Hypoxia can act as an initial trigger to induce erythrocyte sickling and eventual end organ damage in sickle cell disease (SCD). Many factors and metabolites are altered in response to hypoxia and may contribute to the pathogenesis of the disease. Using metabolomic profiling, we found that the steady-state concentration of adenosine in the blood was elevated in a transgenic mouse model of SCD. Adenosine concentrations were similarly elevated in the blood of humans with SCD. Increased adenosine levels promoted sickling, hemolysis and damage to multiple tissues in SCD transgenic mice and promoted sickling of human erythrocytes. Using biochemical, genetic and pharmacological approaches, we showed that adenosine A2B receptor (A2BR)-mediated induction of 2,3-diphosphoglycerate, an erythrocyte-specific metabolite that decreases the oxygen binding affinity of hemoglobin, underlies the induction of erythrocyte sickling by excess adenosine both in cultured human red blood cells and in SCD transgenic mice. Thus, excessive adenosine signaling through the A2BR has a pathological role in SCD. These findings may provide new therapeutic possibilities for this disease.

In this work, a novel photocatalyst, polypyrrole (PPy)-decorated Ag-TiO2 nanofibers (PPy-Ag-TiO2) with core-shell structure, was successfully synthesized using an electrospinning technique, followed by a surfactant-directed in situ chemical polymerization method. The results show that a PPy layer was formed on the surface of Ag-TiO2 nanofiber, which is beneficial for protecting Ag nanoparticles from being oxidized. Meanwhile, the PPy-Ag-TiO2 system exhibits remarkable light absorption in the visible region and high photocurrent. Among them, the 1%-PPy-Ag-TiO2 sample shows the highest photoactivity, which is far exceeds that of the single- and two-component systems. This result may be due to the synergistic effect of Ag, PPy, and TiO2 nanostructures in the ternary system.

A complex biologic network regulates kidney perfusion under physiologic conditions. This system is profoundly perturbed following renal ischemia, a leading cause of acute kidney injury (AKI) -a life-threatening condition that frequently complicates the care of hospitalized patients. Therapeutic approaches to prevent and treat AKI are extremely limited. Better understanding of the molecular pathways promoting postischemic reflow could provide new candidate targets for AKI therapeutics. Due to its role in adapting tissues to hypoxia, we hypothesized that extracellular adenosine has a regulatory function in the postischemic control of renal perfusion. Consistent with the notion that equilibrative nucleoside transporters (ENTs) terminate adenosine signaling, we observed that pharmacologic ENT inhibition in mice elevated renal adenosine levels and dampened AKI. Deletion of the ENTs resulted in selective protection in Ent1 -/-mice. Comprehensive examination of adenosine receptor-knockout mice exposed to AKI demonstrated that renal protection by ENT inhibitors involves the A2B adenosine receptor. Indeed, crosstalk between renal Ent1 and Adora2b expressed on vascular endothelia effectively prevented a postischemic no-reflow phenomenon. These studies identify ENT1 and adenosine receptors as key to the process of reestablishing renal perfusion following ischemic AKI. If translatable from mice to humans, these data have important therapeutic implications. IntroductionAcute kidney injury (AKI) is clinically defined by an abrupt reduction in kidney function (e.g., a decrease in glomerular filtration rate [GFR]), occurring over a period of minutes to days. AKI is frequently caused by an obstruction of renal blood flow (renal ischemia) and represents an important cause of morbidity and mortality of patients (1-3). Indeed, a recent study revealed that only a mild increase (0.3 mg/dl) in the serum creatinine level is associated with a 70% greater risk of death than in patients without this increase (2, 3). Particularly for surgical patients, AKI represents a significant threat. For example, surgical procedures requiring cross-clamping of the aorta and renal vessels are associated with a rate of AKI of up to 30% (4). Similarly, AKI after cardiac surgery occurs in up to 10% of patients under normal circumstances and is associated with dramatic increases in mortality (5). In addition, patients with sepsis frequently go on to develop AKI, and the combination of moder-

