SUMMARY Doxorubicin (DOX) is one of the most widely used and successful antitumor drugs, but its cumulative and dose-dependent cardiac toxicity has been the major concern of oncologists in cancer therapeutic practice for decades. With the increasing population of cancer survivals, there is a growing need to develop preventive strategies and effective therapies against DOX-induced cardiotoxicity, in particular, the late onset cardiomyopathy. Although intensive investigations on the DOX-induced cardiotoxicity have been continued for decades, the underlying mechanisms responsible for DOX-induced cardiotoxicity have not been completely elucidated. A rapidly expanding body of evidence supports that cardiomyocyte death by apoptosis and necrosis is a primary mechanism of DOX-induced cardiomyopathy and other types of cell death, such as autophagy and senescence/aging, may participate in this process. In this review, we will focus on the current understanding of molecular mechanisms underlying DOX-induced cardiomyocyte death, including the major primary mechanism of excess production of reactive oxygen species (ROS) and other recently discovered ROS-independent mechanisms. Different sensitivity to DOX-induced cell death signals between adult and young cardiomyocytes will also be discussed.

Toxoplasma gondii is an important protozoan pathogen of humans that can cause encephalitis in immunocompromised individuals such as those with AIDS. This encephalitis is due to reactivation of latent infection in T. gondii-seropositive patients. Latent organisms survive within tissue cysts, which are specialized parasitophorous vacuoles containing bradyzoites. The cyst wall of this structure is produced by modification of the parasitophorous vacuole by the parasite and is important in cyst survival. The components of the cyst wall have been poorly characterized. By using immunofluorescence and immunoelectron microscopy, we have identified a monoclonal antibody (MAb 93.18) that reacts with the cyst wall. This antibody recognizes a 116-kDa glycoprotein, which we have termed CST1, containing sugar residues that bind Dolichos biflorans lectin (DBA). CST1 is distinct from T. gondii antigen labeled with succinyl Triticum vulgare lectin (S-WGA) and represents the major DBA-binding component in T. gondii. The carbohydrate components of the tissue cyst, such as CST1, are probably important in both providing stability and facilitating persistence in its host. As is seen in the carbohydrate capsules of fungi, glycoproteins in the T. gondii cyst wall may protect cysts from the immune response of the host. Further characterization of the formation of the cyst wall and its components should lead to insights into the mechanism of tissue cyst persistence and may suggest novel therapeutic approaches to eliminate tissue cysts of this organism.

Pathological cardiac hypertrophy caused by diverse etiologies eventually leads to cardiac dilation and functional decompensation. We have recently reported that genetic deletion of Rho-associated coiled-coil containing protein kinase 1 (ROCK1) inhibited several pathological events including cardiomyocyte apoptosis in compensated hypertrophic hearts. The present study investigated whether ROCK1 deficiency can prevent the transition from hypertrophy to heart failure. Transgenic mice with cardiac-restricted overexpression of Gαq develop compensated cardiac hypertrophy at young ages, but progress into lethal cardiomyopathy accompanied by increased apoptosis after pregnancy or at old ages. The studies were first carried out using age-and pregnancy-matched wildtype (WT), Gαq, ROCK1 −/− , and Gαq/ROCK1 −/− mice. The potent beneficial effect of ROCK1 deletion is demonstrated by abolishment of peripartum mortality, and significant attenuation of left ventricular (LV) dilation, wall thinning, and contractile dysfunction in the peripartum Gαq transgenic mice. Increase in cardiomyocyte apoptosis was suppressed by ROCK1 deletion, associated with increased extracellular signal-regulated kinase/mitogen-activated protein kinase (ERK/MAPK) activation and inhibition of mitochondrial translocation of Bax. In addition, ROCK1 deficiency also improved survival, inhibited cardiomyocyte apoptosis, and preserved LV dimension and function in old Gαq mice at 12 months. Furthermore, transgenic overexpression of ROCK1 increased cardiomyocyte apoptosis and accelerated hypertrophic decompensation in Gαq hearts in the absence of pregnancy stress. The present study provides for the first time in vivo evidence for the long-term beneficial effects of ROCK1 deficiency in hypertrophic decompensation and suggests that ROCK1 may be an attractive therapeutic target to limit heart failure progression. KeywordsRho kinase; ROCK1; apoptosis; Gαq; ERK/MAPK; Bax; heart failure Heart failure is a leading cause for human morbidity and mortality, and the incidence of heart failure has been constantly increasing during the past decades. Cardiac hypertrophy is initially Publisher's Disclaimer: This is a PDF file of an unedited manuscript that has been accepted for publication. As a service to our customers we are providing this early version of the manuscript. The manuscript will undergo copyediting, typesetting, and review of the resulting proof before it is published in its final citable form. Please note that during the production process errors may be discovered which could affect the content, and all legal disclaimers that apply to the journal pertain. a compensatory response to diverse etiologies, but it eventually leads to heart failure or sudden death due to decompensation [1][2][3]. Identifying the signaling mechanisms underlying the development of cardiac hypertrophy and the transition to heart failure will be helpful for the design of effective therapeutics. Rho-associated coiled-coil containing protein kinase (ROCK) is a downstream mediator o...

Oligodendrocyte progenitor cells (OPCs) derived from human embryonic stem (hES) cells have been reported to remyelinate axons and improve locomotor function in a rodent model of spinal cord injury. Although remyelination would be expected to have a beneficial effect in spinal cord injury, neurotrophic factor expression may also contribute to functional recovery. Neurotrophic factors could impact the survival of axotomized neurons, as well as promote axonal regeneration in interrupted conduction pathways. This study demonstrates that hES cell-derived OPCs express functional levels of midkine, hepatocyte growth factor (HGF), activin A, transforming growth factor-beta2 (TGF-beta2), and brain-derived neurotrophic factor (BDNF), proteins with reported trophic effects on neurons. The neurotrophic activity of hES cell-derived OPCs is further demonstrated by stimulatory effects on neurite outgrowth of adult rat sensory neurons in vitro.