RHAMM, a receptor for hyaluronan-mediated motility, compensates for CD44 in inflamed CD44-knockout mice: a different interpretation of redundancy

We report here that joint inflammation in collagen-induced arthritis is more aggravated in CD44-knockout mice than in WT mice, and we provide evidence for molecular redundancy as a causal factor. Furthermore, we show that under the inflammatory cascade, RHAMM (receptor for hyaluronan-mediated motility), a hyaluronan receptor distinct from CD44, compensates for the loss of CD44 in binding hyaluronic acid, supporting cell migration, up-regulating genes involved with inflammation (as assessed by microarrays containing 13,000 cDNA clones), and exacerbating collagen-induced arthritis. Interestingly, we further found that the compensation for loss of the CD44 gene does not occur because of enhanced expression of the redundant gene (RHAMM), but rather because the loss of CD44 allows increased accumulation of the hyaluronic acid substrate, with which both CD44 and RHAMM engage, thus enabling augmented signaling through RHAMM. This model enlightens several aspects of molecular redundancy, which is widely discussed in many scientific circles, but the processes are still ill defined.     

Immunostimulatory DNA ameliorates experimental and spontaneous murine colitis

BACKGROUND & AIMS: Impaired mucosal barrier, cytokine imbalance, and dysregulated CD4(+) T cells play important roles in the pathogenesis of experimental colitis and human inflammatory bowel disease. Immunostimulatory DNA sequences (ISS-DNA) and their synthetic oligonucleotide analogs (ISS-ODNs) are derived from bacterial DNA, are potent activators of innate immunity at systemic and mucosal sites, and can rescue cells from death inflicted by different agents. We hypothesized that these combined effects of ISS-DNA could inhibit the damage to the colonic mucosa in chemically induced colitis and thereby limit subsequent intestinal inflammation. METHODS: The protective and the anti-inflammatory effect of ISS-ODN administration were assessed in dextran sodium sulfate-induced colitis and in 2 models of hapten-induced colitis in Balb/c mice. Similarly, these effects of ISS-ODN were assessed in spontaneous colitis occurring in IL-10 knockout mice. RESULTS: In all models of experimental and spontaneous colitis examined, ISS-ODN administration ameliorated clinical, biochemical, and histologic scores of colonic inflammation. ISS-ODN administration inhibited the induction of colonic proinflammatory cytokines and chemokines and suppressed the induction of colonic matrix metalloproteinases in both dextran sodium sulfate- and hapten-induced colitis. CONCLUSIONS: As the colon is continuously exposed to bacterial DNA, these findings suggest a physiologic, anti-inflammatory role for immunostimulatory DNA in the GI tract. Immunostimulatory DNA deserves further evaluation for the treatment of human inflammatory bowel disease.     

Notch signaling regulates cardiomyocyte proliferation during zebrafish heart regeneration

