1wileyonlinelibrary.com uniform core@shell structures with highly functional inner core and porous outer shell by a simple approach.Titanium dioxide (TiO 2 ) has been a semiconductor material of signifi cant research interest due to its fascinating features, such as nontoxicity, good chemical and thermal stability, and excellent electronic, optical, and catalytic properties, [ 5,6 ] which render it a greatly promising material in photocatalysis for the removal of inorganic and organic pollutants, [ 7 ] and for hydrogen generation, [ 8 ] as well as in dye-sensitized solar cells. [ 9 ] However, TiO 2 has a bandgap of 3.0-3.2 eV, and mainly absorbs ultraviolet (UV) light, which accounts for only ≈5% of the incoming solar energy. [ 10,11 ] Therefore, photons with energy lower than the band gap energy of TiO 2 , that is, more than 90% of the solar energy, cannot be harvested for photocatalysis. Furthermore, the fast recombination of charge carriers signifi cantly reduces the catalytic activity in practical applications. To resolve these problems, much effort, including metal-ion, and nonmetal doping, [ 12 ] dye sensitization, [ 13 ] and coupling with narrower band gap semiconductors, [ 14 ] has been undertaken toward developing the next-generation of TiO 2 -based materials. These methods have been able to extend the absorption of TiO 2 -based photocatalysts into the visible region to some extent and/or enhance the charge separation. However, to date, the photocatalytic performance of these materials remains poor and in general, they also suffer from thermal instability and photocorrosion, and are not environmentally friendly. [ 15 ] Therefore, it is challenging, yet highly desirable to develop a simple method for synthesizing a photocatalyst, which can absorb solar photons over a broad wavelength range and show largely improved photocatalytic activity, as well as overcome other problems mentioned above.Au nanoparticles (NPs) show unique, size-tunable surface plasmon resonance (SPR) in the visible range, offering a new opportunity to overcome the limits of current photocatalysts. [16][17][18] -core@porous-TiO 2 -shell microspheres is reported. They exhibit high surface area, good stability, broadband absorption from ultraviolet to near infrared, and excellent photocatalytic activity, signifi cantly better than the benchmark P25 TiO 2 . The enhanced activity is attributed to synergistic effects from nanocomponents arranged into the nanostructured architecture in such a way that favors the effi cient charge/energy transfer among nanocomponents and largely reduced charge recombination. Optical and energy-transfer properties are modeled theoretically to support our interpretations of catalytic mechanisms. In addition to yielding novel materials and interesting properties, the current work provides physical insights that can contribute to the future development of plasmon-enhanced broadband catalysts.

Diabetic nephropathy (DN) is characterized by mesangial cell (MC) expansion and accumulation of extracellular matrixproteins. TGF-␤ is increased in MC under diabetic conditions and in DN and activates key signaling pathways, including the phosphoinositide-3-kinase/Akt (PI3K/Akt) pathway. FoxO transcription factors play roles in cell survival and oxidative stress and are negatively regulated by Akt-mediated phosphorylation. We tested whether phosphorylation-mediated inactivation of FoxO3a by TGF-␤ can mediate MC survival and oxidative stress. TGF-␤ treatment significantly increased levels of p-Akt (activation) and p-FoxO3a (inactivation) in cultured MC. This FoxO3a inactivation was accompanied by significant decreases in the expression of two key FoxO3a target genes, the proapoptotic Bim and antioxidant manganese superoxide dismutase in MC. TGF-␤ treatment triggered the nuclear exclusion of FoxO3a, significantly inhibited FoxO3a transcriptional activity, and markedly protected MC from apoptosis. A PI3K inhibitor blocked these TGF-␤ effects. It is interesting that p-Akt and p-FoxO3A levels also were increased in renal cortical tissues from rats and mice at 2 wk after the induction of diabetes by streptozotocin, thus demonstrating in vivo significance. In summary, TGF-␤ and diabetes can increase FoxO3a phosphorylation and transcriptional inactivation via PI3K/Akt. These new results suggest that Akt/FoxO pathway regulation may be a novel mechanism by which TGF-␤ can induce unopposed MC survival and oxidant stress in early DN, thereby accelerating renal disease.

