Comparative Cardiac Toxicity of Anthracyclines In Vitro and In Vivo in the Mouse

Purpose

The antineoplastic efficacy of anthracyclines is limited by their cardiac toxicity. In this study, we evaluated the toxicity of doxorubicin, non-pegylated liposomal-delivered doxorubicin, and epirubicin in HL-1 adult cardiomyocytes in culture as well as in the mouse in vivo.

Methods

The cardiomyocytes were incubated with the three anthracyclines (1 µM) to assess reactive oxygen generation, DNA damage and apoptotic cell death. CF-1 mice (10/group) received doxorubicin, epirubicin or non-pegylated liposomal-doxorubicin (10 mg/kg) and cardiac function was monitored by Doppler echocardiography to measure left ventricular ejection fraction (LVEF), heart rate (HR) and cardiac output (CO) both prior to and 10 days after drug treatment.

Results

In HL-1 cells, non-pegylated liposomal-doxorubicin generated significantly less reactive oxygen species (ROS), as well as less DNA damage and apoptosis activation when compared with doxorubicin and epirubicin. Cultured breast tumor cells showed similar sensitivity to the three anthracyclines. In the healthy mouse, non-pegylated liposomal doxorubicin showed a minimal and non-significant decrease in LVEF with no change in HR or CO, compared to doxorubicin and epirubicin.

Conclusion

This study provides evidence for reduced cardiac toxicity of non-pegylated-liposomal doxorubicin characterized by attenuation of ROS generation, DNA damage and apoptosis in comparison to epirubicin and doxorubicin.     

Neuroprotection of medical IOP-lowering therapy

Intraocular pressure (IOP)-lowering therapy has been shown to arrest or retard the progression of optic neuropathy typical for glaucoma and can, thus, be described as neuroprotective. At present, six classes of medical therapy are employed, namely parasympathomimetics, alpha/beta-sympathomimetics, β-blockers, carbonic anhydrase inhibitors, α₂-adrenergic receptor agonists and prostaglandin analogues. For several of these substances, some experimental evidence exists of a possible neuroprotective mechanism, beyond their IOP-lowering activity. β-Blockers are involved in the up-regulation of brain-derived neurotrophic factor (BDNF) and can decrease glutamate-mediated NMDA receptor activation. Not only systemic but also topical carbonic anhydrase inhibitors are able to increase retinal blood flow. α₂-Adrenergic receptor agonists can up-regulate the formation of BDNF and anti-apoptotic factors. Prostaglandin analogues increase blood flow to the eye, possibly including the retina. To date, evidence for a neuroprotective effect independent of IOP regulation in human glaucoma is scarce and has only been shown to be likely for the α₂-adrenergic receptor agonist, brimonidine.     

The crystal structure of Toxoplasma gondii nucleoside triphosphate diphosphohydrolase 1 represents a conformational intermediate in the reductive activation mechanism of the tetrameric enzyme

Toxoplasma gondii nucleoside triphosphate diphosphohydrolase (NTPDase) 1 was crystallized in an intermediate tetrameric conformation. The crystal structure is similar to that of T. gondii NTPDase3 and represents an inactive conformation as the activating disulfide bridge is not reduced and the active site cleft between the two domains of each monomer is open. However, the arrangement of the monomers within the tetramer differs from that of the inactive form of NTPDase3 and may represent an intermediate conformation on the path of the closure motion of the tetramer induced upon activation. Proteins 2013; 81:1271–1276. © 2013 Wiley Periodicals, Inc.     

Antifouling substances of natural origin: Activity of benzoquinone compounds from Maesa Lanceolata against marine crustaceans

A screening of antifouling activity from plants extracts led to selection and further study of Maesa lanceolata Forssk. Two p‐benzoquinone compounds were isolated from the fruits and found to be active against Artemia salina. The anti‐crustacean activity of both p‐benzoquinones is reported for the first time.     

Transmembrane Helix Packing of ErbB/Neu Receptor in Membrane Environment: A Molecular Dynamics Study

Abstract

Dimerization or oligomerization of the ErbB/Neu receptors are necessary but not sufficient for initiation of receptor signaling. The two intracellular domains must be properly oriented for the juxtaposition of the kinase domains allowing trans-phosphorylation. This suggests that the transmembrane (TM) domain acts as a guide for defining the proper orientation of the intracellular domains.

Two structural models, with the two helices either in left-handed or in right-handed coiling have been proposed as the TM domain structure of the active receptor. Because experimental data do not distinguish clearly helix-helix packing, molecular dynamics (MD) simulations are used to investigate the energetic factors that drive Neu TM-TM interactions of the wild and the oncogenic receptor (Val664/Glu mutation) in DMPC or in POPC environments. MD results indicate that helix-lipid interactions in the bilayer core are extremely similar in the two environments and raise the role of the juxtamembrane residues in helix insertion and helix-helix packing. The TM domain shows a greater propensity to adopt a left-handed structure in DMPC, with helices in optimal position for strong inter-helical Hbonds induced by the Glu mutation. In POPC, the right-handed structure is preferentially formed with the participation of water in inter-helical Hbonds. The two structural arrangements of the NeuTM helices both with GG4 residue motif in close contact at the interface are permissible in the membrane environment. According to the hypothesis of a monomer-dimer equilibrium of the proteins it is likely that the bilayer imposes structural constraints that favor dimerization- competent structure responsible of the proper topology necessary for receptor activation.     

