SMAC mimetic Debio 1143 synergizes with taxanes, topoisomerase inhibitors and bromodomain inhibitors to impede growth of lung adenocarcinoma cells

Targeting anti-apoptotic proteins can sensitize tumor cells to conventional chemotherapies or other targeted agents. Antagonizing the Inhibitor of Apoptosis Proteins (IAPs) with mimetics of the pro-apoptotic protein SMAC is one such approach. We used sensitization compound screening to uncover possible agents with the potential to further sensitize lung adenocarcinoma cells to the SMAC mimetic Debio 1143. Several compounds in combination with Debio 1143, including taxanes, topoisomerase inhibitors, and bromodomain inhibitors, super-additively inhibited growth and clonogenicity of lung adenocarcinoma cells. Co-treatment with Debio 1143 and the bromodomain inhibitor JQ1 suppresses the expression of c-IAP1, c-IAP2, and XIAP. Non-canonical NF-κB signaling is also activated following Debio 1143 treatment, and Debio 1143 induces the formation of the ripoptosome in Debio 1143-sensitive cell lines. Sensitivity to Debio 1143 and JQ1 co-treatment was associated with baseline caspase-8 expression. In vivo treatment of lung adenocarcinoma xenografts with Debio 1143 in combination with JQ1 or docetaxel reduced tumor volume more than either single agent alone. As Debio 1143-containing combinations effectively inhibited both in vitro and in vivo growth of lung adenocarcinoma cells, these data provide a rationale for Debio 1143 combinations currently being evaluated in ongoing clinical trials and suggest potential utility of other combinations identified here

Current Perspectives on HIV-1 Antiretroviral Drug Resistance

Current advancements in antiretroviral therapy (ART) have turned HIV-1 infection into a chronic and manageable disease. However, treatment is only effective until HIV-1 develops resistance against the administered drugs. The most recent antiretroviral drugs have become superior at delaying the evolution of acquired drug resistance. In this review, the viral fitness and its correlation to HIV-1 mutation rates and drug resistance are discussed while emphasizing the concept of lethal mutagenesis as an alternative therapy. The development of resistance to the different classes of approved drugs and the importance of monitoring antiretroviral drug resistance are also summarized briefly

Ligand binding and activation of the CGRP receptor

İstanbul Bilim Üniversitesi, Tıp Fakültesi.Objective: Malnutrition and loss of appetite remain a frequent problem in patients with chronic kidney disease (CKD). These patients have inflammation accompanied by high levels of plasma leptin, an appetite-modulating hormone. A newly described hormone ghrelin is also involved in regulation food intake and energy balance. In patients with end-stage renal disease and hemodialysis, high plasma ghrelin concentration has been reported, but the metabolic impact of ghrelin in CKD is unknown. The aim of this study was to characterize the changes in circulating levels of ghrelin, obestatin, leptin, interleukin (IL)-6, and tumor necrosis factor-alpha (TNF-a) at different stages of CKD

Appetite-regulating Hormones in Chronic Kidney Disease Patients

WOS: 000291719600007PubMed ID: 21193324Objective: Inflammation and loss of appetite is the most common problem in patients with chronic kidney disease (CKD). This comparative cross-sectional study aimed to characterize the changes in circulating levels of ghrelin, obestatin, leptin, all of which have an effect on food intake, and proinflammatory cytokines interleukin (IL)-6 and tumor necrosis factor-alpha (TNF-alpha) in patients with CKD who were undergoing different treatments. Design and Setting: Study participants included 36 patients who had undergone hemodialysis (body mass index [BMI]: 22.3 +/- 4.17 kg/m(2)); 41 who had undergone peritoneal dialysis (BMI: 23.5 +/- 3.10 kg/m(2)), 30 with early stage CKD (BMI: 24.4 +/- 3.32 kg/m(2)), and 31 healthy subjects (24.3 +/- 2.14 kg/m(2)). The patients with CKD were kept under a standard diet with restricted salt, potassium, and protein intake. Intervention: Levels of leptin, acylated ghrelin, obestatin, TNF-alpha, and IL-6 were measured by commercially available enzyme-linked immunosorbent assay kits. Total nitrite/nitrate was analyzed using colorimetric assay kit. Results: Significantly high leptin levels, accompanied by low acylated ghrelin levels, were observed in patients with CKD. Maintenance dialysis did not affect these levels. TNF-alpha and IL-6 levels were significantly higher in CKD patients than in healthy subjects, the highest being in dialysis patients. Obestatin levels were relatively low in patients who had undergone hemodialysis. Conclusion: Low acyl-ghrelin levels, accompanied with high levels of TNF-alpha and IL-6 may be involved in the loss of appetite and poor nutritional status in CKD patients. (C) 2011 by the National Kidney Foundation, Inc. All rights reserved.Istanbul University [508/05052006, BYP-1789]This work was supported by the Research Fund of Istanbul University; project numbers 508/05052006 and BYP-1789

