PRMT4 inhibitor TP-064 impacts both inflammatory and metabolic processes without changing the susceptibility for early atherosclerotic lesions in male apolipoprotein E knockout mice.

BACKGROUND AND AIMS: Atherosclerotic cardiovascular disease is a metabolic and inflammatory disorder. In vitro studies have suggested that protein arginine methyltransferase 4 (PRMT4) may act as a transcriptional coactivator to modulate inflammatory and metabolic processes. Here we investigated the potential anti-atherogenic effect of PRMT4 inhibitor TP-064 in vivo. METHODS: Male apolipoprotein E knockout mice fed a high cholesterol/high fat Western-type diet were intraperitoneally injected three times a week with 2.5 mg/kg (low dose) or 10 mg/kg (high dose) TP-064 or with DMSO control. RESULTS: TP-064 induced a dose-dependent decrease in lipopolysaccharide-induced ex vivo blood monocyte Tnfα secretion (p < 0.05 for trend) in the context of unchanged blood monocyte concentrations and neutrophilia induction (p < 0.01 for trend). A dose-dependent decrease in gonadal white adipose tissue expression levels of PPARγ target genes was detected, which translated into a reduced body weight gain after high dose TP-064 treatment (p < 0.05). TP-064 treatment also dose-dependently downregulated gene expression of the glycogen metabolism related protein G6pc in the liver (p < 0.001 for trend). In addition, a trend towards lower plasma insulin and higher blood glucose levels was observed, which was paralleled by a reduction in hepatic mRNA expression levels of the insulin-responsive genes Fasn (-55%; p < 0.001) and Gck (-47%; p < 0.001) in high dose-treated mice. Plasma triglyceride levels were reduced by high dose TP-064 treatment (-30%; p < 0.05). However, no change was observed in the size or composition of aortic root atherosclerotic lesions. CONCLUSIONS: The PRMT4 inhibitor TP-064 impacts both inflammatory and metabolic processes without changing atherosclerosis susceptibility of male apolipoprotein E knockout mice.

PRMT4 inhibitor TP-064 inhibits the pro-inflammatory macrophage lipopolysaccharide response in vitro and ex vivo and induces peritonitis-associated neutrophilia in vivo.

Previous in vitro studies have shown that protein arginine N-methyltransferase 4 (PRMT4) is a co-activator for an array of cellular activities, including NF-κB-regulated pro-inflammatory responses. Here we investigated the effect of PRMT4 inhibitor TP-064 treatment on macrophage inflammation in vitro and in vivo. Exposure of RAW 264.7 monocyte/macrophages to TP-064 was associated with a significant decrease in the production of pro-inflammatory cytokines upon a lipopolysaccharide challenge. Similarly, thioglycollate-elicited peritoneal cells isolated from wildtype mice treated with TP-064 showed lowered mRNA expression levels and cytokine production of pro-inflammatory mediators interleukin (IL)-1ß, IL-6, IL-12p40, and tumor necrosis factor-α in response to lipopolysaccharide exposure. However, TP-064-treated mice exhibited an ongoing pro-inflammatory peritonitis after 5 days of thioglycollate exposure, as evident from a shift in the peritoneal macrophage polarization state from an anti-inflammatory LY6ClowCD206hi to a pro-inflammatory LY6ChiCD206low phenotype. In addition, TP-064-treated mice accumulated (activated) neutrophils within the peritoneum as well as in the blood (7-fold higher; P < 0.001) and major organs such as kidney and liver, without apparent tissue toxicity. TP-064 treatment downregulated hepatic mRNA expression levels of the PRMT4 target genes glucose-6-phosphatase catalytic subunit (-50%, P < 0.05) and the cyclin-dependent kinases 2 (-50%, P < 0.05) and 4 (-30%, P < 0.05), suggesting a direct transcriptional effect of PRMT4 also in hepatocytes. In conclusion, we have shown that the PRMT4 inhibitor TP-064 induces peritonitis-associated neutrophilia in vivo and inhibits the pro-inflammatory macrophage lipopolysaccharide response in vitro and ex vivo. Our findings suggest that TP-064 can possibly be applied as therapy in NF-κB-based inflammatory diseases.

Oxytocin modulates human communication by enhancing cognitive exploration.

