G-protein-coupled estrogen receptor 1 promotes peritoneal metastasis of gastric cancer through nicotinamide adenine dinucleotide kinase 1-mediated redox modulation.

Adipose tissue is the second most important site of estrogen production, where androgens are converted into estrogen by aromatase. While gastric cancer patients often develop adipocyte-rich peritoneal metastasis, the underlying mechanism remains unclear. In this study, we identified the G-protein-coupled estrogen receptor (GPER1) as a promoter of gastric cancer peritoneal metastasis. Functional in vitro studies revealed that ß-Estradiol (E2) or the GPER1 agonist G1 inhibited anoikis in gastric cancer cells. Additionally, genetic overexpression or knockout of GPER1 significantly inhibited or enhanced gastric cancer cell anoikis in vitro and peritoneal metastasis in vivo, respectively. Mechanically, GPER1 knockout disrupted the NADPH pool and increased reactive oxygen species (ROS) generation. Conversely, overexpression of GPER1 had the opposite effects. GPER1 suppressed nicotinamide adenine dinucleotide kinase 1(NADK1) ubiquitination and promoted its phosphorylation, which were responsible for the elevated expression of NADK1 at protein levels and activity, respectively. Moreover, genetic inhibition of NADK1 disrupted NADPH and redox homeostasis, leading to high levels of ROS and significant anoikis, which inhibited lung and peritoneal metastasis in cell-based xenograft models. In summary, our study suggests that inhibiting GPER1-mediated NADK1 activity and its ubiquitination may be a promising therapeutic strategy for peritoneal metastasis of gastric cancer.

Targeting tissue-resident memory CD8+ T cells in the kidney is a potential therapeutic strategy to ameliorate podocyte injury and glomerulosclerosis.

Although tissue-resident-memory T (TRM) cells, a recently identified non-circulating memory T cell population, play a crucial role in mediating local immune responses and protect against pathogens upon local reinfection, the composition, effector function, and specificity of TRM cells in the kidney and their relevance for chronic kidney disease remain unknown. In this study, we found that renal tissue displayed high abundance of tissue-resident lymphocytes, and the proportion of CD8+ TRM cells was significantly increased in the kidney from patients and mice with focal segmental glomerulosclerosis (FSGS), diabetic kidney disease (DKD), and lupus nephritis (LN). Mechanistically, IL-15 significantly promoted CD8+ TRM cell formation and activation, thereby promoting podocyte injury and glomerulosclerosis. Interestingly, Sparsentan, the dual angiotensin II (Ang II) receptor and endothelin type A receptor antagonist, can also reduce TRM cell responses by intervening IL-15 signaling, exploring its new pharmacological functions. Mechanistically, Sparsentan inhibited Ang II or endothelin-1 (ET-1)-mediated IL-15 signaling, thereby further regulating renal CD8+ TRM cell fates. Collectively, our studies provide direct evidence for the pivotal role of renal CD8+ TRM cells in podocyte injury and further strengthen that targeting TRM cells represents a novel therapeutic strategy for patients with glomerular diseases.

Experimental and Theoretical Study of Phosphine-Catalyzed Reaction Modes in the Reaction of α-Substituted Allenes with Aryl Imines.

A new phosphine-catalyzed reaction of α-substituted allenes with aryl imines, in stark contrast to classic cycloaddition reactions, has been developed. This reaction delivers valuable highly functionalized itaconimides with excellent stereoselectivities by a new «un-cyclizing¼ reaction mode involving ß'-carbon of α-substituted allenes. Moreover, the present «un-cyclizing¼ reaction can also be carried out in a one-pot fashion and scaled up to the gram scale by using aryl aldehydes, without the need to isolate the aryl imines. Mechanistic studies and control experiments reveal the crucial role of H2 CO3 for the present reaction mode. In addition, density functional theory (DFT) calculations were performed to understand the possible mechanism.

Kallistatin prevents ovarian hyperstimulation syndrome by regulating vascular leakage.

Angiogenesis and increased permeability are essential pathological basis for the development of ovarian hyperstimulation syndrome (OHSS). Kallistatin (KS) is an endogenous anti-inflammatory and anti-angiogenic factor that participates in a variety of diseases, but its role in OHSS remains unknown. In this study, treating a human ovarian granulosa-like tumour cell line KGN and human primary granulosa cells (PGCs) with human chorionic gonadotropin (hCG) reduced the expression of KS, but increased the expression of VEGF. Furthermore, we found that KS could attenuate the protein level of VEGF in both KGN cells and human PGCs. More interestingly, we observed that exogenous supplementation of KS significantly inhibited a series of signs of OHSS in mice, including weight gain, ovarian enlargement, increased vascular permeability and up-regulation of VEGF expression. In addition, KS was proved to be safe on mice ovulation, progression of normal pregnancy and fetus development. Collectively, these findings demonstrated that KS treatment prevented OHSS, at least partially, through down-regulating VEGF expression. For the first time, these results highlight the potential preventive value of KS in OHSS.

