Search

Oxygen-affected cracking commonly presents on thin Ni-based single crystal superalloy components serving in high temperature and oxidizing environments. This study uses a newly developed in-situ thermal-stress environmental transmission electron microscope to investigate the oxidation and fracture behaviors of Ni-based single crystal superalloy at 650°C under stress. The in-situ oxidation was found to change the tensile fracture mode from the close-packed {111} planes of plastic fracture to $ \{001\} $ planes adjacent to γ/γ′ interfaces of brittle fracture. The microanalysis also revealed that the γ′ cuboids, γ phase, and γ/γ interface exhibit different oxidation behavior, thus underscoring the thickness debit effect.

Although accelerated cellular senescence is closely related to the progression of chronic kidney disease (CKD) and renal fibrosis, the underlying mechanisms remain largely unknown. Here, we reported that tubular aberrant expression of Brahma-related gene 1 (BRG1), an enzymatic subunit of the SWItch/Sucrose Non-Fermentable complex, is critically involved in tubular senescence and renal fibrosis. BRG1 was significantly up-regulated in the kidneys, predominantly in tubular epithelial cells, of both CKD patients and unilateral ureteral obstruction (UUO) mice. In vivo, shRNA-mediated knockdown of BRG1 significantly ameliorated renal fibrosis, improved tubular senescence, and inhibited UUO-induced activation of Wnt/β-catenin pathway. In mouse renal tubular epithelial cells (mTECs) and primary renal tubular cells, inhibition of BRG1 diminished transforming growth factor-β1 (TGF-β1)-induced cellular senescence and fibrotic responses. Correspondingly, ectopic expression of BRG1 in mTECs or normal kidneys increased p16INK4a, p19ARF, and p21 expression and senescence-associated β-galactosidase (SA-β-gal) activity, indicating accelerated tubular senescence. Additionally, BRG1-mediated pro-fibrotic responses were largely abolished by small interfering RNA (siRNA)-mediated p16INK4a silencing in vitro or continuous senolytic treatment with ABT-263 in vivo. Moreover, BRG1 activated the Wnt/β-catenin pathway, which further inhibited autophagy. Pharmacologic inhibition of the Wnt/β-catenin pathway (ICG-001) or rapamycin (RAPA)-mediated activation of autophagy effectively blocked BRG1-induced tubular senescence and fibrotic responses, while bafilomycin A1 (Baf A1)-mediated inhibition of autophagy abolished the effects of ICG-001. Further, BRG1 altered the secretome of senescent tubular cells, which promoted proliferation and activation of fibroblasts. Taken together, our results indicate that BRG1 induces tubular senescence by inhibiting autophagy via the Wnt/β-catenin pathway, which ultimately contributes to the development of renal fibrosis.

Podocyte injury is the primary cause of glomerular injury in diabetic nephropathy (DN). Advanced oxidation protein products (AOPPs), the triggers and markers of oxidative stress in DN, have been linked to podocyte damage. However, the underlying mechanism is not yet clear. Here, we investigated the potential role of FOXO3a, a key transcription factor in the response to stress, in mediating AOPPs-induced podocyte injury. We found that FOXO3a expression was increased in the glomeruli of kidney biopsies from patients with DN and it was positively correlated with proteinuria. The serum from patients with DN significantly increased FOXO3a and its downstream genes FasL and Bim, thereby inducing the high level of cleaved caspase3 and the loss of nephrin and podocin expressions in podocytes. Blockade of AOPPs signaling by a neutralizing antibody against the receptor of advanced glycation end products (αRAGE) abolished the effect of DN serum on podocytes, confirming the pathogenic role of AOPPs in DN serum. Downregulation of FOXO3a decreased AOPPs-induced podocyte apoptosis and restored the levels of podocyte markers nephrin and podocin, and upregulation of FOXO3a exacerbated these changes in podocytes after AOPPs treatment. Furthermore, FOXO3a specifically activated proapoptotic genes in podocytes only in the presence of AOPPs. Mechanistically, AOPPs increased the FOXO3a protein levels by inhibiting their autophagic degradation in a ROS/mTOR-dependent manner. Moreover AOPPs activated the accumulated FOXO3a by maintaining FOXO3a in the nucleus, and this process was dependent on ROS-mediated AKT signaling deactivation. These studies suggest that FOXO3a plays a critical role in mediating AOPPs-induced podocyte injury and reveal a new mechanistic linkage of oxidative stress, FOXO3a activation and podocyte injury in DN.

Peritoneal fibrosis is a common complication of long-term peritoneal dialysis (PD) and the principal cause of ultrafiltration failure during PD. The initial and reversible step in PD-associated peritoneal fibrosis is the epithelial-mesenchymal transition (EMT). Although the mechanisms in the EMT have been the focus of many studies, only limited information is currently available concerning microRNA (miRNA) regulation in peritoneal fibrosis. In this study, we aimed to characterize the roles of microRNA-145 (miR-145) and fibroblast growth factor 10 (FGF10) in peritoneal fibrosis. After inducing EMT with transforming growth factor-β1 (TGF-β1) in vitro, we found that miR-145 is significantly up-regulated, whereas FGF10 is markedly down-regulated, suggesting a close link between miR-145 and FGF10 in peritoneal fibrosis, further confirmed in luciferase reporter experiments. Furthermore, in human peritoneal mesothelial cells (i.e. HMrSV5 cells), miR-145 mimics induced EMT, whereas miR-145 inhibition suppressed EMT, and we also observed that miR-145 suppressed FGF10 expression. In vivo, we found that the exogenous delivery of an miR-145 expression plasmid both blocked FGF10 and intensified the EMT, whereas miR-145 inhibition promoted the expression of FGF10 and reversed the EMT. In conclusion, miR-145 promotes the EMT during the development of peritoneal fibrosis by suppressing FGF10 activity, suggesting that miR-145 represents a potential therapeutic target for managing peritoneal fibrosis.

