STAT3 inhibition enhances CDN-induced STING signaling and antitumor immunity.

Cyclic GMP-AMP synthase (cGAS)-stimulator of interferon genes (STING) pathway is a key regulator in innate immunity and has emerged as a promising drug target in cancer treatment, but the utility of this pathway in therapeutic development is complicated by its dichotomous roles in tumor development and immunity. The activation of the STING pathway and the induced antitumor immunity could be attenuated by the feedback activation of IL-6/STAT3 pathway. Here we reported that STAT3 inhibition significantly enhanced the intensity and duration of STING signaling induced by the STING agonist c-diAM(PS)2. Such sensitization effect of STAT3 inhibition on STING signaling depended on STING rather than cGAS, which was mediated by simultaneously upregulating the positive modulators and downregulating the negative modulators of the STING pathway. Furthermore, the combination treatment with the STAT3 inhibitor and STING agonist markedly regressed tumor growth in syngeneic mice by increasing CD8+ T cells and reducing regulatory T cells (Tregs) and myeloid-derived suppressor cells (MDSCs) in the tumor microenvironment. Our work provides a rationale for the combination of STAT3 inhibitors and STING agonists in cancer immunotherapy.

Structural basis for dimerization of the death effector domain of the F122A mutant of Caspase-8.

Caspase-8 is an apoptotic protease that is activated by a proximity-induced dimerization mechanism within the death-inducing signaling complex (DISC). The death effector domain (DED) of caspase-8 is involved in protein-protein interactions and is essential for the activation. Here, we report two crystal structures of the dimeric DEDs of the F122A mutant of caspase-8, both of which illustrate a novel domain-swapped dimerization, while differ in the relative orientation of the two subunits and the solvent exposure of the conserved hydrophobic patch Phe122/Leu123. We demonstrate that mutations disrupting the dimerization of the DEDs abrogate the formation of cellular death effector filaments (DEFs) and the induced apoptosis by overexpressed DEDs. Furthermore, such dimerization-disrupting mutations also impair the activation of the full-length caspase-8 and the downstream apoptosis cascade. The structures provide new insights into understanding the mechanism underlying the activation of procaspase-8 within the DISC and DEFs.

Identification of α-Mangostin as an Agonist of Human STING.

The xanthone derivate 5',6'-dimethylxanthenone-4-acetic acid (DMXAA, also known as ASA404 or vadimezan) is a potent agonist of murine STING (stimulator of interferon genes), but cannot activate human STING. Herein we report that α-mangostin, which bears the xanthone skeleton, is an agonist of human STING, but activates murine STING to a lesser extent. Biochemical and cell-based assays indicate that α-mangostin binds to and activates human STING, leading to activation of the downstream interferon regulatory factor (IRF) pathway and production of type I interferons. Furthermore, our studies show that α-mangostin has the potential to repolarize human monocyte-derived M2 macrophages to the M1 phenotype. The agonist effect of α-mangostin in the STING pathway might account for its antitumor and antiviral activities.

Crystal structure of the death effector domains of caspase-8.

Caspase-8 is a key mediator in various biological processes such as apoptosis, necroptosis, inflammation, T/B cells activation, and cell motility. Caspase-8 is characterized by the N-terminal tandem death effector domains (DEDs) and the C-terminal catalytic protease domain. The DEDs mediate diverse functions of caspase-8 through homotypic interactions of the DEDs between caspase-8 and its partner proteins. Here, we report the first crystal structure of the DEDs of caspase-8. The overall structure of the DEDs of caspase-8 is similar to that of the DEDs of vFLIP MC159, which is composed of two tandem death effector domains that closely associate with each other in a head-to-tail manner. Structural analysis reveals distinct differences in the region connecting helices α2b and α4b in the second DED of the DEDs between caspase-8 and MC159, in which the helix α3b in MC159 is replaced by a loop in caspase-8. Moreover, the different amino acids in this region might confer the distinct features of solubility and aggregation for the DEDs of caspase-8 and MC159.

[Pathogen identification of Pinellia ternata tuber disease and selection of fungicide].

The rotten tuber of Pinellia ternata was found as an important disease during the growing season in Tianshui production area. The isolated pathogens were tested following Koch's postulates and identified as Fusarium oxysporum. The suitable growth conditions for the F. oxysporum were 15-30 degrees C, pH 6-8, the optimal condition was 21.9 degrees C and pH 7.2. Some fungicides were demonstrated to be effective to inhibit the pathogen growth. 70% thiophanate-methyl and 58% metalaxyl MZ were most effective to inhibit the pathogen. The EC50 were 0.002 7, 0.066 2 g x L(-1), respectively.

[Study on mathematical model of optimum fertilizer application to Pinellia ternate cultivation].

OBJECTIVE: To study the mathematical model of optimum fertilizer application to Pinellia by field experiments. METHOD: Three factors and 5 levels quadratic rotational combination design was applied to study the effects of N, P and K. RESULT AND CONCLUSION: N, P and K combination application can achieve the maximum yield of 29,921.4 kg x hm(-2), the amount of N, P2O5, K2O were 413.79, 224.79, 164.01 kg x hm(-2), respectively. The effects of the 3 factors were in following orders: P > N > K.