Gpr97 Exacerbates AKI by Mediating Sema3A Signaling.

Background G protein-coupled receptors (GPCRs) participate in a variety of physiologic functions, and several GPCRs have critical physiologic and pathophysiologic roles in the regulation of renal function. We investigated the role of Gpr97, a newly identified member of the adhesion GPCR family, in AKI.Methods AKI was induced by ischemia-reperfusion or cisplatin treatment in Gpr97-deficient mice. We assessed renal injury in these models and in patients with acute tubular necrosis by histologic examination, and we conducted microarray analysis and in vitro assays to determine the molecular mechanisms of Gpr97 function.Results Gpr97 was upregulated in the kidneys from mice with AKI and patients with biopsy-proven acute tubular necrosis compared with healthy controls. In AKI models, Gpr97-deficient mice had significantly less renal injury and inflammation than wild-type mice. Gpr97 deficiency also attenuated the AKI-induced expression of semaphorin 3A (Sema3A), a potential early diagnostic biomarker of renal injury. In NRK-52E cells subjected to oxygen-glucose deprivation, siRNA-mediated knockdown of Gpr97 further increased the expression of survivin and phosphorylated STAT3 and reduced toll-like receptor 4 expression. Cotreatment with recombinant murine Sema3A protein counteracted these effects. Finally, additional in vivo and in vitro studies, including electrophoretic mobility shift assays and luciferase reporter assays, showed that Gpr97 deficiency attenuates ischemia-reperfusion-induced expression of the RNA-binding protein human antigen R, which post-transcriptionally regulates Sema3A expression.Conclusions Gpr97 is an important mediator of AKI, and pharmacologic targeting of Gpr97-mediated Sema3A signaling at multiple levels may provide a novel approach for the treatment of AKI.

NLRC5 deficiency protects against acute kidney injury in mice by mediating carcinoembryonic antigen-related cell adhesion molecule 1 signaling.

There is significant progress in understanding the structure and function of NLRC5, a member of the nucleotide oligomerization domain-like receptor family. However, in the context of MHC class I gene expression, the functions of NLRC5 in innate and adaptive immune responses beyond the regulation of MHC class I genes remain controversial and unresolved. In particular, the role of NLRC5 in the kidney is unknown. NLRC5 was significantly upregulated in the kidney from mice with renal ischemia/reperfusion injury. NLRC5 deficient mice significantly ameliorated renal injury as evidenced by decreased serum creatinine levels, improved morphological injuries, and reduced inflammatory responses versus wild type mice. Similar protective effects were also observed in cisplatin-induced acute kidney injury. Mechanistically, NLRC5 contributed to renal injury by promoting tubular epithelial cell apoptosis and reducing inflammatory responses were, at least in part, associated with the negative regulation of carcinoembryonic antigen-related cell adhesion molecule 1 (CEACAM1). To determine the relative contribution of NLRC5 expression by parenchymal cells or leukocytes to renal damage during ischemia/reperfusion injury, we generated bone marrow chimeric mice. NLRC5 deficient mice engrafted with wild type hematopoietic cells had significantly lower serum creatinine and less tubular damage than wild type mice reconstituted with NLRC5 deficient bone marrow. This suggests that NLRC5 signaling in renal parenchymal cells plays the dominant role in mediating renal damage. Thus, modulation of the NLRC5-mediated pathway may have important therapeutic implications for patients with acute kidney injury.

Radical Three-Component Nitro Spiro-Cyclization of Unsaturated Sulfonamides/Amides to Access NO2-Featured 4-Azaspiro[4.5]decanes.

Free radical three-component nitration/spirocyclization of unsaturated sulfonamides/amides with tert-butyl nitrite was developed for the construction of diverse NO2-revised 4-azaspiro[4.5]decanes. This tandem system featured metal-free participation, simple operation, good selectivity/yields, and a green/low-cost O source. Meanwhile, one nitro-containing complex molecule and a scaled-up operation were performed well to test the synthetic potential of the cascade reaction. Isotopic labeling, radical inhibition experiments, and DFT analysis were carried out to gain insight into the reaction process.