Micheliolide (MCL), derived from parthenolide (PTL), is known for its antioxidant and anti-inflammatory effects and has multiple roles in inflammatory diseases and tumours. To investigate its effect on renal disease, we intragastrically administrated DMAMCL, a dimethylamino Michael adduct of MCL for in vivo use, in two renal fibrosis models–the unilateral ureteral occlusion (UUO) model and an ischaemia-reperfusion injury (IRI) model and used MCL in combination with transforming growth factor beta 1 (TGF-β1) on mouse tubular epithelial cells (mTEC) in vitro. The expression of fibrotic markers (fibronectin and α-SMA) was remarkably reduced, while the expression of the epithelial marker E-cadherin was restored after DMAMCL treatment both in the UUO and IRI mice. MCL function in TGF-β1-induced epithelial-mesenchymal transition (EMT) in mTEC was consistent with the in vivo results. Metadherin (Mtdh) was activated in the fibrotic condition, suggesting that it might be involved in fibrogenesis. Interestingly, we found that while Mtdh was upregulated in the fibrotic condition, DMAMCL/MCL could suppress its expression. The overexpression of Mtdh exerted a pro-fibrotic effect by modulating the BMP/MAPK pathway in mTECs, and MCL could specifically reverse this effect. In conclusion, DMAMCL/MCL treatment represents a novel and effective therapy for renal fibrosis by suppressing the Mtdh/BMP/MAPK pathway., Micheliolide (MCL) is known for its antioxidant and anti-inflammatory effects and has multiple effects in inflammatory diseases and tumors. The authors studied the effects of an MCL derivative in two renal fibrosis models. They found that the metastasis adhesion protein metadherin (Mtdh) was activated under fibrotic conditions and that MCL suppressed its expression via the BMP/MAPK pathway.

Peritoneal fibrosis (PF) is a major cause of ultrafiltration failure in patients receiving long-term peritoneal dialysis (PD), and effective prevention and treatment strategies are urgently needed. The dimethylamino Michael adduct of a natural product-derived micheliolide (MCL), dimethylaminomicheliolide (DMAMCL), is a new lead compound with the advantages of high stability, low toxicity, and sustainable release of MCL. This study aimed to investigate the protective effect of DMAMCL against PD-related PF and the mechanisms involved. In this study, we found that DMAMCL significantly decreased PD-induced extracellular matrix (ECM) deposition in a mouse model of PD, and that delayed DMAMCL administration halted the progression of PF in an established PD model. In addition, rapamycin administration induced autophagy and significantly ameliorated PF. The protective effect of DMAMCL against PF was weakened when co-administered with DMAMCL and 3-methyladenine. Inducing autophagy by rapamycin decreased transforming growth factor-β1-induced ECM accumulation in vitro. MCL promoted autophagy and inhibited ECM deposition. The anti-fibrotic effect of MCL was eliminated when knocking down ATG7 by siRNA. Taken together, DMAMCL might prevent against PF through activating autophagy. The anti-fibrotic effect of DMAMCL may be a new candidate for the treatment in patients with PD-related PF. KEY MESSAGES: Dimethylaminomicheliolide, the pro-drug of micheliolide, protects against peritoneal fibrosis in a mouse peritoneal dialysis model. Micheliolide inhibits TGF-β1-induced extracellular matrix accumulation in vitro. Autophagy plays a protective role against peritoneal fibrosis. The antifibrogenic effect of dimethylaminomicheliolide may be due to the activation of autophagy.

Topologically close-packed (TCP) phases in Ni-based single crystal superalloys are known to exhibit different morphologies and orientation relationships within the matrix. This study investigated the influence of chemical composition on lattice parameters, which in turn determine the interface lattice misfit between TCP phase and matrix and thus shape and orientation of the TCP phase. In this study, TCP phase particles of different morphologies were formed by ageing at different temperatures. The level of TCP-phase element enrichment was found to increase with increasing growth time and ageing temperature, and thus leads to a same evolution behavior of the atomic volume.

Diabetic nephropathy (DN), a vascular complication of diabetes, is the leading cause of death in patients with diabetes. The contribution of aberrantly expressed circular RNAs (circRNAs) to DN in vivo is poorly understood. Integrated comparative circRNA microarray profiling was used to examine the expression of circRNAs in diabetic kidney of db/db mice. We found that circRNA_010383 expression was markedly downregulated in diabetic kidneys, mesangial cells, and tubular epithelial cells cultured in high-glucose conditions. circRNA_010383 colocalized with miRNA-135a (miR-135a) and inhibited miR-135a function by directly binding to miR-135a. In vitro, the knockdown of circRNA_010383 promoted the accumulation of extracellular matrix (ECM) proteins and downregulated the expression of transient receptor potential cation channel, subfamily C, member 1 (TRPC1), which is a target protein of miR-135a. Furthermore, circRNA_010383 overexpression effectively inhibited the high-glucose–induced accumulation of ECM and increased TRPC1 levels in vitro. More importantly, the kidney target of circRNA_010383 overexpression inhibited proteinuria and renal fibrosis in db/db mice. Mechanistically, we identified that a loss of circRNA_010383 promoted proteinuria and renal fibrosis in DN by acting as a sponge for miR-135a. This study reveals that circRNA_010383 may be a novel therapeutic target for DN in the future.

