Hot off the presses! Apr 01 Trends Mol Med

The Apr 01 issue of the Trends Mol Med is now up on Pubget (About Trends Mol Med): if you're at a subscribing institution, just click the link in the latest link at the home page. (Note you'll only be able to get all the PDFs in the issue if your institution subscribes to Pubget.)

Latest Articles Include:

• Editorial Board
  - Trends Mol Med 15(4):i (2009)
  
• Degenerative diseases, oxidative stress and cytochrome c oxidase function
  - Trends Mol Med 15(4):139-147 (2009)
  Aging and degenerative diseases are associated with increased levels of reactive oxygen species (ROS). ROS are mostly produced in mitochondria, and their levels increase with higher mitochondrial membrane potential. Cellular respiratory control is based on inhibition of respiration by high membrane potentials. However, we have described a second mechanism of respiratory control based on allosteric inhibition of cytochrome c oxidase (CcO), the terminal enzyme of the respiratory chain, at high ATP:ADP ratios. The mechanism is independent of membrane potential. We have proposed that feedback inhibition of CcO by ATP keeps the membrane potential and ROS production at low levels. Various forms of stress switch off allosteric ATP-inhibition via reversible dephosphorylation of CcO, resulting in increased membrane potential and cellular ROS levels. This mechanism is proposed to represent a missing molecular link between stress and degenerative diseases.
• Whole-genome association studies of sporadic amyotrophic lateral sclerosis: are retroelements involved?
  - Trends Mol Med 15(4):148-158 (2009)
  Whole-genome association studies (WGASs) have identified single-nucleotide polymorphisms (SNPs) associated with sporadic amyotrophic lateral sclerosis (sALS). However, WGASs have so far produced results that are not consistent with those obtained from monogenic association studies focused on genes found to be relevant to ALS in functional biological studies. We propose that such inconsistencies might be at least partially alleviated by using approaches that integrate weakly associated SNPs. Several independent studies have detected abnormal reverse transcriptase (RT) activity in sALS patients, suggesting the involvement of retroelements in ALS pathogenesis. Here, we discuss the functions of genes with SNPs or mutations in sALS and consider whether these might implicate the involvement of a putative retroelement associated with sALS pathogenesis. New experimental models for studying retroviral activation and the effects of xenobiotic agents in ALS will be needed to furt! her investigate a potential role of retroelements in the etiology of sALS.
• Mitogen-activated protein kinases in male reproductive function
  - Trends Mol Med 15(4):159-168 (2009)
  Recent studies have shown that male reproductive function is modulated via the mitogen-activated protein kinase (MAPK) cascade. The MAPK cascade is involved in numerous male reproductive processes, including spermatogenesis, sperm maturation and activation, capacitation and acrosome reaction, before fertilization of the oocyte. In this review, we discuss the latest findings in this rapidly developing field regarding the role of MAPK in male reproduction in animal models and in human spermatozoa in vitro. This research will facilitate the design of future studies in humans, although much work is needed before this information can be used to manage male infertility and environmental toxicant-induced testicular injury in men, such as blood–testis-barrier disruption.
• Bronchopulmonary dysplasia and emphysema: in search of common therapeutic targets
  - Trends Mol Med 15(4):169-179 (2009)
  Bronchopulmonary dysplasia of the premature neonate and emphysema of the adult lung are common diseases that are characterized by increased airspace size and respiratory insufficiency and that presently lack efficient treatment. Although the former leads to impaired alveolar development and the latter to alveolar destruction, they have striking similarities in their pathophysiology, including the precipitating effect of oxidative stress, sustained inflammation, enhanced apoptosis, protease–antiprotease imbalance, elastic fiber deterioration and altered microvascularization. This review aims to comparatively analyze their molecular mechanisms to try identify common therapeutic targets. The recent discovery that alveolar developmental and maintenance programs share the same signal molecules and pathways, together with considerable increase in their understanding, have facilitated the development of common innovative strategies that have started to be tested in experime! ntal models and pilot clinical studies.
• Endothelial progenitor cell-based neovascularization: implications for therapy
  - Trends Mol Med 15(4):180-189 (2009)
  Ischemic cardiovascular events are a major cause of death globally. Endothelial progenitor cell (EPC)-based approaches can result in improvement of vascular perfusion and might offer clinical benefit. However, although functional improvement is observed, the lack of long-term engraftment of EPCs into neovessels has raised controversy regarding their mechanism of action. We and others have hypothesized that after ischemic injury, EPCs induce neovascularization through the secretion of cytokines and growth factors, which act in a paracrine fashion and induce sprouting angiogenesis by the surrounding endothelium. In this concise review, we discuss the (patho)physiology of EPC-induced neovascularization and focus on the paracrine signals secreted by EPCs and the effects they elicit. In future therapies, clinical administration of these paracrine modulators using slow-release depots might induce neovascularization and might therefore hold promise for vascular regenerative m! edicine.