Structural Modification of Stilbenoids from Acanthopanax leucorrhizus and Their Cytotoxic Activity

A new cis‐stilbenoid, 1,9‐dihydroxy‐10‐methoxy‐6H‐dibenzo[b,f]oxocin‐6‐one ( 2 ) was isolated from the AcOEt extract of the stem barks of Acanthopanax leucorrhizus, along with three known stilbenoids, 9‐hydroxy‐10‐methoxy‐6H‐dibenzo[b,f]oxocin‐6‐one ( 1 ), 5‐O‐methyl‐(E)‐resveratrol 3‐O‐β‐d ‐glucopyranoside ( 3 ), and (E)‐resveratrol 3‐O‐β‐d ‐xylopyranoside ( 4 ). Two derivatives ( 2a and 2b ) were synthesized by the structural modification of compound 2, which exhibited certain cytotoxic activities against HT‐29 and HeLa cell lines in vitro. All compounds were structurally characterized by comprehensive analysis of their spectroscopic data and comparison with literature information, and evaluated for their cytotoxic activities against three human tumor cell lines (HL‐60, HT‐29, and HeLa) by the standard MTT assay in vitro. The results showed that derivatives 2a and 2b exhibited strong activities than compounds 2 against HT‐29 and HeLa cell lines.     

Histidine button engineered into cardiac troponin I protects the ischemic and failing heart

The myofilament protein troponin I (TnI) has a key isoform-dependent role in the development of contractile failure during acidosis and ischemia. Here we show that cardiac performance in vitro and in vivo is enhanced when a single histidine residue present in the fetal cardiac TnI isoform is substituted into the adult cardiac TnI isoform at codon 164. The most marked effects are observed under the acute challenges of acidosis, hypoxia, ischemia and ischemia-reperfusion, in chronic heart failure in transgenic mice and in myocytes from failing human hearts. In the isolated heart, histidine-modified TnI improves systolic and diastolic function and mitigates reperfusion-associated ventricular arrhythmias. Cardiac performance is markedly enhanced in transgenic hearts during reperfusion despite a high-energy phosphate content similar to that in nontransgenic hearts, providing evidence for greater energetic economy. This pH-sensitive 'histidine button' engineered in TnI produces a titratable molecular switch that 'senses' changes in the intracellular milieu of the cardiac myocyte and responds by preferentially augmenting acute and long-term function under pathophysiological conditions. Myofilament-based inotropy may represent a therapeutic avenue to improve myocardial performance in the ischemic and failing heart.     

New self-assembly nanoparticles and stealth liposomes for the delivery of zoledronic acid: a comparative study

Zoledronic acid (ZOL) is a drug whose potent anti-cancer activity is limited by its short plasma half-life and rapid uptake and accumulation within bone. We have recently proposed new delivery systems to avoid ZOL accumulation into the bone, thus improving extra-skeletal bioavailability. In this work, we have compared the technological and anti-cancer features of either ZOL-containing self-assembly PEGylated nanoparticles (NPs) or ZOL-encapsulating PEGylated liposomes (LIPO-ZOL). ZOL-containing NPs showed superior technological characteristics in terms of mean diameter, size distribution, and ZOL encapsulation efficiency, compared to LIPO-ZOL. Moreover, the anti-cancer activity of NPs in nude mice xenografted with prostate cancer PC3 cells was higher than that one induced by LIPO-ZOL. In addition, NPs induced the complete remission of tumour xenografts and an increase of survival time higher than that one observed with LIPO-ZOL. It has also to be considered that PC3 tumour xenografts were almost completely resistant to the anti-cancer effects induced by free ZOL. Both nanotechnological products did not induce toxic effects not affecting the mice weight nor inducing deaths. Moreover, the histological examination of some vital organs such as liver, kidney and spleen did not find any changes in terms of necrotic effects or modifications in the inflammatory infiltrate. On the other hand, NPs but not LIPO-ZOL caused a statistically significant reduction of the tumour associated macrophages (TAM) in tumour xenografts. This effect was paralleled by a significant increase of both necrotic and apoptotic indexes. The effects of the NPs were also higher in terms of neo-angiogenesis inhibition. These results suggest the future preclinical development of ZOL-encapsulating NPs in the treatment of human cancer.     

Fuzzy modeling in symptomatic HIV virus infected population

This paper introduces a model for the evolution of positive HIV population and manifestation of AIDS (acquired immunideficiency syndrome). The focus is on the nature of the transference rate of HIV to AIDS. Expert knowledge indicates that the transference rate is uncertain and depends strongly on the viral load and the CD4+ level of the infected individuals. Here, we suggest to view the transference rate as a fuzzy set of the viral load and CD4+ level values. In this case the dynamic model results in a fuzzy model that preserves the biological meaning and nature of the transference rate λ. Its behavior fits the natural history of HIV infection reported in the medical science domain. The paper also includes a comparison between the fuzzy model and a classic Anderson’s model using data reported in the literature.     

Differential effects of gadolinium chloride on Kupffer cells in vivo and in vitro

Gadolinium chloride (GdCl) is commonly used to study the role of Kupffer cells in liver disease in vivo. The in vitro effects of GdCl on cultured Kupffer cells are poorly characterised. The aim of this study was to characterise rat Kupffer cell TNFalpha production, phagocytic function, and ED1 and ED2 antigen expression following the administration of GdCl. For in vivo experiments, rats received 10mg/kg GdCl IV or sterile saline. Lipopolysaccharide 3mg/kg IP (LPS) was administered 4h prior to sacrifice on Days 1-3, 5 or 8 following GdCl injection. Hepatic ED1 and ED2 positive macrophage numbers and TNFalpha mRNA levels were determined. For in vitro experiments, Kupffer cells were cultured in the presence of 0-270 microM GdCl for 24h following which viability, TNFalpha protein production in response to LPS (10 ng/ml), phagocytosis, and ED1 and ED2 staining were evaluated. In vivo, the proportion of ED1 positive cells which were ED2 positive was reduced from 87 to 3% and hepatic TNFalpha mRNA levels following LPS declined by 60% over Days 1-5 after injection of GdCl (P<0.01). In vitro, phagocytosis declined with increasing concentrations of GdCl. GdCl (0-27 microM) did not effect cultured Kupffer cell viability, TNFalpha production, ED1 or ED2 staining. We conclude that GdCl significantly reduces ED2 expression by Kupffer cells in vivo. In vitro, GdCl has a dose dependent effect on phagocytosis but only effects viability and TNFalpha production at high concentrations. ED2 expression of cultured Kupffer cells is not affected by GdCl.