Chronic kidney disease (CKD), characterized by sustained inflammation and progressive fibrosis, is highly prevalent and can eventually progress to end-stage kidney disease. However, current treatments to slow CKD progression are limited. Sphingosine 1-phosphate (S1P), a product of sphingolipid catabolism, is a pleiotropic mediator involved in many cellular functions, and drugs targeting S1P signaling have previously been studied particularly for autoimmune diseases. The primary mechanism of most of these drugs is functional antagonism of S1P receptor-1 (S1P1) expressed on lymphocytes and the resultant immunosuppressive effect. Here, we documented the role of local S1P signaling in perivascular cells in the progression of kidney fibrosis using primary kidney perivascular cells and several conditional mouse models. S1P was predominantly produced by sphingosine kinase 2 in kidney perivascular cells and exported via spinster homolog 2 (Spns2). It bound to S1P1 expressed in perivascular cells to enhance production of proinflammatory cytokines/chemokines upon injury, leading to immune cell infiltration and subsequent fibrosis. A small-molecule Spns2 inhibitor blocked S1P transport, resulting in suppression of inflammatory signaling in human and mouse kidney perivascular cells in vitro and amelioration of kidney fibrosis in mice. Our study provides insight into the regulation of inflammation and fibrosis by S1P and demonstrates the potential of Spns2 inhibition as a treatment for CKD and potentially other inflammatory and fibrotic diseases that avoids the adverse events associated with systemic modulation of S1P receptors.

Sphingosine 1-phosphate (S1P) is a pleiotropic signaling molecule that interacts with five G-protein-coupled receptors (S1P1-5) to regulate cellular signaling pathways. S1P export is facilitated by Mfsd2b and spinster homologue 2 (Spns2). While mouse genetic studies suggest that Spns2 functions to maintain lymph S1P, Spns2 inhibitors are necessary to understand its biology and to learn whether Spns2 is a viable drug target. Herein, we report a structure–activity relationship study that identified the first Spns2 inhibitor 16d (SLF1081851). In vitro studies in HeLa cells demonstrated that 16d inhibited S1P release with an IC50 of 1.93 μM. Administration of 16d to mice and rats drove significant decreases in circulating lymphocyte counts and plasma S1P concentrations, recapitulating the phenotype observed in mice made deficient in Spns2. Thus, 16d has the potential for development and use as a probe to investigate Spns2 biology and to determine the potential of Spns2 as a drug target.

We report a chemoselective, phosphine-catalyzed semireduction of primary and secondary propiolamides. In the presence of stoichiometric pinacolborane and catalytic n-tributylphosphine, a variety of propiolamides were successfully converted to the corresponding acrylamides in excellent yield with (E)stereoselectivity. The reaction condition is tolerant of various functional groups including alkene, alkyne, ketone, or ester. Deuterium labeling studies established that the hydride from activated pinacolborane is added to the α-carbon and the proton on the amide nitrogen is abstracted by the ß-carbon to furnish the (E)acrylamides. DFT calculations revealed a clear energetic driving force for the (E)-over the (Z)-isomer.

Studies suggest that only 31% of Europe is thought to have a water supply that is either plentiful or sufficient to meet demands until 2015, and water stress indexes show a number of countries with traditionally wet climates such as Belgium and Bulgaria, under significant water stress. Therefore, there is both a desire and a need to reduce the consumption of water over much of Europe. For industry, often economics determine the viability of water recycling, which does not necessarily fall under the standards currently being set for the major water reuse schemes. While the additional annual recycling capacity in Western Europe is set to increase by 10%, much of the Global market is focussed on major reuse facilities based on the municipal sector. Within the industrial sector there are opportunities to achieve major changes in the water cycle which can have a significant impact on total water consumption. The impact on regional water consumption by industries efforts can be massive, as industry accounts for 50% of the water consumption in Western Europe. When benchmarked data across industry sectors is analysed, we find that industries ranging from paper mills, dairy, beverage, ceramic and electronics have opportunities to reduce their water consumption by around 50%. But what are the mechanisms that drive actions in the industry water cycle, and how great can the impact be? This paper explores industrial water costs across Europe, and the drivers leading to reduced water consumption. As operators of water and wastewater facilities for many industrial customers across Europe, Ondeo Industrial Solutions examine the raw water costs and the viability of recycle schemes. Economics is not the only driver towards the reduction in water consumption on industrial sites. There are political and legislative drivers that can often override the economics such as the European PPC (Pollution Prevention and Control) directive that can often lead to a programme of water consumption reductions.

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