Design, Synthesis, and Antiviral Evaluation of Chimeric Inhibitors of HIV Reverse Transcriptase

In a continuing study of potent bifunctional anti-HIV agents, we rationally designed a novel chimeric inhibitor utilizing thymidine (THY) and a TMC derivative (a diarylpyrimidine NNRTI) linked via a polymethylene linker (ALK). The nucleoside, 5′-hydrogen-phosphonate (H-phosphonate), and 5′-triphosphate forms of this chimeric inhibitor (THY-ALK-TMC) were synthesized and the antiviral activity profiles were evaluated at the enzyme and cellular level. The nucleoside triphosphate (<b>11</b>) and the H-phosphonate (<b>10</b>) derivatives inhibited RT polymerization with an IC₅₀ value of 6.0 and 4.3 nM, respectively. Additionally, chimeric nucleoside (<b>9</b>) and H-phosphonate (<b>10</b>) derivatives reduced HIV replication in a cell-based assay with low nanomolar antiviral potencies

Dimethylarginines and inflammation markers in patients with chronic kidney disease undergoing dialysis

The aim of this study was to investigate the pro-oxidant and proinflammatory biomarkers and their relationship with dimethylarginines (DMAs) in patients at various stages of chronic kidney disease (CKD). We studied 114 CKD patients, 36 were hemodialyzed, 41 peritoneal dialyzed and 37 nondialyzed (early stage) CKD patients. The control group consisted of 31 healthy subjects. Plasma levels of asymmetric dimethylarginine (ADMA), symmetric dimethylarginine (SDMA), l-arginine, nitric oxide (NO) and proinflammatory cytokines (TNF-alpha and IL-6) were determined, and their relationships with the degree of disease were evaluated. Both DMAs were at high levels in all CKD patients, whereas arginine concentrations were low in patients undergoing dialysis. Elevated TNF-alpha and IL-6 in CKD patients were indicative of ongoing chronic inflammatory state. A significant positive correlation between SDMA and creatinine suggests that plasma SDMA level may be an index for renal function

Plasmonic Sensor Could Enable Label-Free DNA Sequencing

We demonstrated a proof-of-principle concept of a label-free platform that enables nucleic acid sequencing by binding methodology. The system utilizes gold surfaces having high fidelity plasmonic nanohole arrays which are very sensitive to minute changes of local refractive indices. Our novel surface chemistry approach ensures accurate identification of correct bases at individual positions along a targeted DNA sequence on the gold surface. Binding of the correct base on the gold sensing surface triggers strong spectral variations within the nanohole optical response, which provides a high signal-to-noise ratio and accurate sequence data. Integrating our label-free sequencing platform with a lens-free imaging-based device, we reliably determined targeted DNA sequences by monitoring the changes within the plasmonic diffraction images. Consequently, this new label-free surface chemistry technique, integrated with plasmonic lens-free imaging platform, will enable monitoring multiple biomolecular binding events, which could initiate new avenues for high-throughput nucleic acid sequencing

Bifunctional Inhibition of Human Immunodeficiency Virus Type 1 Reverse Transcriptase: Mechanism and Proof-of-Concept as a Novel Therapeutic Design Strategy

Human immunodeficiency virus type 1 reverse transcriptase (HIV-1 RT) is a major target for currently approved anti-HIV drugs. These drugs are divided into two classes: nucleoside and non-nucleoside reverse transcriptase inhibitors (NRTIs and NNRTIs). This study illustrates the synthesis and biochemical evaluation of a novel bifunctional RT inhibitor utilizing d4T (NRTI) and a TMC-derivative (a diarylpyrimidine NNRTI) linked via a poly­(ethylene glycol) (PEG) linker. HIV-1 RT successfully incorporates the triphosphate of d4T-4PEG-TMC bifunctional inhibitor in a base-specific manner. Moreover, this inhibitor demonstrates low nanomolar potency that has 4.3-fold and 4300-fold enhancement of polymerization inhibition in vitro relative to the parent TMC-derivative and d4T, respectively. This study serves as a proof-of-concept for the development and optimization of bifunctional RT inhibitors as potent inhibitors of HIV-1 viral replication