Macrophage-related therapeutic strategies: Regulation of phenotypic switching and construction of drug delivery systems.

Macrophages, as highly phenotypic plastic immune cells, play diverse roles in different pathological conditions. Changing and controlling the phenotypes of macrophages is considered a novel potential therapeutic intervention. Meanwhile, specific transmembrane proteins anchoring on the surface of the macrophage membrane are relatively conserved, supporting its functional properties, such as inflammatory chemotaxis and tumor targeting. Thus, a series of drug delivery systems related to specific macrophage membrane proteins are commonly used to treat chronic inflammatory diseases. This review summarizes macrophages-based strategies for chronic diseases, discusses the regulation of macrophage phenotypes and their polarization processes, and presents how to design and apply the site-specific targeted drug delivery systems in vivo based on the macrophages and their derived membrane receptors. It aims to provide a better understanding of macrophages in immunoregulation and proposes macrophages-based targeted therapeutic approaches for chronic diseases.

Efficient synthesis of antiviral agent uprifosbuvir enabled by new synthetic methods.

An efficient route to the HCV antiviral agent uprifosbuvir was developed in 5 steps from readily available uridine in 50% overall yield. This concise synthesis was achieved by development of several synthetic methods: (1) complexation-driven selective acyl migration/oxidation; (2) BSA-mediated cyclization to anhydrouridine; (3) hydrochlorination using FeCl3/TMDSO; (4) dynamic stereoselective phosphoramidation using a chiral nucleophilic catalyst. The new route improves the yield of uprifosbuvir 50-fold over the previous manufacturing process and expands the tool set available for synthesis of antiviral nucleotides.

Invention of MK-8262, a Cholesteryl Ester Transfer Protein (CETP) Inhibitor Backup to Anacetrapib with Best-in-Class Properties.

Cholesteryl ester transfer protein (CETP) represents one of the key regulators of the homeostasis of lipid particles, including high-density lipoprotein (HDL) and low-density lipoprotein (LDL) particles. Epidemiological evidence correlates increased HDL and decreased LDL to coronary heart disease (CHD) risk reduction. This relationship is consistent with a clinical outcomes trial of a CETP inhibitor (anacetrapib) combined with standard of care (statin), which led to a 9% additional risk reduction compared to standard of care alone. We discuss here the discovery of MK-8262, a CETP inhibitor with the potential for being the best-in-class molecule. Novel in vitro and in vivo paradigms were integrated to drug discovery to guide optimization informed by a critical understanding of key clinical adverse effect profiles. We present preclinical and clinical evidence of MK-8262 safety and efficacy by means of HDL increase and LDL reduction as biomarkers for reduced CHD risk.

Dynamics of Scroll Wave in a Three-Dimensional System with Changing Gradient.

The dynamics of a scroll wave in an excitable medium with gradient excitability is studied in detail. Three parameter regimes can be distinguished by the degree of gradient. For a small gradient, the system reaches a simple rotating synchronization. In this regime, the rigid rotating velocity of spiral waves is maximal in the layers with the highest filament twist. As the excitability gradient increases, the scroll wave evolutes into a meandering synchronous state. This transition is accompanied by a variation in twisting rate. Filament twisting may prevent the breakup of spiral waves in the bottom layers with a low excitability with which a spiral breaks in a 2D medium. When the gradient is large enough, the twisted filament breaks up, which results in a semi-turbulent state where the lower part is turbulent while the upper part contains a scroll wave with a low twisting filament.

Synthesis of the GPR40 Partial Agonist MK-8666 through a Kinetically Controlled Dynamic Enzymatic Ketone Reduction.

A scalable and efficient synthesis of the GPR40 agonist MK-8666 was developed from a simple pyridine building block. The key step to set the stereochemistry at two centers relied on an enzymatic dynamic kinetic reduction of an unactivated ketone. Directed evolution was leveraged to generate an optimized ketoreductase that provided the desired trans alcohol in >30:1 dr and >99% ee. Further, it was demonstrated that all four diastereomers of this hydroxy-ester could be prepared in high yield and selectivity. Subsequently, a challenging intramolecular displacement was carried out to form the cyclopropane ring system with perfect control of endo/exo selectivity. The endgame coupling strategy relied on a Pd-catalyzed C-O coupling to join the headpiece chloropyridine with the benzylic alcohol tailpiece.

[Multiplication technique of rice T(P) GMS line with double low critical temperature values using cold water irrigation].

In this paper, cold-water irrigation multiplication technique was used to solve the difficulty of multiplying rice TGMS line 96-5-2S(Oryza sative L.) with double low critical temperature values under natural air temperature condition. The results indicated that irrigating rice TGMS line 96-5-2S with different temperature underground cold water from the stage of pistil and stamen primordia differentiation to the stage of pollen filling for 15 days, and keeping the water depth 18-22 cm, the seed set rate of 96-5-2S decreased with increasing irrigating water temperature. When the average temperature of irrigation water was 18.5-19.8 degrees C, the seed set rate ranged from 40.5% to 57.6%, and the yield ranged from 3.30 t.hm-2 to 4.35 t.hm-2. While the temperature was 20.5-21.3 degrees C, the seed set rate and yield sharply decreased to 2.5-10.4% and 0.21-0.90 t.hm-2, respectively. When the average temperature was 22.3-23.5 degrees C, both the seed set rate and yield were zero. Under the same irrigation water temperature (average 19.8 degrees C) and the same irrigating period (phase IV to phase VII), the seed set rate and yield of 96-5-2S with deep water irrigation (18-22 cm) was very significantly higher than those of 96-5-2S with shallow water irrigation (7-10 cm). Under the conditions of same irrigation water temperature (average 19.8 degrees C) and same water depth (18-22 cm) but different irrigating periods (15 days from phase IV to phase VII, 20 days from phase III to phase VII, and 25 days from phase II to phase VII), the difference of seed set rate and yield of 96-5-2S between 15-day treatment and 20-25-day treatment was not significantly different. It is confident that 96-5-2S could multiply with underground cold water irrigation. The main technique index was that irrigating water temperature should be 18-20 degrees C, irrigating period should be from phase IV to phase VII, and irrigating water depth should be 18-22 cm.