacology - September 22, 2009 Category: Drugs & Pharmacology Authors: Antoine DJ, Srivastava A, Pirmohamed M, Park BK Tags: Biochem Pharmacol Source Type: journals

Oleanane Triterpenoid CDDO-Me Inhibits Growth and Induce Apoptosis in Prostate Cancer Cells through a ROS-dependent Mechanism.Email this article to a colleague. Save this article to My Clippings. Discuss or comment on this article.
CDDO-Me, a synthetic triterpenoid derived from oleanolic acid, is a promising anticancer agent that has shown strong activity against a wide variety cancer types in vitro and in vivo. We have previously shown that CDDO-Me induces apoptosis in prostate cancer cells irrespective of their hormonal status. To further understand the proapoptotic mechanism of CDDO-Me, we investigated the role of reactive oxygen species (ROS) in mediating the apoptosis inducing activity of CDDO-Me in LNCaP and PC-3 prostate cancer cell lines. Here, we show that CDDO-Me induces ROS generation from both nonmitochondrial and mitochondrial source...
Source: Biochemical Pharmacology - September 22, 2009 Category: Drugs & Pharmacology Authors: Deeb D, Gao X, Jiang H, Janic B, Arbab AS, Rojanasakul Y, Dulchavsky SA, Gautam SC Tags: Biochem Pharmacol Source Type: journals

TCDD-induced Cyclooxygenase-2 Expression Is Mediated by the Nongenomic Pathway in Mouse MMDD1 Macula Densa Cells and Kidneys.Email this article to a colleague. Save this article to My Clippings. Discuss or comment on this article.
In this study we found that induction of Cox-2 by TCDD in MMDD1, a mouse macula densa cell line, is accompanied with a rapid increase in the enzymatic activity of cytosolic phospholipase A2 (cPLA2) as well as activation of protein kinases. Calcium serves as a trigger for such an action of TCDD in this cell line. These observations indicate that the basic mode of action of TCDD to induce the rapid inflammatory response in MMDD1 is remarkably similar to those mediated by the nongenomic pathway of aryl hydrocarbon receptor (AhR) found in other types of cells. Such an action of TCDD to induce Cox-2 in MMDD1 was not affected by...
Source: Biochemical Pharmacology - September 22, 2009 Category: Drugs & Pharmacology Authors: Dong B, Nishimura N, Vogel CF, Tohyama C, Matsumura F Tags: Biochem Pharmacol Source Type: journals