Chronic kidney disease is a common disease closely related to renal tubular inflammation and oxidative stress, and no effective treatment is available. Activation of the nucleotide-binding oligomerization domain-like receptor protein 3 (NLRP3) inflammasome is an important factor in renal inflammation, but the mechanism remains unclear. Micheliolide (MCL), which is derived from parthenolide, is a new compound with antioxidative and anti-inflammatory effects and has multiple roles in tumors and inflammatory diseases. In this study, we investigated the effect of MCL on lipopolysaccharide- (LPS-) induced inflammation in renal tubular cells and the related mechanism. We found that MCL significantly suppressed the LPS-induced NF-κB signaling and inflammatory expression of cytokines, such as tumor necrosis factor-α and monocyte chemoattractant protein-1 in a rat renal proximal tubular cell line (NRK-52E). MCL also prevented LPS- and adenosine triphosphate-induced NLRP3 inflammasome activation in vitro, as evidenced by the inhibition of NLRP3 expression, caspase-1 cleavage, and interleukin-1β and interleukin-18 maturation and secretion. Additionally, MCL inhibited the reduction of mitochondrial membrane potential and decreases the release of reactive oxygen species (ROS). Moreover, MCL can prevent NLRP3 inflammasome activation induced by rotenone, a well-known mitochondrial ROS (mROS) agonist, indicating that the mechanism of MCL’s anti-inflammatory effect may be closely related to the mROS. In conclusion, our study indicates that MCL can inhibit LPS-induced renal inflammation through suppressing the mROS/NF-κB/NLRP3 axis in tubular epithelial cells.

The anti-inflammatory, immunomodulatory, and anticancer effects of micheliolide (MCL) isolated from Michelia champaca were previously reported, but its role and underlying mechanisms in relieving liver steatosis remain unclear. Herein, we investigated the effects of MCL on hepatic steatosis using a db/db mouse model and lipid mixture (LM)-induced AML12 and LO2 cells. The body and liver weights, food consumption, lipid content and liver aminotransferase levels in serum, the lipid content and inflammatory cytokine levels in liver tissue, and the extent of hepatic steatosis in db/db mice were increased compared with those in db/m mice, and these increases were reversed by MCL treatment. Similarly, MCL also attenuated the inflammatory responses and lipid accumulation in LM-treated AML12 and L02 cells by upregulating PPAR-γ and decreasing p-IкBα and p-NF-κB/p65, thereby inhibiting the NF-κB pathway and reducing lipotoxicity. Furthermore, MCL administration increased LC3B, Atg7 and Beclin-1 expression and the LC3B-II/I ratio in db/db mouse livers and LM-treated AML12 and L02 cells, and these MCL-induced increases were mediated by the activation of PPAR-γ and p-AMPK and inhibition of p-mTOR and induce autophagy. These effects were blocked by PPAR-γ and AMPK inhibitors. Our findings suggest that MCL ameliorates liver steatosis by upregulating PPAR-γ expression, thereby inhibiting NF-κB-mediated inflammation and activating AMPK/mTOR-dependent autophagy.

Metabolic reprogramming of cancer cells is essential for tumorigenesis in which pyruvate kinase M2 (PKM2), the low activity isoform of pyruvate kinase, plays a critical role. Herein, we describe the identification of a nature-product-derived micheliolide (MCL) that selectively activates PKM2 through the covalent binding at residue cysteine424 (C424), which is not contained in PKM1. This interaction promotes more tetramer formation, inhibits the lysine433 (K433) acetylation, and influences the translocation of PKM2 into the nucleus. In addition, the pro-drug dimethylaminomicheliolide (DMAMCL) with similar properties as MCL significantly suppresses the growth of leukemia cells and tumorigenesis in a zebrafish xenograft model. Cell-based assay with knock down PKM2 expression verifies that the effects of MCL are dependent on PKM2 expression. DMAMCL is currently in clinical trials in Australia. Our discovery may provide a valuable pharmacological mechanism for clinical treatment and benefit the development of new anticancer agents.

Selective oxidation is one of the most important oxidation phenomena in multi-phase or multi-component alloys. Complex multi-layered oxides with randomly distributed pores beneath the outer oxide deeply and comprehensively hamper conventional studies. Multi-dimensional structures and elemental distributions are reconstructed on the initial oxidation of typical second- and third-generation Ni-based single crystal superalloys by electron tomography. The initial oxidation of the second-generation alloy has a two-layered structure with an outer Ni-rich oxide layer and an inner Al-rich oxide layer. The γ phase in the third-generation alloy is easily oxidized to form a rough surface with extruded oxide particles.

Understanding the high-temperature initial oxidation mechanism and its dynamic processes is generally important because a small amount of initial oxidation can induce rapid corrosion and cause catastrophic failure. We reveal the mechanism of initial oxidation in a third-generation Ni-based superalloy by in situ visualizations and investigations of the nano- and atomic-scale dynamic processes from room temperature to 900 °C with a Cs-corrected environmental transmission electron microscope. The initial oxidation starts from the γ/γ′ interface at low temperatures. The high-temperature oxidation process with deficient oxygen prefers oxidation sites at the cross-junctions of the γ/γ′ interfaces. The growth rate of the oxide nanoparticles depends on the oxidation temperatures, with a low rate below 600 °C and a rapid-growth speed at temperatures higher than 700 °C. Mass transfer from the γ′ and γ phases to the γ/γ′ interface, particularly at the cross-junctions of these interfaces, is observed to cause oxide accumulation. This study provides a direct observation of the interphase, interface-junction-initiated outward oxidization including Al and Cr elements. These results shed light on the initial oxidation mechanisms of materials containing a second phase with interphase interfaces and the materials at deficient oxygen conditions as well as those with protection coating layers.

