Research articles

Jian-Xun Wang et al. show that mitochondrial fission, which occurs during cell death, is regulated in cardiomyocytes by the microRNA miR-499 through a mechanism involving the phosphatase calcineurin and its substrate Drp1. Overexpression of miR-499 was able to reduce mitochondrial fission and apoptosis in the hearts of mice or rats injured by ischemia-reperfusion and to improve heart function, suggesting new therapeutic approaches for myocardial injury.

The protein hormone adiponectin is known to have many beneficial systemic effects, including promoting cell survival, anti-inflammation and insulin sensitivity. Phil Scherer and his colleagues have found that these pleiotropic effects are mediated by a ceramidase activity associated with the two known isoforms of the adiponectin receptor.

A major problem in the clinical management of patients with brain tumors is distinguishing tumor recurrence from radiation-induced necrosis after brain tumor therapy. Zhou et al. use an MRI technique called amide proton transfer imaging to noninvasively differentiate between these two pathologies. The approach is successfully evaluated by comparing two orthotopic glioma models with a radiation necrosis model in rats.

Yujin Zhang et al. discovered that the concentration of adenosine in the blood is increased both in a mouse model of sickle cell disease and in humans with this disease. Adenosine seems to have a pathological role in this disease, as it induced sickling of human erythrocytes through a mechanism involving activation of the A_2B adenosine receptor. Treatment of the mouse model of sickle cell disease with an agent to lower adenosine levels or with an A_2B adenosine receptor antagonist had beneficial effects, pointing to new therapeutic strategies for this disease.

Histidine decarboxylase (Hdc) is required for the endogenous production of histamine, but its role in tumorigenesis is unclear. Yang et al. now report that Hdc-deficient mice develop more tumors in models of chemically induced carcinogenesis, associated with an increased recruitment of immature myeloid cells to the tumors and higher amounts of interleukin-6. The authors further show that Hdc deficiency inhibits myeloid cell maturation and that exogenous histamine promotes monocyte differentiation and suppresses tumor growth.

The antithrombotic drug clopidogrel, widely prescribed after heart attacks, is a prodrug and must be metabolically activated. The efficiency of this activation step varies among individuals and is thought to account for clopidogrel's variable clinical efficacy, a major drawback to its use. Heleen Bouman et al. provide biochemical, clinical and epidemiological evidence to show that a common polymorphism in the gene encoding paraoxonase-1 is largely responsible for this variability. Paraoxonase-1 genotyping might identify those individuals unlikely to benefit from clopidogrel treatment.

Adenovirus type 37 (Ad37) causes epidemic keratoconjunctivitis, a highly contagious disease for which there is no specific antiviral therapy. The receptor for Ad37 infection was previously unidentified, but known to contain sialic acid. Nilsson et al. report here that Ad37 binds to the GD1a glycan motif of the GD1a ganglioside. This finding may facilitate the development of antiviral agents targeting Ad37-associated disease.

A subset of series B adenoviruses binds epithelial cells via a previously unknown receptor. Wang et al. now identify this receptor as desmoglein-2 (DSG-2), which has a role in intercellular adhesion. Binding of group B Ad3 to DSG-2 triggered an epithelial to mesenchymal transition, opened intercellular junctions and increased access to junction-localized proteins, which together may contribute to the spread of these viruses though epithelial tissues.

Proteinuria results from defects in glomerular filtration, often as a result of kidney injury or inflammation. Sumant Chugh and his colleagues now show that the glycoprotein Angptl4 is highly upregulated in minimal change disease, a type of human proteinuria, and that genetic deletion protects against experimentally induced proteinuria in mice.

Bhang and colleagues have developed a tumor-specific imaging strategy that uses the progression elevated gene-3 (PEG-3) promoter, known to be specifically associated with malignant transformation, to selectively drive the expression of luciferase or herpes simplex virus 1 thymidine kinase reporters. Systemic delivery of PEG-3 promoter–driven constructs using a nonviral gene delivery vehicle allowed detection of both primary tumors and micrometastatic disease in mouse models of human melanoma and breast cancer.

Pandemic influenza viruses often cause severe disease in middle-aged adults without preexisting comorbidities. A serum antibody preexisting in middle-aged adults cross-reacts with, but does not protect against, 2009 H1N1 influenza virus. The existence of this antibody may account for the unusual age distribution of severe flu cases during pandemics.

Expression of miR-124, a microglial microRNA, reduces disease in a mouse model of multiple sclerosis by inhibiting the transcription factor C/EBP-α and its downstream target PU.1.

Dysfunction of the dopamine neurotransmitter system has long been implicated in depression. Now, Fang Liu and colleagues show that the interaction between two dopamine receptor subtypes is increased in the brain of subjects with major depression. Blocking this interaction in rodent models of depression can result in antidepressant-like effects.

One complication arising from gastrointestinal surgery is ileus, in which local manipulation of the intestine leads to dysmotility and paralysis of the entire intestine. Christian Kurts and his colleagues find that after surgery T helper type 1 memory cells are activated by intestinal dendritic cells via interleukin-12, and migration of memory T cells through the portal vein induces paralysis of unmanipulated sites. Inhibition of interleukin-12 or prevention of lymphocyte egress with FTY720 prevents ileus and suggests new targets for therapeutic intervention.

Brain injury after stroke requires glutamate receptor activation of neuronal nitric oxide synthase (nNOS), but inhibiting either of these proteins can cause side effects. Now, Dong-Ya Zhu and colleagues show that a drug that blocks the interaction between nNOS and a glutamate receptor docking protein can reduce stroke damage in vivo, with no observed side effects.

Deficiencies with current in vitro methods to assess cancer invasion prompted Todd Ridky and his colleagues to design a three-dimensional human organotypic epithelial cancer model using primary epithelial cells from multiple stratified epithelial tissues. The model recapitulates many of the features of tumor progression, including epithelial invasion through the intact basement membrane and supporting stroma. Studying epithelial tumor cell invasion in a more physiologic manner may help identify potential therapeutic targets for a range of epithelial tumors.

By acting on the P2X₇ receptor, ATP released upon cell damage functions as a danger signal to promote acute graft-versus-host disease after bone marrow transplantation in mice.

Physiological Stat3 signaling is temporally restricted. In cancer, Stat3 activity is often persistently elevated and fosters progression through its effects on tumor cells and their microenvironment. This report identifies the reciprocal positive regulation of S1PR1 and Stat3 in tumors as a mechanism by which tumor cells and their environment crosstalk to maintain Stat3 activity. This persistent loop is required for tumor progression and metastasis and could be a potential therapeutic target to block oncogenic Stat3 signaling.

Under certain conditions, endothelial cells can transform into mesenchymal cell types, a process known as endothelial-to-mesenchymal transition. Damian Medici et al. now provide evidence that this type of transition contributes to the generation of the ossified lesions of individuals with fibrodysplasia ossificans progressiva. Experiments in mice and in cultured endothelial cells indicate that activation of the ALK2 receptor in endothelial cells endows them with the ability to differentiate into a number of cell types.

The authors characterize a previously undescribed function of Snf5 that involves interaction with the transcription factor Gli1 and downregulation of its activity via chromatin remodeling. Snf5 is shown to restrict Hedgehog (Hh) signaling in normal development and cancer. Hh inhibition emerges as a potential therapeutic strategy for malignant rhabdoid tumors in which Snf5 is commonly lost.