Did Clinical Trials in Which Erythropoietin Failed to Reduce Acute Myocardial Infarct Size Miss a Narrow Therapeutic Window?

Background: To test a hypothesis that in negative clinical trials of erythropoietin in patients with acute myocardial infarction (MI) the erythropoietin (rhEPO) could be administered outside narrow therapeutic window. Despite overwhelming evidence of cardioprotective properties of rhEPO in animal studies, the outcomes of recently concluded phase II clinical trials have failed to demonstrate the efficacy of rhEPO in patients with acute MI. However, the time between symptoms onset and rhEPO administration in negative clinical trials was much longer that in successful animal experiments. Methodology/Principal Findings: MI was induced in rats either by a permanent ligation of a descending coronary artery or by a 2-hr occlusion followed by a reperfusion. rhEPO, 3000 IU/kg, was administered intraperitoneally at the time of reperfusion, 4 hrs after beginning of reperfusion, or 6 hrs after permanent occlusion. MI size was measured histologically 24 hrs after coronary occlusion. The area of myocardium at risk was similar among groups. The MI size in untreated rats averaged,42 % of area at risk, or,24 % of left ventricle, and was reduced by more than 50 % (p,0.001) in rats treated with rhEPO at the time of reperfusion. The MI size was not affected by treatment administered 4 hrs after reperfusion or 6 hrs after permanent coronary occlusion. Therefore, our study in a rat experimental model of MI demonstrates that rhEPO administered within 2 hrs of a coronary occlusion effectively reduces MI size, but when rhEPO was administered following a delay similar to that encountered in clinical trials, it had no effect on MI size

Fumarate is cardioprotective via activation of the Nrf2 antioxidant pathway

The citric acid cycle (CAC) metabolite fumarate has been proposed to be cardioprotective; however, its mechanisms of action remain to be determined. To augment cardiac fumarate levels and to assess fumarate's cardioprotective properties, we generated fumarate hydratase (Fh1) cardiac knockout (KO) mice. These fumarate-replete hearts were robustly protected from ischemia-reperfusion injury (I/R). To compensate for the loss of Fh1 activity, KO hearts maintain ATP levels in part by channeling amino acids into the CAC. In addition, by stabilizing the transcriptional regulator Nrf2, Fh1 KO hearts upregulate protective antioxidant response element genes. Supporting the importance of the latter mechanism, clinically relevant doses of dimethylfumarate upregulated Nrf2 and its target genes, hence protecting control hearts, but failed to similarly protect Nrf2-KO hearts in an in vivo model of myocardial infarction. We propose that clinically established fumarate derivatives activate the Nrf2 pathway and are readily testable cytoprotective agents. © 2012 Elsevier Inc

Third order optical non-linearity of a novel chalcone derivative through Z scan technique

844-850A novel chalcone derivative 4-{(1E,3Z)-3-(4-bromo phenyl]-3-[2-(2,4-dinitrophenyl) hydrazinylidene] prop-1-en-1-yl} phenol [BPDP] has been synthesized and structurally characterized by NMR and FTIR studies. The third order non-linear optical properties of the BPDP have been studied using single beam Z scan technique with a nanosecond-pulsed Nd: YAG laser source at 532 nm. The coefficient of non linear refraction () of the compound is found to be negative as revealed by the signature of closed aperture data. The results obtained under open aperture configuration indicate that the material exhibits reverse saturation absorption. The magnitude of real part of third-order optical susceptibility ((3) ) and of molecular second order hyperpolarizability (h) are found to be –3.5×10-20 m2V-2 and –5.9×10-48 m5V-2, respectively. The thermo gravimetric analysis shows that the material possesses a very good thermal stability up to 203<span style="font-family:Symbol;mso-ascii-font-family: " times="" new="" roman";mso-fareast-font-family:ttb5o00;mso-hansi-font-family:"times="" roman";="" mso-char-type:symbol;mso-symbol-font-family:symbol"="" lang="EN-GB">°C. <b style="mso-bidi-font-weight: normal"> </span

Green synthesis and characterization of selenium nanoparticles (Se NPs) from the skin (testa) of Pistacia vera L. (Siirt pistachio) and investigation of antimicrobial and anticancer potentials

Metallic nanoparticles created by ecologically friendly synthesis processes are becoming increasingly useful in a variety of applications. Because of their strong bioactive component qualities, biocompatible architectures, high stability, and low toxicity, green-produced selenium nanoparticles are particularly signifcant materials for various medicinal applications. Plants include a wealth of essential phytochemicals with therapeutic and medical capabilities. Pistachio vera L. (Siirt pistachio) is a seasonal fruit that is frequently consumed for its nutritional worth and health advantages. However, the outer colored skin of the P. vera (Siirt pistachio) fruit, which is not consumed, contains many biologically active compounds. In this study, plant-mediated synthesis of selenium nanoparticles (SeNPs) was successfully accomplished after adding the sodium selenite solution to the aqueous extract of P. vera colored skin waste. The synthesized Se NPs were characterized with UV–Vis, transmission electron microscopy (TEM), dynamic light scattering (DLS), zeta distribution, atomic force microscope (AFM), Fourier transform infrared spectrum (FTIR), thermogravimetric (TGA) and diferential thermal analysis, X-ray difraction (XRD), and energy-dispersive X-ray spectrum (EDX). Biogenic Pistacia vera (PV) PV-SeNPs were also tested for their ability to suppress the development of various pathogenic bacteria and cancerous cell lines. The UV-visible (UV–Vis) spectra revealed an absorption peak at 325 nm, which refected the surface plasmon band. The signifcant selenium signal on the EDX spectrum at 1.5 keV confrmed the creation of Se NPs. The presence of several peaks on the FTIR spectrum of the aqueous extract of Pv and the nanoparticles indicated the presence of some important functional groups such as amines, carbonyl compounds, and phenols, which are important in facilitating the process of capping and bioreduction, as well as conferring stability to nanoparticles. The TEM microphotographs revealed that the nanoparticles were highly distributed, had a spherical morphological form, and were monodisperse below 10 nm. Biogenic Pv-SeNPs exhibited similar antimicrobial activity as standard antibiotics. However, it was determined that the cytotoxic activity of Se-NPs against cancer cell lines was quite high depending on the dose and time. As a result, the Pv-SeNPs are likely to be extremely benefcial in the pharmaceutical and cosmetic sectors, as well as in the food and cosmetic industries, in producing antimicrobial and/or anticancer medications

Early adipogenesis is regulated through USP7-mediated deubiquitination of the histone acetyltransferase TIP60

Transcriptional coregulators, including the acetyltransferase Tip60, have a key role in complex cellular processes such as differentiation. Whereas post-translational modifications have emerged as an important mechanism to regulate transcriptional coregulator activity, the identification of the corresponding demodifying enzymes has remained elusive. Here we show that the expression of the Tip60 protein, which is essential for adipocyte differentiation, is regulated through polyubiquitination on multiple residues. USP7, a dominant deubiquitinating enzyme in 3T3-L1 adipocytes and mouse adipose tissue, deubiquitinates Tip60 both in intact cells and in vitro and increases Tip60 protein levels. Furthermore, inhibition of USP7 expression and activity decreases adipogenesis. Transcriptome analysis reveals several cell cycle genes to be co-regulated by both Tip60 and USP7. Knockdown of either factor results in impaired mitotic clonal expansion, an early step in adipogenesis. These results reveal deubiquitination of a transcriptional coregulator to be a key mechanism in the regulation of early adipogenesi