A novel kind of 3D interconnected porous carbon-bonded B4C preform with flexural strength of about 20MPa is fabricated by gel-casting method. As the control, the B4C/C preforms via molding-produced method are fabricated. The B4C/C preforms own the same carbon content and almost the same porosity with different molding method. Compared with the conventional compression molding-produced B4C/C preform, the 3D-interconnected porous carbon-bonded boron carbide preforms afford three-fold advantages in the fabrication of reaction-bonded boron carbide (RBBC) composite via the liquid silicon infiltration (LSI) process, including induced formation of continuous SiC-bonded boron carbide skeleton structure, a reduction in the size of residual silicon, and prevented the coarsening of ceramic grains as well. As a result, the RBBC composite fabricated by gel-casting appears as a more refined structure resulting in enhanced mechanical properties: the Vickers hardness, flexural strength, and fracture toughness of I-GC composites fabricated from 3D-interconnected porous carbon/B4C preforms are 19.4 ± 1.3 GPa, 389 ± 17 MPa, and 4.37 ± 0.1 MPa·m1/2, respectively, which are statistically higher than those of RBBC fabricated by the conventional compression molding-produced B4C/C preform.

M23C6 carbide is a common precipitate phase present in Ni-based superalloys. The carbide is generally an alloy carbine and often contains more than one metallic element. In this study, the site preference of metallic elements in M23C6 carbide in a Ni-based single crystal was determined by means of aberration-corrected High-Angle Annular Dark Field Scanning Transmission Electron Microscopy (HAADF-STEM) technique and quantitative STEM (QSTEM)-based image simulation method. The carbide was found to contain mostly Cr and Re, with a small amount of Mo. The HAADF-STEM and QSTEM-based simulation analyses indicate that heavy atoms prefer to substitute Cr at 8c sites. Keywords: Ni-based superalloy, Creep, Carbides, Rhenium, Aberration-corrected HAADF-STEM

The precipitation of the lamellar-shaped M23C6 carbide within the dendritic matrix of a cobalt-base superalloy during thermal exposure at 1000 °C has been investigated. Such a precipitation is not commonly observed in cobalt-base superalloys. It is found that M23C6 particles nucleate preferentially at stacking faults (SFs) in the dendritic matrix and grow along the SFs to develop a lamellar character. Additionally, a Cr depletion zone is observed in the vicinity of the lamellar M23C6 carbide, which strongly supports the presence of Suzuki segregation.

In this work, two components of poly(ethylene glycol) (PEG) are used as dual-templates for facile and cost-effective preparation of hierarchically mesoporous silica monoliths (HMSMs) with controllable mesostructures and co-continuous macrostructures from low-toxicity tetraethoxysilane. The influence of different preparative parameters on the porous structures was studied, including the proportions of PEGs and acidity. The typical HMSM (PEG-1.5/0.5) with skeleton mesopore size of 6.3 nm, skeleton thickness of 1.25 μm and macropores of 1.87 μm can be obtained. The total pore volume and high surface area reach 711 m2 g− 1 and 3.37 cm3 g− 1 (including mesopore volume of 0.93 cm3 g− 1), respectively. The PEG400 and PEG35k are proved to play cooperative roles as dual-templates in harnessing the mesoporous skeletons and co-continuous macrostructures. Interestingly, in such preparation system, the use of PEG400 is found to be play key role in inducing the formation of skeletons with relatively large mesopores, while the amount of PEG35k is a more sensitive factor in shaping the macroporous structures. This work is believed to open a new path to engineering the macroporous and mesoporous structures via the TEOS/PEG/HCl(aq.) synthesis system.

The resorcinol-formaldehyde (RF) gel-casting system is employed for the first time to fabricate a hierarchical porous B4C/C preform, which was subsequently used for the fabrication of reaction bonded boron carbide (RBBC) composites via a liquid silicon infiltration process. The effect of the carbon content and carbon structures of this perform on the microstructures and mechanical properties of B4C/C preform and the resultant RBBC composites is reported. The B4C/C preform (16 wt% carbon) exhibit a strength of 34±1 MPa. The obtained RBBC composites shown uniform microstructure is consisted of SiC particles bonded boron carbide scaffold and an interpenetrating residual silicon phase. The Vickers hardness, flexural strength and fracture toughness of the RBBC composites (16 wt% carbon) are 24 GPa, 452 MPa and 4.32 MPa m1/2, respectively.

Irbesartan (Irb), a unique subset of angiotensin II receptor blockers (ARBs) with PPAR-γ activation function, has been reported to play a role in renal dysfunction, glucose metabolism, and abnormal lipid profile in diabetic animal models and humans. However, the underlying mechanisms that improve hyperlipidemia and liver steatosis are unclear. This study investigated the effects of Irb on lipid metabolism and hepatic steatosis using the spontaneous type 2 diabetic db/db mouse model. The results demonstrated body and liver weight, food consumption, lipid content in serum and liver tissue, and liver dysfunction as well as hepatic steatosis were increased in db/db mice compared with db/m mice, whereas the increases were reversed by Irb treatment. Moreover, Irb administration resulted in an increase in LC3BII as well as the LC3BII/I ratio through activating PPAR-γ and p-AMPK and inhibiting p-Akt and p-mTOR, thereby inducing autophagy in the db/db mouse liver. Therefore, our findings suggest that Irb can ameliorate hyperlipidemia and liver steatosis by upregulating the expression of PPAR-γ, activating the AMPK/Akt/mTOR signaling pathway and inducing liver autophagy.