The human heart’s failure to replace ischemia-damaged myocardium with regenerated muscle contributes significantly to the worldwide morbidity and mortality associated with coronary artery disease. Remarkably, certain vertebrate species, including the zebrafish, achieve complete regeneration of amputated or injured myocardium through the proliferation of spared cardiomyocytes. Nonetheless, the genetic and cellular determinants of natural cardiac regeneration remain incompletely characterized. Here, we report that cardiac regeneration in zebrafish relies on Notch signaling. Following amputation of the zebrafish ventricular apex, Notch receptor expression becomes activated specifically in the endocardium and epicardium, but not the myocardium. Using a dominant negative approach, we discovered that suppression of Notch signaling profoundly impairs cardiac regeneration and induces scar formation at the amputation site. We ruled out defects in endocardial activation, epicardial activation, and dedifferentiation of compact myocardial cells as causative for the regenerative failure. Furthermore, coronary endothelial tubes, which we lineage traced from preexisting endothelium in wild-type hearts, formed in the wound despite the myocardial regenerative failure. Quantification of myocardial proliferation in Notch-suppressed hearts revealed a significant decrease in cycling cardiomyocytes, an observation consistent with a noncell autonomous requirement for Notch signaling in cardiomyocyte proliferation. Unexpectedly, hyperactivation of Notch signaling also suppressed cardiomyocyte proliferation and heart regeneration. Taken together, our data uncover the exquisite sensitivity of regenerative cardiomyocyte proliferation to perturbations in Notch signaling.When blood flow to a segment of the human heart becomes acutely interrupted, the hypoxic muscle suffers irreparable damage termed an acute myocardial infarction (1). An important public health concern, myocardial infarctions cause significant morbidity and mortality worldwide (2). As one of the least regenerative organs in the human body, the heart replaces the infarcted myocardium with noncontractile scar tissue instead of new muscle. As a result, the spared myocardium carries an increased hemodynamic burden that often leads to adverse ventricular remodeling and congestive heart failure. Therefore, the development of novel therapeutic strategies to stimulate human cardiac regeneration remains a top priority.Unlike mammals, adult zebrafish completely regenerate their hearts following amputation, cryoinjury, hypoxia/reoxygenation injury, or genetic ablation of cardiomyocytes (3–11). Lineage tracing studies have demonstrated that new cardiomyocytes arise by proliferation of partially dedifferentiated cardiomyocytes spared from injury (12, 13). Specifically, cardiomyocytes in the compact muscular layer proximal to the wound break down their sarcomeres, activate gata4 regulatory sequences, and initiate cell cycling with cytokinesis (12, 13). Interestingly, 1-d-old neonatal mice also achieve heart regeneration through cardiomyocyte proliferation following amputation injury (14). However, this endogenous regenerative potential is dampened by neonatal day 7 as cardiomyocytes exit the cell cycle through the up-regulation of meis1 and miR-15 (15, 16). Ultimately, the natural capacity for cardiac regeneration exhibited by adult zebrafish and neonatal mice suggests that the human heart could be stimulated to regenerate if the cellular and genetic determinants of cardiomyocyte proliferation were fully elucidated.Although adult mammalian cardiomyocytes have long been considered quiescent, recent stable isotope labeling studies in mice and humans have uncovered bona fide cardiomyocyte cell division during adult life (17–19). Moreover, following experimental myocardial infarction in mice, ∼3% of cardiomyocytes in the peri-infarct region arise through cardiomyocyte proliferation (19). These data demonstrate that, although insufficient to restore heart function, cardiomyocyte renewal does occur in the adult mammalian heart. These observations highlight the potential of augmenting endogenous cardiomyocyte proliferation as an effective treatment for myocardial infarction.The Notch signaling pathway plays fundamental roles in myriad developmental and regenerative processes (20). A previous study reported that partial amputation of the zebrafish ventricle stimulates expression of the Notch signaling components deltaC and notch1b (8), but the functional significance of this observation remains unexplored. Here, we report that amputation injury stimulates expression of three Notch receptors specifically in the endocardium and epicardium. Furthermore, Notch pathway suppression impaired the regeneration of new muscle and induced scar formation at the site of injury. Activation of the endocardium, epicardium, and gata4 cis-regulatory elements in compact myocardium were grossly unaffected by Notch suppression, but cardiomyocyte proliferation was significantly impaired. Unexpectedly, ubiquitous Notch pathway activation also inhibited cardiomyocyte proliferation and cardiac regeneration. These studies demonstrate that cardiomyocyte proliferative renewal is exquisitely sensitive to perturbations in Notch signaling.     

Positioning sulphonylureas in a modern treatment algorithm for patients with type 2 diabetes: Expert opinion from a European consensus panel

The large number of pharmacological agents available to treat type 2 diabetes (T2D) makes choosing the optimal drug for any given patient a complex task. Because newer agents offer several advantages, whether and when sulphonylureas (SUs) should still be used to treat T2D is controversial. Published treatment guidelines and recommendations should govern the general approach to diabetes management. However, expert opinions can aid in better understanding local practices and in formulating individual choices. The current consensus paper aims to provide additional guidance on the use of SUs in T2D. We summarize current local treatment guidelines in European countries, showing that SUs are still widely proposed as second-line treatment after metformin and are often ranked at the same level as newer glucose-lowering medications. Strong evidence now shows that sodium-glucose co-transporter-2 inhibitors (SGLT-2is) and glucagon-like peptide-1 receptor agonists (GLP-1RAs) are associated with low hypoglycaemia risk, promote weight loss, and exert a positive impact on vascular, cardiac and renal endpoints. Thus, using SUs in place of SGLT-2is and GLP-1RAs may deprive patients of key advantages and potentially important cardiorenal benefits. In subjects with ascertained cardiovascular disease or at very high cardiovascular risk, SGLT-2is and/or GLP-1RAs should be used as part of diabetes management, in the absence of contraindications. Routine utilization of SUs as second-line agents continues to be acceptable in resource-constrained settings.