YVO(4) nano/microcrystals with multiform morphologies, such as nanoparticles, microdoughnut, micropancake, pillar structure, and microflower, have been synthesized via a facile hydrothermal route. A series of controlled experiments indicate that the shape and size of as-prepared architectures can be tuned effectively by controlling the reaction conditions, such as reaction time, vanadium sources, different organic additives, and the molar ratio of organic additive trisodium citrate (Cit(3-)):Y(3+). It is found that Cit(3-) as a ligand and shape modifier has the dynamic effect by adjusting the growth rate of different facets under different experimental conditions, resulting in the formation of various geometries of the final products. The possible formation mechanisms for products with diverse architectures have been presented in detail. Additionally, we systematically investigate the luminescent properties of the YVO(4):Ln(3+) (Ln = Eu, Dy, Sm, and Er). Because of an efficient energy transfer from vanadate groups to dopants, YVO(4):Ln(3+) (Ln = Eu, Dy, Sm, and Er) phosphors showed their strong characteristic emission under ultraviolet excitation and low-voltage electron beam excitation. The ability to generate YVO(4) nano/microstructures with diverse shapes, multicolor emission, and higher quantum efficiency provides a great opportunity for systematically evaluating their luminescence properties, as well as fully exploring their applications in many types of color display fields.

Diabetic nephropathy (DN) remains a major complication in both type 1 and type 2 diabetes. Systemic administration of antitransforming growth factor-beta (TGF-beta) antibody has shown some promise in mouse models of DN. However, chronic blockade of the multifunctional TGB-beta could be problematic. Several downstream effects of TGF-beta are mediated by connective tissue growth factor (CTGF), which is up-regulated in several renal cells and secreted in the urine in the diabetic state. Using murine models of DN (type 1 and type 2) and a CTGF antisense oligonucleotide (ASO) of novel chimeric chemistry, we evaluated the specific role of this target in DN. In the type 1 model of DN, C57BL6 mice were made diabetic using streptozotocin injections and hyperglycemic animals were treated with CTGF ASOs (20 mg/kg/2 qw) for 4 months. ASO, but not mismatch control oligonucleotide, -treated animals showed significant reduction in target CTGF expression in the kidney with a concomitant decrease in proteinuria and albuminuria. Treatment with the CTGF ASO for 8 wk reduced serum creatinine and attenuated urinary albuminuria and proteinuria in diabetic db/db mice, a model of type 2 DN. The ASO also reduced expression of genes involved in matrix expansion such as fibronectin and collagen (I and IV) and an inhibitor of matrix degradation, PAI-1, in the renal cortex, contributing to significant reversal of mesangial expansion in both models of DN. Pathway analyses demonstrated that diabetes-induced phosphorylation of p38 MAPK and its downstream target CREB was also inhibited by the ASO. Our results strongly suggest that blocking CTGF using a chimeric ASO holds substantial promise for the treatment of DN.

Expansion of myeloid-derived suppressor cells (MDSCs) has been documented in some murine models and patients with autoimmune diseases, but the exact role of MDSCs in this process remains largely unknown. The current study investigates this question in patients with systemic lupus erythematosus (SLE). Patients with active SLE showed a significant increase in HLA-DR−CD11b+CD33+ MDSCs, including both CD14+CD66b− monocytic and CD14−CD66b+ granulocytic MDSCs, in the peripheral blood compared to healthy controls (HCs). The frequency of MDSCs was positively correlated with the levels of serum arginase-1 (Arg-1) activity, T helper 17 (TH17) responses, and disease severity in SLE patients. Consistently, in comparison with MDSCs from HCs, MDSCs from SLE patients exhibited significantly elevated Arg-1 production and increased potential to promote TH17 differentiation in vitro in an Arg-1–dependent manner. Moreover, in a humanized SLE model, MDSCs were essential for the induction of TH17 responses and the associated renal injuries, and the effect of MDSCs was Arg-1–dependent. Our data provide direct evidence demonstrating a pathogenic role for MDSCs in human SLE. This study also provides a molecular mechanism of the pathogenesis of SLE by demonstrating an Arg-1–dependent effect of MDSCs in the development of TH17 cell–associated autoimmunity, and suggests that targeting MDSCs or Arg-1 may offer potential therapeutic strategies for the treatment of SLE and other TH17 cell–mediated autoimmune diseases.