Transforming growth factor (TGF)-β/Smad signalling plays a central role in the pathogenesis of peritoneal fibrosis related to peritoneal dialysis (PD). Parthenolide (PTL), a naturally occurring phytochemical, is isolated from the shoots of feverfew (Tanacetum parthenium) and displays analgesia, anti-inflammation and anticancer activities. In this study, we examined the therapeutic potential of PTL on PD-related peritoneal fibrosis induced by daily intraperitoneal injection of 4.25% dextrose-containing PD fluid (PDF) in vivo and TGF-β1-induced epithelial-mesenchymal transition (EMT) in vitro. PTL was administered daily before PDF injection or after 14 days of PDF injection. Both PTL treatments showed a protective effect on peritoneal fibrosis and prevented peritoneal dysfunction. Similarly, PTL suppressed the expression of fibrotic markers (fibronectin and collagen I) and restored the expression of the epithelial marker (E-cadherin) in TGF-β1-treated HMrSV5 cells. Furthermore, PTL inhibited TGF-β1-induced Smad2 and Smad3 phosphorylation and nuclear translocation but did not influence Smad1/5/9 phosphorylation or activate other downstream signalling pathways of TGF-β1, including AKT, extracellular signal-regulated kinase (ERK) or p38. In conclusion, PTL treatment may represent an effective and novel therapy for PD-associated peritoneal fibrosis by suppressing the TGF-β/Smad pathway.

Spallation of thermal oxidation-induced cavities is the main failure mode in CoAl-based alloys, and the γ/γ′ phase structure in Co–Al–W–Ti–Ta alloys has a propensity to form oxide cavities. Multidimensional investigations were carried out herein on irregular oxide cavities by analytical microscopy, including electron tomography and energy dispersive X-ray spectroscopy techniques, to disclose the time-resolved three-dimensional morphological structure and elemental distributions. The alloy nanotip was exposed isothermally in air at 350 °C, and its oxidation evolution was characterized and analysed. The size and quantities of cavities in the γ phase were larger than those in the γ′ phase, which was attributed to the higher content of cobalt in the γ phase than in the γ′ phase. Different migration rates between cobalt outward and aluminium inward prompted the formation of cavities between the outer and inner layers.

This work demonstrated that mesoporous TiO2 (meso-TiO2) with controllable mesoporous and crystalline structures can be facilely prepared by using poly (ethylene glycol) (PEG) as structure-directing (SD) agent and peroxotitanic acid (PTA) as precursor. Meso-TiO2 with high specific surface area (157 m2∙g-1), pore volume (0.45 cm3∙g-1) and large mesopore size of 13.9 nm can be obtained after calcination at 450°C. Such meso-TiO2 also shows relatively high thermal stability. BET surface area still reaches 114 m2∙g-1 after calcination at 550°C. In the synthesis and calcination process, PEG that plays multiple and important roles in delivering thermally stable and tunable mesoporous and crystalline structures shows to be a suitable low-cost SD agent for the controllable preparation of nanocrystalline meso-TiO2. The photocatalytic activity tests show that both high surface area and bi-crystallinity of obtained meso-TiO2 are important in enhancing the performance in photo-decomposing Rhodamine B in water.

Based on the synthesis of hydroxyapatite (HA) with different morphologies, such as nanorod-like, flower-like and sphere-like assembled HA nanorods, a new strategy has been developed for the removal of heavy metal ions such as Pb2+, Cu2+, Mn2+, Zn2+. The dependence of removal efficiency on the morphology and the suspended concentration of trapping agent, the removal time and selectivity were evaluated and discussed. The experimental results proved that the removal capacity of flower-like assembled HA nanorods (NAFL-HA) was the best, and the maximum removal ratio for Pb2+ ion was 99.97%. The mechanism of Pb2+ removal was studied in detail, noting that some metal ions were completely incorporated into hydroxyapatitie to produce Pb-HA. It reveals that the metal ions capture by HA is mainly controlled by sample surface adsorption and co-precipitation, which are directly controlled by sample morphology.

Hypochlorite-modified albumin (HOCl-alb) has been linked to endothelial dysfunction, which plays an important role in the development of hypertension, diabetes, and chronic kidney disease. However, whether HOCl-alb induces endothelial dysfunctionviavascular inflammation and whether a signaling pathway is involved are unknown and have not been investigated. HOCl-alb was found to upregulate ICAM-1 expression in human umbilical vein endothelial cells (HUVECs) in a time- and dose-dependent manner. HOCl-alb time-dependently phosphorylated ERK1/2 andp38MAPK. HOCl-alb also activated NF-κB. ICAM-1 expression was dose-dependently inhibited by U0126 (a specific inhibitor of MEK1/2, a signal upstream from ERK1/2), SB203580 (a specific inhibitor ofp38MAPK), and SN50 (a specific inhibitor of NF-κB). U0126 and SB203580 both counteracted the activation of NF-κB, whereas the phosphorylation of ERK1/2 andp38MAPKwas not blocked by SN50. ERK1/2 phosphorylation was blocked by U0126 but not by SB203580, andp38MAPKactivity was reduced by SB203580 but not by U0126. Apocynin, a specific NADPH oxidase (NOX) inhibitor, inhibited ICAM-1 expression and the activity of ERK1/2,p38MAPK, and NF-κB. These results indicate that HOCl-alb-induced ICAM-1 expression is caused by the activation of a redox-sensitive intracellular signal cascade involving ERK1/2 andp38MAPK, culminating in the activation of NF-κB and involving NOXs among the upstream signals.