Chronic elevation of adenosine, which occurs in the setting of repeated or prolonged tissue injury, can exacerbate cellular dysfunction, suggesting that it may contribute to the pathogenesis of CKD. Here, mice with chronically elevated levels of adenosine, resulting from a deficiency in adenosine deaminase (ADA), developed renal dysfunction and fibrosis. Both the administration of polyethylene glycol-modified ADA to reduce adenosine levels and the inhibition of the A 2B adenosine receptor (A 2B R) attenuated renal fibrosis and dysfunction. Furthermore, activation of A 2B R promoted renal fibrosis in both mice infused with angiotensin II (Ang II) and mice subjected to unilateral ureteral obstruction (UUO). These three mouse models shared a similar profile of profibrotic gene expression in kidney tissue, suggesting that they share similar signaling pathways that lead to renal fibrosis. Finally, both genetic and pharmacologic approaches showed that the inflammatory cytokine IL-6 mediates adenosine-induced renal fibrosis downstream of A 2B R. Taken together, these data suggest that A 2B R-mediated induction of IL-6 contributes to renal fibrogenesis and shows potential therapeutic targets for CKD.

Priapism is a condition of persistent penile erection in the absence of sexual excitation. Of men with sickle cell disease (SCD), 40% display priapism. The disorder is a dangerous and urgent condition, given its association with penile fibrosis and eventual erectile dysfunction. Current strategies to prevent its progression are poor because of a lack of fundamental understanding of the molecular mechanisms for penile fibrosis in priapism. Here we demonstrate that increased adenosine is a novel causative factor contributing to penile fibrosis in two independent animal models of priapism, adenosine deaminase (ADA)-deficient mice and SCD transgenic mice. An important finding is that chronic reduction of adenosine by ADA enzyme therapy successfully attenuated penile fibrosis in both mouse models, indicating an essential role of increased adenosine in penile fibrosis and a novel therapeutic possibility for this serious complication. Subsequently, we identified that both mice models share a similar fibrotic gene expression profile in penile tissue (including procollagen I, TGF-beta(1), and plasminogen activator inhibitor-1 mRNA), suggesting that they share similar signaling pathways for progression to penile fibrosis. Thus, in an effort to decipher specific cell types and underlying mechanism responsible for adenosine-mediated penile fibrosis, we purified corpus cavernosal fibroblast cells (CCFCs), the major cell type involved in this process, from wild-type mice. Quantitative RT-PCR showed that the major receptor expressed in these cells is the adenosine receptor A(2B)R. Based on this fact, we further purified CCFCs from A(2B)R-deficient mice and demonstrated that A(2B)R is essential for excess adenosine-mediated penile fibrosis. Finally, we revealed that TGF-beta functions downstream of the A(2B)R to increase CCFC collagen secretion and proliferation. Overall, our studies identify an essential role of increased adenosine in the pathogenesis of penile fibrosis via A(2B)R signaling and offer a potential target for prevention and treatment of penile fibrosis, a dangerous complication seen in priapism.-Wen, J., Jiang, X., Dai, Y., Zhang, Y., Tang, Y., Sun, H., Mi, T., Phatarpekar, P. V., Kellems, R. E., Blackburn, M. R., Xia, Y. Increased adenosine contributes to penile fibrosis, a dangerous feature of priapism, via A(2B) adenosine receptor signaling.

