The STING antagonist H-151 ameliorates psoriasis via suppression of STING/NF-κB-mediated inflammation.

BACKGROUND AND PURPOSE: Psoriasis is a chronic inflammatory skin disease associated with both innate and adaptive immune responses. The stimulator of interferon genes (STING) protein engages in sensing of cytosolic DNA to initiate dsDNA-driven immune responses. In vitro and in vivo anti-psoriasis effects of STING antagonist H-151 were explored. EXPERIMENTAL APPROACH: We analysed the gene expression profile of STING and related downstream targets in the skin samples of healthy people and psoriasis patients from the GEO database. Cellular inhibitory activity of H-151 on STING pathway was confirmed via qPCR and western blotting. The preventive effect of topical application of H-151 on imiquimod-induced psoriatic mice was examined through histological, immunohistochemical, immunofluorescent, flow cytometric analysis, ELISA Kits and other approaches. Preliminary mechanistic studies were also performed. KEY RESULTS: Gene expressions of STING and its downstream target were up-regulated in lesional skin samples from psoriasis patients. Topical administration of H-151 attenuated the skin lesions in imiquimod-induced psoriatic mouse model, while the secretion of pro-inflammatory cytokines (IL-17, IL-23 and IL-6), infiltration of M1 macrophages and differentiation of Th17 cells were significantly suppressed by H-151 treatment. Mechanistically, H-151 inhibited STING/NF-κB signalling in both keratinocytes and immune cells. CONCLUSION AND IMPLICATIONS: H-151 displayed anti-inflammatory activity in both keratinocytes and immune cells, and decreased the severity of psoriatic response in vivo. Inhibition of STING signalling pathway may represent a novel therapeutic approach to psoriasis and related complications.

STING inhibitors target the cyclic dinucleotide binding pocket.

Cytosolic DNA activates cGAS (cytosolic DNA sensor cyclic AMP-GMP synthase)-STING (stimulator of interferon genes) signaling, which triggers interferon and inflammatory responses that help defend against microbial infection and cancer. However, aberrant cytosolic self-DNA in Aicardi-Goutière's syndrome and constituently active gain-of-function mutations in STING in STING-associated vasculopathy with onset in infancy (SAVI) patients lead to excessive type I interferons and proinflammatory cytokines, which cause difficult-to-treat and sometimes fatal autoimmune disease. Here, in silico docking identified a potent STING antagonist SN-011 that binds with higher affinity to the cyclic dinucleotide (CDN)-binding pocket of STING than endogenous 2'3'-cGAMP. SN-011 locks STING in an open inactive conformation, which inhibits interferon and inflammatory cytokine induction activated by 2'3'-cGAMP, herpes simplex virus type 1 infection, Trex1 deficiency, overexpression of cGAS-STING, or SAVI STING mutants. In Trex1-/- mice, SN-011 was well tolerated, strongly inhibited hallmarks of inflammation and autoimmunity disease, and prevented death. Thus, a specific STING inhibitor that binds to the STING CDN-binding pocket is a promising lead compound for STING-driven disease.

Source or sink? A study on the methane flux from mangroves stems in Zhangjiang estuary, southeast coast of China.

Mangrove ecosystems are an important component of "blue carbon". However, it is not clear whether the stems play roles in the CH4 budget of mangrove ecosystems. This study investigated the CH4 emission from mangrove stems and its potential driving factors. We set up six sample plots in the Zhangjiang Estuary National Mangrove Nature Reserve, where Kandelia obovata, Avicennia marina and Aegiceras corniculata are the main mangrove tree species. Soil properties such as total carbon content, redox potential and salinity were determined in each plot. The dynamic chamber method was used to measure mangrove stems and soil CH4 fluxes. Combined field survey results with Principal Component Analysis (PCA) of soil properties, we divided the six plots into two sites (S1 and S2) to perform statistical analyses of stem CH4 fluxes. Then the CH4 fluxes from mangrove tree stems and soil were further scaled up to the ecosystem level through the mapping model. Under different backgrounds of soil properties, salinity and microbial biomass carbon were the main factors modified soil CH4 fluxes in the two sites, and further affected the stem CH4 fluxes of mangroves. The soil of both sites are sources of CH4, and the soil CH4 emission of S2 was about twice higher than that of S1. Results of upscaling model showed that mangrove stems in S1 were CH4 sinks with -105.65 g d-1. But stems in S2 were CH4 sources around 1448.24 g d-1. Taken together, our results suggested that CH4 emission from mangrove soils closely depends on soils properties. And mangrove stems were found to act as both CH4 sources and CH4 sinks depend on soil CH4 production. Therefore, when calculating the CH4 budget of the mangrove ecosystem, the contribution of mangrove plant stems cannot be ignored.

Discovery of AdipoRon analogues as novel AMPK activators without inhibiting mitochondrial complex I.

Activation of AMPK emerges as a potential therapeutic approach to metabolic diseases. AdipoRon is claimed to be an adiponectin receptor agonist that activates AMPK through adiponectin receptor 1 (AdipoR1). However, AdipoRon also exhibits moderate inhibition of mitochondrial complex I, leading to increased risk of lactic acidosis. In order to find novel AdipoRon analogues that activate AMPK without inhibition of complex I, 27 analogues of AdipoRon were designed, synthesized and biologically evaluated. As results, benzyloxy arylamide B10 was identified as a potent AMPK activator without inhibition of complex I. B10 dose-dependently improved glucose tolerance in normal mice, and significantly lowered fasting blood glucose level and ameliorated insulin resistance in db/db diabetic mice. More importantly, unlike the pan-AMPK activator MK-8722, B10 did not cause cardiac hypertrophy, probably owing to its selective activation of AMPK in the muscle tissue but not in the heart tissue. Together, B10 represents a novel class of AMPK activators with promising therapeutic potential against metabolic disease.

Co-crystallization of hemimellitic acid with 4,4'-bipyridine forming a pillar-layered hydrogen-bonded network.

Co-crystallization of hemimellitic acid (benzene-1,2,3-tricarboxylic acid) dihydrate (H3HMA.2H2O) with 4,4'-bipyridine (4,4'-bpy) affords the 1:1 co-crystal benzene-1,2,3-tricarboxylic acid-4,4'-bipyridine (1/1), H3HMA.4,4'-bpy or C9H6O6.C10H8N2. Strong O-H...O hydrogen bonds connect the acid molecules to form a one-dimensional zigzag chain, around which the 4,4'-bpy components are fixed as arms via O-H...N interactions, resulting in a ladder motif. Through weak C-H...O non-covalent forces, the resulting acid layers are extended into a three-dimensional pillar-layered architecture supported by rod-like 4,4'-bpy components. The influence on hydrogen-bonding models is also discussed, with the discovery of an unexpected interaction motif that does not follow the routine hydrogen-bonded hierarchical rule in the construction of an acid-base co-crystal.