Mesoporous titania (meso-TiO2) has received extensive attention owing to its versatile potential applications. This paper reports a low-temperature templating approach for the fabrication of meso-TiO2 using the peroxo titanic acid (PTA) sol as precursor and Pluronic P123 as nonionic template. The TGA, XRD, N2 sorption, FE-SEM and HRTEM were used to characterize the obtained samples. The results showed that meso-TiO2 with high surface area up to 163 m2·g–1 and large pore volume of 0.65 cm3·g–1 can be obtained. The mesopore sizes can be varied between 13 and 20 nm via this synthesis approach. The amount of P123 and the calcination conditions were found to have great influence on the mesoporous and crystalline structures of meso-TiO2. The photocatalytic activity testing clearly shows that the high surface area and bi-crystallinity phases of meso-TiO2 play important roles in enhancing photocatalytic properties of meso-TiO2 in photo-decomposing Rhodamine B in water.

Modern in situ oxidation processes can be observed down to the nanoscale using environmental transmission electron microscope (TEM), and this technology has been applied to conventional corrosion science to provide more detailed intrinsic information on the oxidation properties of materials. The influence of chromium (0–10 at.%) addition on the microstructure and oxidation properties of a γ/γ′ two-phase Co82Al9W9-based superalloy was systematically investigated. The in situ oxidation behaviour of Cr-containing alloys was studied using environmental TEM, and the addition of moderate Cr amounts is suggested for the alloy design.

Inflammation is a relevant factor in the pathogenesis of diabetes nephropathy (DN). Sesquiterpene lactones (SLs), originally isolated fromTanacetum parthenium, have been reported to exhibit anti-inflammatory effects but few studies have examined their effects on DN. To determine whether advanced oxidation protein products (AOPPs) can induce the expression of chemokine monocyte chemoattractant protein- (MCP-) 1 in cultured mouse podocytes and to explore the mechanisms of the potential renoprotection of SLs, we treated podocytes with AOPPs and SLs (parthenolide and its derivatives micheliolide, compound 1, and compound 2). MCP-1 mRNA and protein expression were tested using quantitative real-time PCR and ELISA, respectively, and the protein levels of IKKβ, phospho-IKKβ, IκBα, NF-κB p65, phospho-NF-κB p65, and tubulin were analyzed by Western blotting. AOPPs activated the expression of MCP-1 mRNA and protein in a dose- and time-dependent manner, activated IKKβand NF-κB p65, and promoted IκBαdegradation. The IKK/NF-κB inhibitor parthenolide decreased AOPP-induced MCP-1 expression. Pretreatment with SLs inhibited MCP-1 mRNA and protein expression and suppressed IKKβand NF-κB p65 phosphorylation and IκBαdegradation. Taken together, these findings provide a novel explanation for the anti-inflammatory effects of SLs that will ultimately benefit DN and potentially other inflammatory and immune renal diseases.

Glyphosate-resistant (GR) transgenic soybean has never been cultivated commercially in China. It is essential to develop the separation measures required to prevent out-crossing between GR and conventional soybean (Glycine max (L.) Merr.) by characterizing the transgene flow before GR soybean is released. In this study, the transgene flow from a GR transgenic soybean AG5601 to conventional soybeans was characterized. First, natural out-crossing rate was evaluated using 36 conventional soybean varieties interplanted with GR soybean AG5601 transformed with a cp4 EPSPS gene conferring the resistance to herbicide glyphosate in the field in 2007 and 2008 in China. Second, drift distance of cp4 EPSPS gene from GR soybean AG5601 to soybean cv. Zhonghuang13 was evaluated using the progenies harvested from eight directions at different distance. Third, the relationship of gene flow of GR soybean AG5601 with flowering synchronization days or insect pollinators of each variety was analyzed using regression analysis. Thirty-two of 36 tested conventional soybean varieties had surviving progenies after two times of sprays of glyphosate, and 49 of 41,679 progenies were verified to be glyphosate-tolerant heterozygous offspring. The out-crossing rates in positive varieties (having surviving offspring after two times of sprays of glyphosate) ranged from 0.039 to 0.934 %. The farthest distance (drift distance) between soybean AG5601 and cv. Zhonghuang13 at which out-pollinating was still able to be observed was 15 m, with an out-crossing rate of 0.012 %. Regression analysis showed that there was a positive relationship between cross-pollination frequency and flowering synchronization days or pollinator insects. Therefore, when GR soybean is released to the field, it should be critically separated with the conventional soybean in space and cultivation time with efficient insect control during flowering.