Oxytocin is a neuropeptide known to influence how humans share material resources. Here we explore whether oxytocin influences how we share knowledge. We focus on two distinguishing features of human communication, namely the ability to select communicative signals that disambiguate the many-to-many mappings that exist between a signal's form and meaning, and adjustments of those signals to the presumed cognitive characteristics of the addressee ("audience design"). Fifty-five males participated in a randomized, double-blind, placebo controlled experiment involving the intranasal administration of oxytocin. The participants produced novel non-verbal communicative signals towards two different addressees, an adult or a child, in an experimentally-controlled live interactive setting. We found that oxytocin administration drives participants to generate signals of higher referential quality, i.e. signals that disambiguate more communicative problems; and to rapidly adjust those communicative signals to what the addressee understands. The combined effects of oxytocin on referential quality and audience design fit with the notion that oxytocin administration leads participants to explore more pervasively behaviors that can convey their intention, and diverse models of the addressees. These findings suggest that, besides affecting prosocial drive and salience of social cues, oxytocin influences how we share knowledge by promoting cognitive exploration.

Communicative knowledge pervasively influences sensorimotor computations.

Referential pointing is a characteristically human behavior, which involves moving a finger through space to direct an addressee towards a desired mental state. Planning this type of action requires an interface between sensorimotor and conceptual abilities. A simple interface could supplement spatially-guided motor routines with communicative-ostensive cues. For instance, a pointing finger held still for an extended period of time could aid the addressee's understanding, without altering the movement's trajectory. A more complex interface would entail communicative knowledge penetrating the sensorimotor system and directly affecting pointing trajectories. We compare these two possibilities using motion analyses of referential pointing during multi-agent interactions. We observed that communicators produced ostensive cues that were sensitive to the communicative context. Crucially, we also observed pervasive adaptations to the pointing trajectories: they were tailored to the communicative context and to partner-specific information. These findings indicate that human referential pointing is planned and controlled on the basis of partner-specific knowledge, over and above the tagging of motor routines with ostensive cues.

What drives successful verbal communication?

THERE IS A VAST AMOUNT OF POTENTIAL MAPPINGS BETWEEN BEHAVIORS AND INTENTIONS IN COMMUNICATION: a behavior can indicate a multitude of different intentions, and the same intention can be communicated with a variety of behaviors. Humans routinely solve these many-to-many referential problems when producing utterances for an Addressee. This ability might rely on social cognitive skills, for instance, the ability to manipulate unobservable summary variables to disambiguate ambiguous behavior of other agents ("mentalizing") and the drive to invest resources into changing and understanding the mental state of other agents ("communicative motivation"). Alternatively, the ambiguities of verbal communicative interactions might be solved by general-purpose cognitive abilities that process cues that are incidentally associated with the communicative interaction. In this study, we assess these possibilities by testing which cognitive traits account for communicative success during a verbal referential task. Cognitive traits were assessed with psychometric scores quantifying motivation, mentalizing abilities, and general-purpose cognitive abilities, taxing abstract visuo-spatial abilities. Communicative abilities of participants were assessed by using an on-line interactive task that required a speaker to verbally convey a concept to an Addressee. The communicative success of the utterances was quantified by measuring how frequently a number of Evaluators would infer the correct concept. Speakers with high motivational and general-purpose cognitive abilities generated utterances that were more easily interpreted. These findings extend to the domain of verbal communication the notion that motivational and cognitive factors influence the human ability to rapidly converge on shared communicative innovations.

A dissociation between linguistic and communicative abilities in the human brain.

Although language is an effective vehicle for communication, it is unclear how linguistic and communicative abilities relate to each other. Some researchers have argued that communicative message generation involves perspective taking (mentalizing), and-crucially-that mentalizing depends on language. We employed a verbal communication paradigm to directly test whether the generation of a communicative action relies on mentalizing and whether the cerebral bases of communicative message generation are distinct from parts of cortex sensitive to linguistic variables. We found that dorsomedial prefrontal cortex, a brain area consistently associated with mentalizing, was sensitive to the communicative intent of utterances, irrespective of linguistic difficulty. In contrast, left inferior frontal cortex, an area known to be involved in language, was sensitive to the linguistic demands of utterances, but not to communicative intent. These findings show that communicative and linguistic abilities rely on cerebrally (and computationally) distinct mechanisms.