Theoretical Study of the TiO2 and MgO Surface Acidity and the Adsorption of Acids and Bases

We present ab-initio periodic Hartree–Fock calculations (crystal program) of small molecules on TiO₂ and MgO. The adsorption of the molecules may be molecular or dissociative. This depends on their acid and basic properties in the gas phase. For the molecular adsorption, the molecules are adsorbed as bases on Ti(+IV) sites, the adsorption energies correlate with the proton affinities. The dissociations on the surface correlate with the gas phase cleavages: thus, the dissociation of MeOH leads to a preferential basic cleavage (the fragment HO– is adsorbed on a Ti⁺⁴ ion and the fragment Me⁺ is adsorbed on a O²– ion of the oxide). The opposite result is obtained with MeSH. Another important factor is the adsorbate–adsorbate interaction: favorable cases are a sequence of H-bonds for the hydroxyl groups resulting from the water dissociation and the mode of adsorption for the ammonium ions. Lateral interactions also force the adsorbed CO₂ molecules to bend over the surface so that their mutual orientation resembles the geometry of the CO₂ dimer. With respect to water adsorption, MgO appears to be a basic oxide. As experimentally observed, NH₃ adsorbs preferentially on TiO₂ and CO₂ on MgO. However, this difference of reactivity should not be expressed in terms of acid vs. basic behaviour but in terms of hard and soft acidity. The MgO surface is a 'soft' acidic surface that reacts preferentially with the soft base, CO₂.     

Alterations of plasma lipids in mice via adenoviral-mediated hepatic overexpression of human ABCA1

ATP binding cassette transporter A1 (ABCA1) is a widely expressed lipid transporter essential for the generation of HDL. ABCA1 is particularly abundant in the liver, suggesting that the liver may play a major role in HDL homeostasis. To determine how hepatic ABCA1 affects plasma HDL cholesterol levels, we treated mice with an adenovirus (Ad)-expressing human ABCA1 under the control of the cytomegalovirus promoter. Treated mice showed a dose-dependent increase in hepatic ABCA1 protein, ranging from 1.2-fold to 8.3-fold using doses from 5 x 108 to 1.5 x 109 pfu, with maximal expression observed on Day 3 posttreatment. A selective increase in HDL cholesterol occurred at Day 3 in mice treated with 5 x 108 pfu Ad-ABCA1, but higher doses did not further elevate HDL cholesterol levels. In contrast, total cholesterol, triglycerides, phospholipids, non-HDL cholesterol, and apolipoprotein B levels all increased in a dose-dependent manner, suggesting that excessive overexpression of hepatic ABCA1 in the absence of its normal regulatory sequences altered total lipid homeostasis. At comparable expression levels, bacterial artificial chromosome transgenic mice, which express ABCA1 under the control of its endogenous regulatory sequences, showed a greater and more specific increase in HDL cholesterol than Ad-ABCA1-treated mice. Our results suggest that appropriate regulation of ABCA1 is critical for a selective increase in HDL cholesterol levels.     

A unique FGF23 with the ability to activate FGFR signaling through both αKlotho and βKlotho

Three fibroblast growth factor (FGF) molecules, FGF19, FGF21, and FGF23, form a unique subfamily that functions as endocrine hormones. FGF19 and FGF21 can regulate glucose, lipid, and energy metabolism, while FGF23 regulates phosphate homeostasis. The FGF receptors and co-receptors for these three FGF molecules have been identified, and domains important for receptor interaction and specificity determination are beginning to be elucidated. However, a number of questions remain unanswered, such as the identification of fibroblast growth factor receptor responsible for glucose regulation. Here, we have generated a variant of FGF23: FGF23-21c, where the C-terminal domain of FGF23 was replaced with the corresponding regions from FGF21. FGF23-21c showed a number of interesting and unexpected properties in vitro. In contrast to wild-type FGF23, FGF23-21c gained the ability to activate FGFR1c and FGFR2c in the presence of βKlotho and was able to stimulate glucose uptake into adipocytes in vitro and lower glucose levels in ob/ob diabetic mice model to similar extent as FGF21 in vivo. These results suggest that βKlotho/FGFR1c or FGFR2c receptor complexes are sufficient for glucose regulation. Interestingly, without the FGF23 C-terminal domain, FGF23-21c was still able to activate fibroblast growth factor receptors in the presence of αKlotho. This suggests not only that sequences outside of the C-terminal region may also contribute to the interaction with co-receptors but also that FGF23-21c may be able to regulate both glucose and phosphate metabolisms. This raises an interesting concept of designing an FGF molecule that may be able to address multiple diseases simultaneously. Further understanding of FGF/receptor interactions may allow the development of exciting opportunities for novel therapeutic discovery.     