This work for the first time demonstrated that hierarchically meso–mesoporous silicas can be facilely prepared in a simple ternary non-ionic surfactant templating system (TEOS/HCl(aq.)/P123) based on a previously reported partitioned cooperative self-assembly (PCSA) principle. As a result, unique clew-like hierarchically meso–mesoporous (HMM) silica particles with the first mode of worm-like mesostructures (3D-interconnected wormholes with pore size of 7–10 nm) and the second mode of 3D-interconnected intra-particulate mesochannels (16–32 nm in sizes) can be obtained in a controllable way without resorting to complicated synthesis procedures or special additives or multi-templates. Associated with the large mesopore sizes in both modes, very large mesoporosity (up to 2.37 cm3 g−1) can be achieved. Based on systematic investigations on the synthesis conditions, synthesis domains for preparation of such HMM silicas were also presented. It is proposed that the formation of two mode mesoporosities follows different mechanisms: the first mode mesoporosity results from the self-assembly between P123 and silicate, though it is shown to be disordered due to the partitioning effect, while the formation of the second mode mesoporosity starts from loosely packed silicate/P123 hybrid aggregates/flocs formed upon the 1st addition of TEOS, and then is initiated and finished by the 2nd TEOS addition. This synthesis protocol therefore constitutes a new, simple and reliable pathway to prepare HMM silicas.

Background: Monocyte chemoattractant protein-1 (MCP-1) plays an important role in extracellular matrix accumulation through macrophage recruitment and activation in the development and progression of diabetic nephropathy. Therefore, this study examined whether advanced oxidation protein products (AOPPs) are involved in nuclear factor-κB (NF-κB) activation and MCP-1 mRNA and protein expression in mesangial cells (MCs) and evaluated the effects of derivatives of sesquiterpene lactones (SLs) on AOPP-induced renal damage. Methods: MCP-1 mRNA and protein expression in MCs were determined by quantitative real-time PCR and ELISA, respectively. The level of intracellular reactive oxygen species (ROS) was determined by flow cytometry. The protein expression of tubulin, P47, NF-κB p65, phospho-NF-κB p65, IκB, phospho-IκB, IKKß and phospho-IKKß was evaluated by Western blot. Results: AOPPs caused oxidative stress in MCs and activated the NF-κB pathway by inducing IκBa phosphorylation and degradation. Inhibition of ROS by SOD (ROS inhibitor) blocked the AOPP-mediated NF-κB pathway. Moreover, the inhibition of AOPP-induced overproduction of MCP-1 mRNA and protein was associated with inhibition of IκBa degradation by SLs. Conclusion: AOPPs induce MCP-1 expression by activating the ROS/NF-κB pathway and can be inhibited by SLs. These findings may provide a novel approach to treat inflammatory and immune renal diseases, including diabetic nephropathy.

Diabetic nephropathy (DN) is one of the most common and serious chronic complications of diabetes mellitus, however, no efficient clinical drugs exist for the treatment of DN. We selected and synthesized several sesquiterpene lactones (SLs), and then used the MTT assay to detect rat mesangial cells (MCs) proliferation, ELISA to measure the expression level of monocyte chemoattractant protein-1 (MCP-1), transforming growth factor beta (TGF-β1) and fibronectin(FN), real-time fluorescent quantitative PCR analysis to measure the MCP-1 and TGF-β1 gene expression, western blot to detect the level of IκBα protein and EMSA to measure the activation of nuclear factor kappa B (NF-κB). We discovered that SLs, including parthenolide (PTL), micheliolide (MCL), arglabin, and isoalantolactone (IAL), as well as several synthetic analogs of these molecules, could effectively attenuate the high glucose-stimulated activation of NF-κB, the degradation of IκBα, and the expression of MCP-1, TGF-β1 and FN in rat mesangial cells (MCs). These findings suggest that SLs and their derivatives have potential as candidate drugs for the treatment of DN.

The receptor activator of NF-κB ligand (RANKL) and its receptor RANK are overexpressed in focal segmental glomerular sclerosis (FSGS), IgA nephropathy (IgAN), and membranous nephropathy (MN). However, the expression and the potential roles of RANKL and RANK in diabetic nephropathy (DN) remain unclear. Irbesartan (Irb) has beneficial effects against diabetes-induced renal damage, but its mechanisms are poorly understood. Our present study investigated the effects of Irb in DN and whether the renal protective effects of Irb are mediated by RANKL/RANK and the downstream NF-κB pathway in db/db mice. Our results showed that db/db mice revealed severe metabolic abnormalities, renal dysfunction, podocyte injury, and increased MCP-1; these symptoms were reversed by Irb. At the molecular level, RANKL and RANK were overexpressed in the kidneys of db/db mice and Irb downregulated RANKL and RANK and inhibited the downstream NF-κB pathway. Our study suggests that Irb can ameliorate DN by suppressing the RANKL-RANK-NF-κB pathway.

Apoptosis, one of the major causes of podocyte loss, has been reported to have a vital role in diabetic nephropathy (DN) pathogenesis, and understanding the mechanisms underlying the regulation of podocyte apoptosis is crucial. Metadherin (MTDH) is an important oncogene, which is overexpressed in most cancers and responsible for apoptosis, metastasis, and poor patient survival. Here we show that the expression levels of Mtdh and phosphorylated p38 mitogen-activated protein kinase (MAPK) are significantly increased, whereas those of the microRNA-30 family members (miR-30s) are considerably reduced in the glomeruli of DN rat model and in high glucose (HG)-induced conditionally immortalized mouse podocytes (MPC5). These levels are positively correlated with podocyte apoptosis rate. The inhibition of Mtdh expression, using small interfering RNA, but not Mtdh overexpression, was shown to inhibit HG-induced MPC5 apoptosis and p38 MAPK pathway, and Bax and cleaved caspase 3 expression. This was shown to be similar to the effects of p38 MAPK inhibitor (SB203580). Furthermore, luciferase assay results demonstrated that Mtdh represents the target of miR-30s. Transient transfection experiments, using miR-30 microRNA (miRNA) inhibitors, led to the increase in Mtdh expression and induced the apoptosis of MPC5, whereas the treatment with miR-30 miRNA mimics led to the reduction in Mtdh expression and apoptosis of HG-induced MPC5 cells in comparison with their respective controls. Our results demonstrate that Mtdh is a potent modulator of podocyte apoptosis, and that it represents the target of miR-30 miRNAs, facilitating podocyte apoptosis through the activation of HG-induced p38 MAPK-dependent pathway.