Preparation of bio-jet fuels by a controllable integration process: Coupling of biomass fermentation and olefin polymerization.

This work demonstrated that bio-jet fuels can be directionally prepared from bagasse (a typical lignocellulose biomass) by integrating bio- and chemical catalysis reaction processes. This controllable transformation started with the preparation of acetone/butanol/ethanol (ABE) intermediates through the enzymolysis and fermentation of bagasse. Pretreatment of bagasse by deep eutectic solvent (DES) promoted the enzymatic hydrolysis and fermentation because it destroyed the structure of biomass and remove lignin in lignocellulose. Subsequently, the selective catalytic conversion of sugarcane derived ABE broth to jet range fuels was achieved through an integrated process: ABE dehydration to light olefins over the HSAPO-34 catalyst and olefin polymerization to bio-jet fuels over the Ni/HBET catalyst. The dual catalyst bed synthesis mode improved the selectively of bio-jet fuels. High selectivity of jet range fuels (83.0 %) and high conversion of ABE (95.3 %) were obtained by the integrated process.

The crosslink between the hyaluronic acid and drugs treated by reactive oxygen species produced in plasma based on the molecular dynamics simulation.

Hyaluronic Acid (HA)-based pre-drugs can enable targeted drug delivery to cancer cells with CD44-high expressing, thus, it is essential to design an efficient, target specific drug delivery system based on HA. Plasma, as a simple and clean tool, has been widely used in the modification and crosslinking of biological materials in recent years. In this paper, we used the Reactive Molecular Dynamic (RMD) to explore the reaction between reactive oxygen species (ROS) in plasma and HA with drugs (PTX, SN-38, and DOX), in order to examine possible drug-coupled systems. The simulation results indicated the acetylamino groups in HA could be oxidized to unsaturated acyl groups, which offers the possibility of crosslinking. Three drugs also exposed the unsaturated atoms under the impact of ROS, which can cross-link directly to HA through CO and CN bonds, forming a drug coupling system with better release. This study revealed the exposure of active sites on HA and drugs by ROS impact in plasma, allowing us to study the crosslinking mechanism between HA and drugs at molecular level deeply, and also provided a new light for establishment of HA-based targeted drug delivery system.

Two successive bidirectional leaders propagated in triggered lightning channel.

A stepped leader propagated along the previous return-stroke channel in triggered lightning. After the stepped leader decayed, the first bidirectional leader went through the process of initiation, propagation and dissipation. Then the second bidirectional leader initiated at the termination of the decayed first bidirectional leader and propagated toward the ground, generating the fourth return-stroke. The observations were synchronously performed through a high-speed camera and electromagnetic field measurements. The first bidirectional leader was characterized by similar average upward and downward velocities of 0.76 × 106 m/s and 0.67 × 106 m/s. The velocity of the upward positive leader of the first bidirectional leader was noticeably fluctuated, ranging 0.39 × 106-1.78 × 106 m/s. The second bidirectional leader was characterized by a sustainable propagating upward end with an average velocity of 1.82 × 106 m/s. The velocity fluctuation trend of the upward end depends on the neutralization amount of the residual negative charge and the positive charge in UPL.

Transition-metal free C-N bond formation from alkyl iodides and diazonium salts via halogen-atom transfer.

Construction of C-N bond continues to be one part of the most significant goals in organic chemistry because of the universal applications of amines in pharmaceuticals, materials and agrochemicals. However, E2 elimination through classic SN2 substitution of alkyl halides lead to generation of alkenes as major side-products. Thus, formation of a challenging C(sp3)-N bond especially on tertiary carbon center remains highly desirable. Herein, we present a practical alternative to prepare primary, secondary and tertiary alkyl amines with high efficiency between alkyl iodides and easily accessible diazonium salts. This robust transformation only employs Cs2CO3 promoting halogen-atom transfer (XAT) process under transition-metal-free reaction conditions, thus providing a rapid method to assemble diverse C(sp3)-N bonds. Moreover, diazonium salts served as alkyl radical initiator and amination reagent in the reaction. Mechanism studies suggest this reaction undergo through halogen-atom transfer process to generate active alkyl radical which couples with diazonium cations to furnish final products.

Interleukin-33 Promotes Cell Survival via p38 MAPK-Mediated Interleukin-6 Gene Expression and Release in Pediatric AML.