Background-Preeclampsia is a prevalent life-threatening hypertensive disorder of pregnancy. The circulating antiangiogenic factor, soluble endoglin (sEng), is elevated in the blood circulation of women with preeclampsia and contributes to disease pathology; however, the underlying mechanisms responsible for its induction in preeclampsia are unknown. Methods and Results-Here, we discovered that a circulating autoantibody, the angiotensin receptor agonistic autoantibody (AT 1 -AA), stimulates sEng production via AT 1 angiotensin receptor activation in pregnant mice but not in nonpregnant mice. We subsequently demonstrated that the placenta is a major source contributing to sEng induction in vivo and that AT 1 -AA-injected pregnant mice display impaired placental angiogenesis. Using drug screening, we identified tumor necrosis factor-␣ as a circulating factor increased in the serum of autoantibody-injected pregnant mice contributing to AT 1 -AA-mediated sEng induction in human umbilical vascular endothelial cells. Subsequently, among all the drugs screened, we found that hemin, an inducer of heme oxygenase, functions as a break to control AT 1 -AA-mediated sEng induction by suppressing tumor necrosis factor-␣ signaling in human umbilical vascular endothelial cells. Finally, we demonstrated that the AT 1 -AA-mediated decreased angiogenesis seen in human placenta villous explants was attenuated by tumor necrosis factor-␣-neutralizing antibodies, soluble tumor necrosis factor-␣ receptors, and hemin by abolishing both sEng and soluble fms-like tyrosine kinase-1 induction. Conclusions-Our findings demonstrate that AT 1 -AA-mediated tumor necrosis factor-␣ induction, by overcoming its negative regulator, heme oxygenase-1, is a key underlying mechanism responsible for impaired placental angiogenesis by inducing both sEng and soluble fms-like tyrosine kinase-1 secretion from human villous explants. Our results provide important new targets for diagnosis and therapeutic intervention in the management of preeclampsia. (Circulation. 2010;121:436-444.)Key Words: angiogenesis Ⅲ antibodies Ⅲ endothelium Ⅲ hypertension Ⅲ inflammation Ⅲ pregnancy Ⅲ signal transduction P reeclampsia is a prevalent life-threatening hypertensive disorder of pregnancy with high maternal and fetal rates of morbidity and mortality. 1,2 A growing body of evidence indicates that a circulating maternal autoantibody, the angiotensin II type I receptor agonistic autoantibody (AT 1 -AA), is a prominent component in the pathogenesis of preeclampsia. Numerous early studies demonstrated that AT 1 -AAs activate AT 1 receptors on a variety of cell types and provoke biological responses relevant to the pathophysiology of preeclampsia. 3-8 Recently, we have extended these in vitro studies by showing that key features of preeclampsia are generated in pregnant mice injected with either total immunoglobulin G (IgG) or affinity-purified AT 1 -AAs from preeclamptic women. 9 These studies provided the first direct evidence for the pathogenic nature of AT 1 -AAs in preecla...

Introduction Penile erection is a hemodynamic process, which results from increased flow and retention of blood in the penile organ due to the relaxation of smooth muscle cells. Adenosine, a physiological vasorelaxant, has been shown to be a modulator of penile erection. Aim To summarize the research on the role of adenosine signaling in normal penile erection and erectile disorders. Main Outcome Measures Evidence in the literature on the association between adenosine signaling and normal and abnormal penile erection, i.e., erectile dysfunction (ED) and priapism. Methods The article reviews the literature on the role of endogenous and exogenous adenosine in normal penile erection, as well as in erectile disorders namely, ED and priapism. Results Adenosine has been shown to relax corpus cavernosum from various species including human in both in vivo and in vitro studies. Neuromodulatory role of adenosine in corpus cavernosum has also been demonstrated. Impaired adenosine signaling through A2B receptor causes partial resistance of corpus cavernosum, from men with organic ED, to adenosine-mediated relaxation. Increased level of adenosine has been shown to be a causative factor for priapism. Conclusion Overall, the research reviewed here suggests a general role of exogenous and endogenous adenosine signaling in normal penile erection. From this perspective, it is not surprising that impaired adenosine signaling is associated with ED, and excessive adenosine signaling is associated with priapism. Adenosine signaling represents a potentially important diagnostic and therapeutic target for the treatment of ED and priapism.

Simultaneous combined MPCNL and flexible ureteroscopic lithotripsy is an effective and safe treatment for partial staghorn calculi, with significantly higher one-step SFR when compared to conventional MPCNL monotherapy, without additional procedure-related complications.