Antioxidant,antibacterial, and catalytic performance of biosynthesized silver nanoparticles of Rhus javanica,Rumex hastatus,and Callistemon viminalis

Rhus javanica (Anacardiaceae) containing abundant glucopyranosidal constituents, is traditionally used to treat gastric and duodenal ulcer, dysentery, and diarrhea. Rumex hastatus (Polygonaceae) widely distributed in Pakistan, has traditional importance in treating wound healing, jaundice, rheumatism, and skin diseases. Callistemon viminalis (Myrtaceae), a rich source of essential oils, saponins, triterpenoids, phloroglucinols, and flavonoids is used in industries, perfumes, nutrition, and cosmetics. Taking the importance of the subject plants, this study is designed to synthesize silver nanoparticles via aqueous extracts of R. javanica (RJAgNPs), R. hastatus (RHAgNPs), and C. viminalis (CVAgNPs). Synthesis, surface, and sizes of silver nanoparticles (AgNPs) were confirmed using spectroscopic techniques including ultraviolet–visible (UV–Vis), Fourier transform-infrared (FT-IR), and scanning electron microscopy (SEM). AgNPs were produced in ratios 1:15, 1:16, and 1:9 and inferred via appearance of a sharp surface plasmon resonance (SPR) absorption peak (400–435 nm), which represented well-defined, stable, and spherical AgNPs. From SEM analysis, the sizes of RJAgNPs, RHAgNPs, and CVAgNPs were found to be 67 nm, 61 nm, and 55 nm, respectively. The synthesized AgNPs exhibited potential free radical scavenging, antibacterial, and catalytic properties in degradation of dyes including Congo red, methylene blue, methyl orange, rhodamine B, ortho and para-nitrophenols, and several food colours. Hence, the subject AgNPs in the current study might display promising role in drug development and remediation of environmental/industrial effluents.     

Human genetics of tuberculosis: a long and winding road

Only a small fraction of individuals exposed to Mycobacterium tuberculosis develop clinical tuberculosis (TB). Over the past century, epidemiological studies have shown that human genetic factors contribute significantly to this interindividual variability, and molecular progress has been made over the past decade for at least two of the three key TB-related phenotypes: (i) a major locus controlling resistance to infection with M. tuberculosis has been identified, and (ii) proof of principle that severe TB of childhood can result from single-gene inborn errors of interferon-γ immunity has been provided; genetic association studies with pulmonary TB in adulthood have met with more limited success. Future genetic studies of these three phenotypes could consider subgroups of subjects defined on the basis of individual (e.g. age at TB onset) or environmental (e.g. pathogen strain) factors. Progress may also be facilitated by further methodological advances in human genetics. Identification of the human genetic variants controlling the various stages and forms of TB is critical for understanding TB pathogenesis. These findings should have major implications for TB control, in the definition of improved prevention strategies, the optimization of vaccines and clinical trials and the development of novel treatments aiming to restore deficient immune responses.     

Modulation of Macrophage Activation State Protects Tissue from Necrosis during Critical Limb Ischemia in Thrombospondin-1-Deficient Mice

Background

Macrophages, key regulators of healing/regeneration processes, strongly infiltrate ischemic tissues from patients suffering from critical limb ischemia (CLI). However pro-inflammatory markers correlate with disease progression and risk of amputation, suggesting that modulating macrophage activation state might be beneficial. We previously reported that thrombospondin-1 (TSP-1) is highly expressed in ischemic tissues during CLI in humans. TSP-1 is a matricellular protein that displays well-known angiostatic properties in cancer, and regulates inflammation in vivo and macrophages properties in vitro. We therefore sought to investigate its function in a mouse model of CLI.

Methods and Findings

Using a genetic model of tsp-1 ^−/− mice subjected to femoral artery excision, we report that tsp-1 ^−/− mice were clinically and histologically protected from necrosis compared to controls. Tissue protection was associated with increased postischemic angiogenesis and muscle regeneration. We next showed that macrophages present in ischemic tissues exhibited distinct phenotypes in tsp-1 ^−/− and wt mice. A strong reduction of necrotic myofibers phagocytosis was observed in tsp-1 ^−/− mice. We next demonstrated that phagocytosis of muscle cell debris is a potent pro-inflammatory signal for macrophages in vitro. Consistently with these findings, macrophages that infiltrated ischemic tissues exhibited a reduced postischemic pro-inflammatory activation state in tsp-1 ^−/− mice, characterized by a reduced Ly-6C expression and a less pro-inflammatory cytokine expression profile. Finally, we showed that monocyte depletion reversed clinical and histological protection from necrosis observed in tsp-1 ^−/− mice, thereby demonstrating that macrophages mediated tissue protection in these mice.

Conclusion

This study defines targeting postischemic macrophage activation state as a new potential therapeutic approach to protect tissues from necrosis and promote tissue repair during CLI. Furthermore, our data suggest that phagocytosis plays a crucial role in promoting a deleterious intra-tissular pro-inflammatory macrophage activation state during critical injuries. Finally, our results describe TSP-1 as a new relevant physiological target during critical leg ischemia.     

Elucidation of signaling and functional activities of an orphan GPCR, GPR81

GPR81 is an orphan G protein-coupled receptor (GPCR) that has a high degree of homology to the nicotinic acid receptor GPR109A. GPR81 expression is highly enriched and specific in adipocytes. However, the function and signaling properties of GPR81 are unknown because of the lack of natural or synthetic ligands. Using chimeric G proteins that convert Gi-coupled receptors to Gq-mediated inositol phosphate (IP) accumulation, we show that GPR81 can constitutively increase IP accumulation in HEK293 cells and suggest that GPR81 couples to the Gi signaling pathway. We also constructed a chimeric receptor that expresses the extracellular domains of cysteinyl leukotriene 2 receptor (CysLT2R) and the intracellular domains of GPR81. We show that the CysLT2R ligand, leukotriene D(4) (LTD4), is able to activate this chimeric receptor through activation of the Gi pathway. In addition, LTD4 is able to inhibit lipolysis in adipocytes expressing this chimeric receptor. These results suggest that GPR81 couples to the Gi signaling pathway and that activation of the receptor may regulate adipocyte function and metabolism. Hence, targeting GPR81 may lead to the development of a novel and effective therapy for dyslipidemia and a better side effect profile than nicotinic acid.