Aims The aim of this research was to investigate the effects of cyclopropanyldehydrocostunolide (also named LJ), a derivative of sesquiterpene lactones (SLs), on high glucose (HG)-induced podocyte injury and the associated molecular mechanisms. Methods Differentiated mouse podocytes were incubated in different treatments. The migration and albumin filtration of podocytes were examined by Transwell filters. The protein and mRNA levels of MCP-1 were measured using enzyme-linked immunosorbent assay (ELISA) and quantitative real-time PCR (q-PCR). Protein expression and phosphorylation were detected by western blot, and the nuclear translocation of NF-κB was performed with a confocal microscope. The gene expression of the receptor activator for NF-κB (RANK) was silenced by small interfering RNA (siRNA). Results Our results showed that HG enhanced migration, albumin filtration and MCP-1 expression in podocytes. At the molecular level, HG promoted the phosphorylation of NF-κB/p65, IKKβ, IκBα, mitogen-activated protein kinase (MAPK) and the nuclear translocation of p65. LJ reversed the effects of HG in a dose-dependent manner. Furthermore, our data provided the first demonstration that the receptor activator for NF-κB ligand (RANKL) and its cognate receptor RANK were overexpressed in HG-induced podocytes and were downregulated by LJ. RANK siRNA also attenuated HG-induced podocyte injury and markedly inhibited the activation of NF-κB and MAPK signaling pathways. Conclusions LJ attenuates HG-induced podocyte injury by suppressing RANKL/RANK-mediated NF-κB and MAPK signaling pathways.

Pectate lyases are known to play a key role in pectin degradation by catalyzing the random cleavage of internal polymer linkages (endo-pectinases). In this paper, four novel cDNAs, designated Hg-pel-3, Hg-pel-4, Hg-pel-6 and Hg-pel-7, that encode pectate lyases were cloned and characterized from the soybean cyst nematode, Heterodera glycines. The predicted protein sequences of HG-PEL-3, HG-PEL-4 and HG-PEL-6 differed significantly in both their amino acid sequences and their genomic structures from other pectate lyases of H. glycines (HG-PEL-1, HG-PEL-2 and HG-PEL-7). A phylogenetic study revealed that the pectate lyase proteins of H. glycines are clustered into distinct clades and have distinct numbers and positioning of introns, which suggests that the pectate lyase genes of H. glycines may have evolved from at least two ancestral genes. A Southern blot analysis revealed that multiple Hg-pel-6-like genes were present in the H. glycines genome. In situ hybridization showed that four novel pectate lyases (Hg-pel-3, Hg-pel-4, Hg-pel-6 and Hg-pel-7) were actively transcribed in the subventral esophageal gland cells. A semi-quantitative RT-PCR assay supported the finding that the expression of these genes was strong in the egg, pre-parasitic second-stage juvenile (J2) and early parasitic J2 stages and that it declined in further developmental stages of the nematode. This expression pattern suggests that these proteins play a role in the migratory phase of the nematode life cycle. Knocking down Hg-pel-6 using in vitro RNA interference resulted in a 46.9% reduction of the number of nematodes that invaded the plants and a 61.5% suppression of the development of H. glycines females within roots compared to the GFP-dsRNA control. Plant host-derived RNAi induced the silencing of the Hg-pel-6gene, which significantly reduced the nematode infection levels at 7 Days post inoculation (dpi). Similarly, this procedure reduced the number of female adults at 40 dpi, which suggests the important roles of this gene in the early stages of parasitism. Our combined data suggest that two types of pectate lyases are present in the H. glycines genome and may have different roles during infection.

Rakicidin A is a cyclic depsipeptide that has exhibited unique growth inhibitory activity against chronic myelogenous leukemia stem cells. Furthermore, rakicidin A has five chiral centers with unknown stereochemical assignment, and thus, can be represented by one of 32 possible stereoisomers. To predict the most probable stereochemistry of rakicidin A, calculations and structural comparison with natural cyclic depsipeptides were applied. A total synthesis of the proposed structure was subsequently completed and highlighted by the creation of a sterically hindered ester bond (C1-C15) through trans-acylation from an easily established isomer (C1-C13). The analytic data of the synthetic target were consistent with that of natural rakicidin A, and then the absolute configuration of rakicidin A was assigned as 2S, 3S, 14S, 15S, 16R. This work suggests strategies for the determination of unknown chiral centers in other cyclic depsipeptides, such as rakicidin B, C, D, BE-43547, and vinylamycin, and facilitates the investigations of rakicidin A as an anticancer stem cell agent.

This work presents a new PEEC-based inductor simulation tool, entitled L-simulator, which employs a magPEEC modeling algorithm and an existing FastCap modeling algorithm to address both magnetic and electrical coupling effects respectively, hence being capable to simulate 3D magnetic-enhanced RF IC inductors of arbitrary geometries. Applications on micromachined inductors in 0.2/spl mu/m GaAs HEMT process and magnetic-cored micro inductors in 0.18/spl mu/m CMOS technology are discussed.