The receptor for advanced glycation end products (RAGE) and its ligands have been implicated in the activation of oxidant stress and inflammatory pathways in vascular smooth muscle cells (VSMCs) leading to the initiation and augmentation of atherosclerosis. Here we report that non-receptor Src tyrosine kinase and the membrane protein caveolin-1 (Cav-1) play a key role in the activation of RAGE by S100B in VSMCs. S100B increased the activation of Src kinase and tyrosine phosphorylation of caveolin-1 in VSMCs. A RAGEspecific antibody blocked both these effects. An inhibitor of Src kinase, PP2, significantly blocked S100B-induced activation of Src kinase, mitogen-activated protein kinases, transcription factors NF-B and STAT3, superoxide production, tyrosine phosphorylation of Cav-1, VSMC migration, and expression of the pro-inflammatory genes monocyte chemotactic protein-1 and interleukin-6. Cholesterol depletion also inhibited S100B-induced effects indicating the requirement for intact caveolae in RAGE-specific signaling. Nucleofection of either a Src dominant negative mutant, or a Cav-1 mutant lacking the scaffolding domain, or Cav-1 short hairpin RNA significantly reduced S100B-induced inflammatory gene expression in VSMCs. Furthermore, VSMCs derived from insulin-resistant and diabetic db/db mice displayed increased RAGE expression, Src activation, and migration compared with those from control db/؉ mice. The RAGE antibody blocked enhanced migration in db/db cells. These studies demonstrate for the first time that, in VSMCs, Src kinase and Cav-1 play important roles in RAGE-mediated inflammatory gene expression and migration, key events associated with diabetic vascular complications. Vascular smooth muscle cell (VSMC)2 proliferation, migration, and inflammatory gene expression play important roles in the development of atherosclerotic lesions. Diabetic conditions have been shown to enhance these processes, which lead to accelerated atherosclerosis (1-4). Evidence shows that the accumulation of advanced glycation end products (AGEs) and activation of the receptor for AGEs (RAGE) are key factors mediating these events (5-8). RAGE is a member of the immunoglobulin superfamily of cell-surface molecules and is expressed in many cell types, including VSMCs. It can be activated by multiple ligands such as amphoterin, ␤-amyloid peptide, and several short peptides belonging to the S100/calgranulin family, which includes S100B (9, 10). Recent studies using animal models showed that diabetes-induced accelerated atherosclerosis in apoE null mice is associated with enhanced accumulation of RAGE ligands and increased expression of RAGE itself (11, 12). The expression of RAGE as well as its ligands, including S100B, was increased in neointimal and medial cells. Administration of sRAGE could reduce neointimal thickening as well as VSMC proliferation in these animal models. Furthermore, RAGE null mice showed reduced arterial injury responses, whereas transgenic mice expressing DN-RAGE specifically in smooth muscle cells displa...

We have reported that sulforaphane (SFN) prevented diabetic cardiomyopathy in both type 1 and type 2 diabetes (T2DM) animal models via the upregulation of nuclear transcription factor erythroid 2–related factor 2 (Nrf2) and metallothionein (MT). In this study, we tested whether SFN protects the heart from T2DM directly through Nrf2, MT, or both. Using Nrf2-knockout (KO), MT-KO, and wild-type (WT) mice, T2DM was induced by feeding a high-fat diet for 3 months followed by a small dose of streptozotocin. Age-matched controls were given a normal diet. Both T2DM and control mice were then treated with or without SFN for 4 months by continually feeding a high-fat or normal diet. SFN prevented diabetes-induced cardiac dysfunction as well as diabetes-associated cardiac oxidative damage, inflammation, fibrosis, and hypertrophy, with increases in Nrf2 and MT expressions in the WT mice. Both Nrf2-KO and MT-KO diabetic mice exhibited greater cardiac damage than WT diabetic mice. SFN did not provide cardiac protection in Nrf2-KO mice, but partially or completely protected the heart from diabetes in MT-KO mice. SFN did not induce MT expression in Nrf2-KO mice, but stimulated Nrf2 function in MT-KO mice. These results suggest that Nrf2 plays the indispensable role for SFN cardiac protection from T2DM with significant induction of MT and other antioxidants. MT expression induced by SFN is Nrf2 dependent, but is not indispensable for SFN-induced cardiac protection from T2DM.

Farnesoid X receptor (FXR) (nuclear receptor subfamily 1, group H, member 4) is a member of nuclear hormone receptor superfamily, which plays essential roles in metabolism of bile acids, lipid, and glucose. We previously showed spontaneously hepatocarcinogenesis in aged FXR(-/-) mice, but its relevance to human hepatocellular carcinoma (HCC) is unclear. Here, we report a systematical analysis of hepatocarcinogenesis in FXR(-/-) mice and FXR expression in human liver cancer. In this study, liver tissues obtained from FXR(-/-) and wild-type mice at different ages were compared by microarray gene profiling, histological staining, chemical analysis, and quantitative real-time PCR. Primary hepatic stellate cells and primary hepatocytes isolated from FXR(-/-) and wild-type mice were also analyzed and compared. The results showed that the altered genes in FXR(-/-) livers were mainly related to metabolism, inflammation, and fibrosis, which suggest that hepatocarcinogenesis in FXR(-/-) mice recapitulated the progression of human liver cancer. Indeed, FXR expression in human HCC was down-regulated compared with normal liver tissues. Furthermore, the proinflammatory cytokines, which were up-regulated in human HCC microenvironment, decreased FXR expression by inhibiting the transactivity of hepatic nuclear factor 1α on FXR gene promoter. Our study thereby demonstrates that the down-regulation of FXR has an important role in human hepatocarcinogenesis and FXR(-/-) mice provide a unique animal model for HCC study.