Taking in account the inspiring outcomes of ERK inhibitors in preclinical research, ERK1/2 might be the optimal target to overcome acquired drug resistance in RAF-MEK-ERK pathway.

Background and Purpose: Inflammasome-mediated pyroptosis is an important neuronal cell death mechanism. Previous studies reported that activation of melanocortin MC 4 receptor exerted neuroprotection in several neurological diseases. Here, we have investigated the role of MC 4 receptor activation with RO27-3225 in suppressing neuronal pyroptosis after experimental intracerebral haemorrhage (ICH) and the underlying mechanism.Experimental Approach: One hundred and sixty-nine male CD1 mice were used. ICH was induced by injection of bacterial collagenase into the right-side basal ganglia.RO27-3225, a selective agonist of MC 4 receptor, was injected intraperitoneally at 1 hr after ICH. To elucidate the underlying mechanism, we used the specific MC 4 receptor antagonist HS024 and NQDI-1, a specific inhibitor of the apoptosis signalling-regulating kinase 1 (ASK1). Neurological tests, Western blot, Fluoro-Jade C, TUNEL, and immunofluorescence staining were conducted.Key Results: Expression of MC 4 receptor and the NOD-like receptor family, pyrin domain containing 1 (NLRP1) inflammasome in brain were increased after ICH. RO27-3225 treatment decreased neuronal pyroptosis and neurobehavioural deficits at 24 and 72 hr after ICH. RO27-3225 reduced the expression of p-ASK1, p-JNK, p-p38 MAPK, NLRP1 inflammasome, cleaved caspase-1, and IL-1β after ICH. HS024 pretreatment prevented the effects of RO27-3225. Similar to RO27-3225, NQDI-1 alone improved neurological functions and down-regulated ASK1/JNK/ p38MAPK expression after ICH. Conclusions and Implications: RO27-3225 suppressed NLRP1-dependent neuronal pyroptosis and improved neurological function, possibly mediated by activation of MC 4 receptor and inhibition of ASK1/JNK/p38 MAPK signalling pathways, after experimental ICH in mice. The MC 4 receptor may be a promising therapeutic target for the management of ICH. Abbreviations: ASK1, apoptosis signalling-regulating kinase 1; FJC, Fluoro-Jade C; ICH, intracerebral haemorrhage; MSH, melanocyte-stimulating hormones; NLRP1, NOD-like receptor (NLR) family, pyrin domain containing 1

Premise Outcomes of species interactions, especially mutualisms, are notoriously dependent on environmental context, and environments are changing rapidly. Studies have investigated how mutualisms respond to or ameliorate anthropogenic environmental changes, but most have focused on nutrient pollution or climate change and tested stressors one at a time. Relatively little is known about how mutualisms may be altered by or buffer the effects of multiple chemical contaminants, which differ fundamentally from nutrient or climate stressors and are especially widespread in aquatic habitats. Methods We investigated the impacts of two contaminants on interactions between the duckweed Lemna minor and its microbiome. Sodium chloride (salt) and benzotriazole (a corrosion inhibitor) often co‐occur in runoff to water bodies where duckweeds reside. We tested three L. minor genotypes with and without the culturable portion of their microbiome across field‐realistic gradients of salt (3 levels) and benzotriazole (4 levels) in a fully factorial experiment (24 treatments, tested on each genotype) and measured plant and microbial growth. Results Stressors had conditional effects. Salt decreased both plant and microbial growth and decreased plant survival more as benzotriazole concentrations increased. In contrast, benzotriazole did not affect microbial abundance and even benefited plants when salt and microbes were absent, perhaps due to biotransformation into growth‐promoting compounds. Microbes did not ameliorate duckweed stressors; microbial inoculation increased plant growth, but not at high salt concentrations. Conclusions Our results suggest that multiple stressors matter when predicting responses of mutualisms to global change and that beneficial microbes may not always buffer hosts against stress.

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