Acute myeloid leukemia (AML) is a fatal disease characterized by the accumulation of immature myeloid blasts in the bone marrow (BM). Cytokine provide signals for leukemia cells to improve their survival in the BM microenvironment. Previously, we identified interleukin-33 (IL-33) as a promoter of cell survival in a human AML cell line and primary mouse leukemia cells. In this study, we report that the cell surface expression of IL-33-specific receptor, Interleukin 1 Receptor Like 1 (IL1RL1), is elevated in BM cells from AML patients at diagnosis, and the serum level of IL-33 in AML patients is higher than that of healthy donor controls. Moreover, IL-33 levels are found to be positively associated with IL-6 levels in pediatric patients with AML. In vitro, IL-33 treatment increased IL-6 mRNA expression and protein level in BM and peripheral blood (PB) cells from AML patients. Evidence was also provided that IL-33 inhibits cell apoptosis by activating p38 mitogen-activated protein kinase (MAPK) pathway using human AML cell line and AML patient samples. Finally, we confirmed that IL-33 activated IL-6 expression in a manner that required p38 MAPK pathway using clinical AML samples. Taken together, we identified a potential mechanism of IL-33-mediated survival involving p38 MAPK in pediatric AML patients that would facilitate future drug development.

Electrochemical catalytic reforming of oxygenated-organic compounds: a highly efficient method for production of hydrogen from bio-oil.

A novel approach to produce hydrogen from bio-oil was obtained with high carbon conversion (>90%) and hydrogen yield (>90%) at T<500 degrees C by using the electrochemical catalytic reforming of oxygenated-organic compounds over 18%NiO/Al(2)O(3) reforming catalyst; thermal electrons play important promoting roles in the decomposition and reforming of the oxygenated-organic compounds in the bio-oil.

Effects of straw application on nitrate leaching in fields in the Yellow River irrigation zone of Ningxia, China.

A five-year field experiment was conducted to investigate the effects of straw application on nitrate leaching loss. Treatments included soil that was not treated (control), soil treated with straw at a low rate (4,500 kg ha-2, T1) and soil treated with straw at a high rate (9,000 kg ha-2, T2). Nitrate-nitrogen leaching in the 10, 20, 30, 60, and 90 cm soil layers was measured using the resin-core method. The results indicated that straw application could reduce soil nitrate leaching losses in the 0-30 cm layer. In this layer, the nitrate leaching values for T1 (13.76 kg ha-2) and T2 (13.74 kg ha-2) were both significantly lower than those of the control (15.76 kg ha-2) (P < 0.05); the soil nitrate leaching losses decreased by 12.71% and 12.84% for those two treatments, respectively. However, no significant differences in losses were observed (P > 0.05) between T1 and T2. The effects of straw application were apparent only in the ploughing layer (30 cm-depth soil layer). In the deeper layers (60 and 90 cm), no significant differences were observed between the treatments and the control, and the same results were observed in the topsoil layers (10 and 20 cm).

ß-Arrestin-1 deficiency ameliorates renal interstitial fibrosis by blocking Wnt1/ß-catenin signaling in mice.

Despite substantial progress being made in understanding the mechanisms contributing to the pathogenesis of renal fibrosis, there are only a few therapies available to treat or prevent renal fibrosis in clinical use today. Therefore, identifying the key cellular and molecular mediators involved in the pathogenesis of renal fibrosis will provide new therapeutic strategy for treating patients with chronic kidney disease (CKD). ß-Arrestin-1, a member of ß-arrestin family, not only is a negative adaptor of G protein-coupled receptors (GPCRs), but also acts as a scaffold protein and regulates a diverse array of cellular functions independent of GPCR activation. In this study, we identified for the first time that ß-arrestin-1 was upregulated in the kidney from mice with unilateral ureteral obstruction nephropathy as well as in the paraffin-embedded sections of human kidneys from the patients with diabetic nephropathy, polycystic kidney, or uronephrosis, which normally causes renal fibrosis. Deficiency of ß-arrestin-1 in mice significantly alleviated renal fibrosis by the regulation of inflammatory responses, kidney fibroblast activation, and epithelial-mesenchymal transition (EMT) in both in vivo and in vitro studies. Furthermore, we found that among the major isoforms of Wnts, Wnt1 was regulated by ß-arrestin-1 and gene silencing of Wnt1 inhibited the activation of ß-catenin and suppressed ß-arrestin-1-mediated renal fibrosis. Collectively, our results indicate that ß-arrestin-1 is one of the critical components of signal transduction pathways in the development of renal fibrosis. Modulation of these pathways may be an innovative therapeutic strategy for treating patients with renal fibrosis. KEY MESSAGES: ß-Arrestin-1 was upregulated in the kidney from mice with UUO nephropathy. ß-Arrestin-1 regulated kidney fibroblast activation and epithelial-mesenchymal transition. ß-Arrestin-1 exacerbated renal fibrosis via mediating Wnt1/ß-catenin signaling.

