Development of M1 mAChR Allosteric and Bitopic Ligands: Prospective Therapeutics for the Treatment of Cognitive Deficits

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Cobalt-dithiolene complexes for the photocatalytic and electrocatalytic reduction of protons in aqueous solutions

Artificial photosynthesis (AP) is a promising method of converting solar energy into fuel (H(2)). Harnessing solar energy to generate H(2) from H(+) is a crucial process in systems for artificial photosynthesis. Widespread application of a device for AP would rely on the use of platinum-free catalysts due to the scarcity of noble metals. Here we report a series of cobalt dithiolene complexes that are exceptionally active for the catalytic reduction of protons in aqueous solvent mixtures. All catalysts perform visible-light-driven reduction of protons from water when paired with as the photosensitizer and ascorbic acid as the sacrificial donor. Photocatalysts with electron withdrawing groups exhibit the highest activity with turnovers up to 9,000 with respect to catalyst. The same complexes are also active electrocatalysts in 11 acetonitrile/water. The electrocatalytic mechanism is proposed to be ECEC, where the Co dithiolene catalysts undergo rapid protonation once they are reduced to . Subsequent reduction and reaction with H(+) lead to H(2) formation. Cobalt dithiolene complexes thus represent a new group of active catalysts for the reduction of protons.     

Gut microbiota regulates NKG2D ligand expression on intestinal epithelial cells

Intestinal epithelial cells (IECs) are one of a few cell types in the body with constitutive surface expression of natural killer group 2 member D (NKG2D) ligands, although the magnitude of ligand expression by IECs varies. Here, we investigated whether the gut microbiota regulates the NKG2D ligand expression on small IECs. Germ‐free and ampicillin‐treated mice were shown to have a significant increase in NKG2D ligand expression. Interestingly, vancomycin treatment, which propagated the bacterium Akkermansia muciniphila and reduced the level of IFN‐γ and IL‐15 in the intestine, decreased the NKG2D ligand expression on IECs. In addition, a similar increase in A. muciniphila and a decreased NKG2D ligand expression was seen after feeding with dietary xylooligosaccharides. A pronounced increase in NKG2D ligand expression was furthermore observed in IL‐10‐deficient mice. In summary, our results suggest that the constitutive levels of NKG2D ligand expression on IECs are regulated by microbial signaling in the gut and further disfavor the intuitive notion that IEC NKG2D ligand expression is caused by low‐grade immune reaction against commensal bacteria. It is more likely that constitutively high IEC NKG2D ligand expression is kept in check by an intestinal regulatory immune milieu induced by members of the gut microbiota, for example A. muciniphila.     

偏向性配体——阿片类镇痛药设计新思路

吗啡等阿片类药物作为镇痛药应用已有数百年历史,但其致呼吸抑制、耐受和成瘾等副作用限制了该类药物的使用,因此人们一直致力于寻找副作用更低的新型镇痛药。近年研究发现,μ阿片受体下游除了经典的G 蛋白依赖型通路外,还独立存在由β-arrestin 介导的信号通路,吗啡激活μ阿片受体产生的镇痛、镇静效应主要通过G 蛋白依赖型通路介导,而胃肠功能紊乱、呼吸抑制、耐受等副反应则由β-arrestin 依赖型通路介导。如果能发现只激活G 蛋白依赖型通路而不激活β-arrestin 依赖型通路的偏向性配体,就可能得到镇痛效应强而副作用低的化合物,这为设计新型强效、低副作用的阿片类镇痛药提供了新思路。该文将对μ阿片受体下游β-arrestin 依赖型信号通路及偏向性配体的发现、发展和应用进行综述。     

NMDA receptor activation antagonizes the NMDA antagonist-induced antianxiety effect in the elevated plus-maze test in mice

BackgroundThe purpose of this study was to determine how the activation of different regulatory domains of the NMDAcomplex affects the antianxiety effect of antagonists acting at its distinct binding sites.MethodsThe anxiolytic-like activity was assessed by the elevated plus-maze test in mice.ResultsThe anxiolytic activity of CGP 37849 (a competitive NMDAreceptor antagonist) and L-701,324 (an antagonist at glycine site) was confirmed, but effects of both were significantly reduced by N-methyl-D-aspartic acid (NMDA) or by D-serine agonists at glutamate and glycine site of the NMDA receptor complex, respectively.ConclusionThe obtained data suggest that stimulation of the glutamate or glycine recognition site of the NMDAreceptor complex significantly decreases the antianxiety properties of antagonists of either site.     