Topology,glycosylation and conformational changes in the membrane domain of the vacuolar H+‐ATPase a subunit

Published topological models of the integral membrane a subunit of the vacuolar proton‐translocating ATPase complex have not been in agreement with respect to either the number of transmembrane helices within the integral membrane domain, or their limits and orientations within the lipid bilayer. In the present work we have constructed a predictive model of the membrane insertion of the yeast a subunit, Vph1p, from a consensus of seven topology prediction algorithms. The model was tested experimentally using epitope tagging, green fluorescent protein fusion, and protease accessibility analysis in purified yeast vacuoles. Results suggest that a consensus prediction of eight transmembrane helices with both the amino‐terminus and carboxyl‐terminus in the cytoplasm is correct. Characterization of two glycosylation sites within the homologous mouse a subunit membrane domain further corroborates this topology. Moreover, the model takes into account published data on cytoplasmic and luminal accessibility of specific amino acids. Changes in the degree of protease accessibility in response to the V‐ATPase substrate, MgATP, and the V‐ATPase‐specific inhibitor, concanamycin A, suggest that functional conformational changes occur in the large cytoplasmic loop between TM6 and TM7 of Vph1p. These data substantially confirm one topological model of the V‐ATPase a subunit and support the notion that conformational changes occur within the membrane domain, possibly involving previously proposed axial rotation and/or linear displacement of TM7 in the proton transport cycle. J. Cell. Biochem. 114: 1474–1487, 2013. © 2013 Wiley Periodicals, Inc.     

Multi‐generational long‐distance migration of insects: studying the painted lady butterfly in the Western Palaearctic

Long‐range, seasonal migration is a widespread phenomenon among insects, allowing them to track and exploit abundant but ephemeral resources over vast geographical areas. However, the basic patterns of how species shift across multiple locations and seasons are unknown in most cases, even though migrant species comprise an important component of the temperate‐zone biota. The painted lady butterfly Vanessa cardui is such an example; a cosmopolitan continuously‐brooded species which migrates each year between Africa and Europe, sometimes in enormous numbers. The migration of 2009 was one of the most impressive recorded, and thousands of observations were collected through citizen science programmes and systematic entomological surveys, such as high altitude insect‐monitoring radar and ground‐based butterfly monitoring schemes. Here we use V. cardui as a model species to better understand insect migration in the Western Palaearctic, and we capitalise on the complementary data sources available for this iconic butterfly. The migratory cycle in this species involves six generations, encompassing a latitudinal shift of thousands of kilometres (up to 60 degrees of latitude). The cycle comprises an annual poleward advance of the populations in spring followed by an equatorward return movement in autumn, with returning individuals potentially flying thousands of kilometres. We show that many long‐distance migrants take advantage of favourable winds, moving downwind at high elevation (from some tens of metres from the ground to altitudes over 1000 m), pointing at strong similarities in the flight strategies used by V. cardui and other migrant Lepidoptera. Our results reveal the highly successful strategy that has evolved in these insects, and provide a useful framework for a better understanding of long‐distance seasonal migration in the temperate regions worldwide.     

Dating the Lower to Middle Paleolithic transition in the Levant: A view from Misliya Cave,Mount Carmel,Israel

The transition from the Lower to the Middle Paleolithic in the Levant is a crucial event in human evolution, since it may involve the arrival of a new human population. In the current study, we present thermoluminescence (TL) dates obtained from 32 burnt flints retrieved from the late Lower Paleolithic (Acheulo-Yabrudian) and Early Middle Paleolithic (Mousterian) layers of Misliya Cave, Mount Carmel, Israel. Early Middle Paleolithic industries rich in Levallois and laminar products were assigned mean ages ranging from ∼250 to ∼160 ka (thousands of years ago), suggesting a production of this industry during MIS 7 and the early part of MIS 6. The mean ages obtained for the samples associated with the Acheulo-Yabrudian (strengthened by an isochron analysis) indicate a production of this cultural complex ∼250 ka ago, at the end of MIS 8. According to the Misliya TL dates, the transition from the Lower to the Middle Paleolithic in the site took place at the limit MIS 8/7 or during the early part of MIS 7. The dates, together with the pronounced differences in lithic technology strongly suggest the arrival of a new population during this period.     

Ernst Rüdin: Hitler’s Racial Hygiene Mastermind

Ernst Rüdin (1874–1952) was the founder of psychiatric genetics and was also a founder of the German racial hygiene movement. Throughout his long career he played a major role in promoting eugenic ideas and policies in Germany, including helping formulate the 1933 Nazi eugenic sterilization law and other governmental policies directed against the alleged carriers of genetic defects. In the 1940s Rüdin supported the killing of children and mental patients under a Nazi program euphemistically called “Euthanasia.” The authors document these crimes and discuss their implications, and also present translations of two publications Rüdin co-authored in 1938 showing his strong support for Hitler and his policies. The authors also document what they see as revisionist historical accounts by leading psychiatric genetic authors. They outline three categories of contemporary psychiatric genetic accounts of Rüdin and his work: (A) those who write about German psychiatric genetics in the Nazi period, but either fail to mention Rüdin at all, or cast him in a favorable light; (B) those who acknowledge that Rüdin helped promote eugenic sterilization and/or may have worked with the Nazis, but generally paint a positive picture of Rüdin’s research and fail to mention his participation in the “euthanasia” killing program; and (C) those who have written that Rüdin committed and supported unspeakable atrocities. The authors conclude by calling on the leaders of psychiatric genetics to produce a detailed and complete account of their field’s history, including all of the documented crimes committed by Rüdin and his associates.