Reducing reaction of Fe3O4 in nanoscopic reactors of a-CNTs.

A reduction of Fe3O4 nanowires in nanoscopic reactors of amorphous C:H nanotubes (a-CNTs) was taken to understand features of the chemical reaction mechanism in nanoscale reactors. Fe3O4 nanowires encapsulated in a-CNTs were reduced into iron at a relatively low temperature of 570 degrees C, producing iron nanoparticles encapsulated in CNTs accompanied by the crystallization of the a-CNT shell. It was found that carbon in the a-CNT shell rather than hydrogen (5.5 wt % in it) reduced Fe3O4, showing features different from those in a macroscopic system. The possible mechanisms behind this phenomenon are discussed.

Reduction features of NO over a potassium-doped C12A7-O- catalyst.

The NO reduction features over a noble-metal-free NO(x) storage/reduction catalyst ([Ca24Al28O64](4+*)4O-/K, defined as C12A7-O-/K), including the NO conversion, the N2 selectivity, and sulfur tolerance, were investigated with hydrogen and C3H6 as the reducing agents in a fixed-bed continuous flow reactor. The NO conversion and the N2 selectivity on the C12A7-O-/K catalyst mainly depends on the sample temperature, the percentage of potassium, the reducing agents, and the composition of the mixture of gases. The C12A7-O-/10%K catalyst possessed the highest selective reduction ability (to N2) among the catalysts C12A7-O-/x%K. Over 50% of NO can be reduced to N2 with H2 as the reduction agent at 550-700 degrees C. The C12A7-O-/K catalyst also shows higher NO(x) storage capacity (183.9 micromol/g at about 550 degrees C) as well as sulfur tolerance for both the NO(x) storage and the reduction processes. The catalyst characteristics and the intermediate species formed in the NO storage and reduction processes were investigated by the X-ray diffraction, X-ray photoelectron spectroscopy, Fourier transform infrared spectroscopy, and time-of-flight mass spectrometry. The mechanism of NO(x) reduction was addressed according to the above investigations.

Features and mechanism of H- anion emission from 12 CaO x 7 Al2O3 surface.

The hydrogen anion (H-) and other anionic species (O-, OH-, e-) in the gas phase, emitted from the synthesized crystal surface of 12 CaO x 7 Al2O3-H- (C12A7-H-), have been observed. The emission intensity of all the anionic species strongly depends on the sample surface temperature and the extraction field. H- has the highest emission branch ratio, and the extraction field can reduce its apparent activation energy. H- emission current at a microA/cm2-level has been achieved, which is about 4 orders of magnitude higher than that obtained from the thermal desorption process of CaH2. The observed anions of H- and OH- are attributed to their migration from the C12A7-H- cages onto the surface [i.e., Y-(cages) --> Y-(surface) --> Y-(gas phase) (Y = H, OH)]. The weak O- and electron emission would both arise from the dissociation of O2-: O2-(surface) --> O-(surface) + e-(surface) --> O-(gas phase) + e-(space).

Mechanistic features for hydroxyl anion emission from the modified 12CaO.7Al2O3 surface.

OH(-), O(-), and H(-) emissions from the [Ca(24)Al(28)O(64)](4+).4(OH(-)) (defined as C12A7-OH(-)) surface were investigated by time-of-flight (TOF) spectrometry. The emission intensities were sensitive to surface temperature and extraction field. The apparent activation energies of anions decreased with the increase of applied extraction field. At an extraction field of 800 V/cm, the emission ratio of OH(-) to total anions is 0.98-0.65 in the temperature range of 870-1075 K. The OH(-) emission from C12A7-OH(-) was described by the following kinetic processes: the OH(-) anions in the cages migrated onto the sample surface by field enhanced thermal diffusion, and then desorbed to form the gas-phase anions of OH(-). The O(-) emission originated from the dissociation of O(2-) and OH(-). Similarly, H(-) emission was also attributed to the dissociation of OH(-) on the C12A7-OH(-) surface.

One-step synthesis of phenol by O- and OH- emission material.

A novel approach to the direct synthesis of phenol from benzene was obtained with high benzene conversion (30%) and phenol selectivity (approximately 90%) by using a microporous material [Ca24Al28O64]4+.4O-(C12A7-O-) as catalyst with oxygen and water; active O- and OH- anions are proposed to play important roles in the formation of phenol by hydroxylating the aromatic ring of benzene.