Designing oral vaccines targeting intestinal dendritic cells

Introduction: Most pathogens colonize and invade the host at mucosal surfaces, such as the lung and the intestine. To combat intestinal pathogens the induction of local adaptive immune responses is required, which is mainly achieved through oral vaccination. However, most vaccines are ineffective when given orally owing to the hostile environment in the gastrointestinal tract. The encapsulation of antigens in biodegradable microparticulate delivery systems enhances their immunogenicity; however, the uptake of these delivery systems by intestinal immune cells is rather poor. Surface decoration of the particulates with targeting ligands could increase the uptake and mediate the selective targeting of the vaccine to intestinal antigen-presenting cells, including dendritic cells.

Areas covered: In this review, current knowledge on dendritic cell subsets is discussed, along with progress in the development of selective antigen targeting to these cells, in addition to focusing on data obtained in mice and, where possible, the pig, as a non-rodent animal model for humans. Moreover, the potential use and benefits of Fcγ receptor-mediated targeting of antigen delivery systems are highlighted.

Expert opinion: In conclusion, dendritic cell targeting ligands grafted on antigen carrier systems should preferably bind to a conserved endocytotic receptor, facilitating the design of a multispecies vaccine platform, which could elicit robust protective immune responses against enteric pathogens.     

Serum arylhydrocarbon receptor transactivating activity is elevated in type 2 diabetic patients with diabetic nephropathy

Aims/Introduction

Evidence is emerging that exposure to persistent organic pollutants (POPs) is a risk factor for obesity‐related diseases and for diabetes mellitus (DM). We found that POPs could be measured by a cell‐based arylhydrocarbon receptor (AhR)‐dependent reporter assay. We tested if serum AhR transactivating (AHRT) activities are a risk factor for diabetic nephropathy in people with type 2 diabetes.

Materials and Methods

We enrolled diabetic patients with normoalbuminuria (n = 36), microalbuminuria (n = 29), macroalbuminuria (n = 8) and end‐stage renal disease (n = 31). Sera were tested for their AHRT activities, which were standardized by an AhR ligand, 2,3,7,8‐tetrachlorodibenzo‐p‐dioxin (TCDD) and expressed as TCDD equivalents (TCDDeq pmol/L).

Results

Mean serum AHRT activities were higher in patients with microalbuminuria (40.1 ± 7.1 pmol/L), macroalbuminuria (37.4 ± 5.5 pmol/L) and end‐stage renal disease (59.1 ± 20.0 pmol/L) than in subjects with normoalbuminuria (12.7 ± 5.4 pmol/L; P < 0.05 for all comparisons). Serum AhR ligands showed a correlation with estimated glomerular filtration rate (eGFR; r = −0.663, P < 0.001), serum creatinine level (r = 0.635, P < 0.001), systolic blood pressure (r = 0.223, P = 0.026), glycated hemoglobim (r = 0.339, P < 0.001) and diabetic duration (r = 0.394, P < 0.001). In a multiple regression analysis, diabetic nephropathy was found to be an independent risk factor for higher AHRT activity after controlling for the confounding factors.

Conclusions

The present findings suggest serum AHRT activity, thus serum AhR ligands, is a risk factor for diabetic nephropathy. Further studies are required to clarify if an accumulation of POPs in the body is causally related to diabetic nephropathy.     

Pregnancy,immunology and evolution

Vertebrate systems of innate and adaptive immunity are more than 400 million years old, whereas mammalian placentation evolved 130 million years ago. Placentation evolved in the context of an immune system and has co-opted immune system cells and molecules. Natural killer (NK) cells are lymphocytes that provide defence against viral infection and also co-operate with trophoblast on the invasive remodeling of maternal vessels that supply the placenta with blood. Controlloing these processes are highly variable NK cell receptors that recognize polymorphic major histocompatibility complex (MHC) class I molecules as their ligands. As a consequence of strong and varying selection pressures, these systems of ligands and receptors evolve rapidly and are inherently unstable; thus they have been lost and reinvented on several occasions during mammalian evolution. The human system of killer cell immunoglobulin-like receptors (KIR) only has counterparts in monkeys and apes, species in which the co-evolution of receptors has been tracked. The emergence and diversification of MHC-C and its cognate KIR in hominids correlates with an increasingly invasive placenta. During human evolution the KIR system has undergone unique, qualitative changes that set it apart from the chimpanzee KIR system. The possible causes of these differences will be discussed.VIDEO LINK: http://sms.cam.ac.uk/media/1400816