Discovery and Preclinical Evaluation of a Novel Inhibitor of FABP5, ART26.12, Effective in Oxaliplatin-Induced Peripheral Neuropathy.

Oxaliplatin-induced peripheral neuropathy (OIPN) is a dose-limiting toxicity characterised by mechanical allodynia and thermal hyperalgesia, without any licensed medications. ART26.12 is a fatty acid-binding protein (FABP) 5 inhibitor with antinociceptive properties, characterised here for the prevention and treatment of OIPN. ART26.12 binds selectively to FABP5 compared to FABP3, FABP4, and FABP7, with minimal off-target liabilities, high oral bioavailability, and a NOAEL of 1,000 mg/kg/day in rats and dogs. In an established preclinical OIPN model, acute oral dosing (25-100 mg/kg) showed a cannabinoid receptor type 1 (CB1)-dependent anti-allodynic effect lasting up to 8 hours (persisting longer than plasma exposure to ART26.12). Antagonists of cannabinoid receptor type 2 (CB2), peroxisome proliferator-activated receptor alpha, and transient receptor potential cation channel subfamily V member 1 (TRPV1) may have also been implicated. Twice daily oral dosing (25 mg/kg bis in die (BID) for 7 days) showed anti-allodynic effects in an established OIPN model without the development of tolerance. In a prevention paradigm, coadministration of ART26.12 (10 and 25 mg/kg BID for 15 days) with oxaliplatin prevented thermal hyperalgesia, mitigated mechanical allodynia, and attenuated OXA-induced weight loss. Multi-scale analyses revealed widespread lipid modulation, particularly among N-acyl amino acids in the spinal cord, including potential analgesic mediators. Additionally, ART26.12 administration led to upregulation of ion channels in the periaqueductal grey, and broad translational upregulation within the plasma proteome. These results show promise that ART26.12 is a safe and well-tolerated candidate for the treatment and prevention of OIPN through lipid modulation. PERSPECTIVE: Inhibition of fatty acid-binding protein 5 (FABP5) is a novel target for reducing pain associated with chemotherapy. ART26.12 is a safe and well-tolerated small molecule FABP5 inhibitor effective at preventing and reducing pain induced with oxaliplatin through lipid modulation and activation of cannabinoid receptors.

Satisfaction With Governmental Risk Communication Both Increases and Decreases COVID-19 Mitigation Behaviours.

Objectives: Over 3 years of the COVID-19 pandemic, and intense societal and governmental response, a wealth of research has examined risk perceptions and public risk mitigation behaviours. The vast majority of this inquiry has focused on health risks. Nevertheless, as a "total social fact" influencing nearly every aspect of quotidian life, the pandemic engenders a wide range of risk perceptions. Methods: Via a survey (N = 4,206) of representative samples of the general public in five European countries (Germany, Norway, Sweden, Switzerland, United Kingdom), we explore perceptions of a range of personal/public health, economic, and societal risks. We also investigate the effects of perceptions of official governmental risk communication in one's country on risk perceptions and risk mitigation behaviours. Results: Structural equation modelling reveals that whilst perceptions of effective risk communication directly increase behaviours that mitigate COVID-19 health risks, these same perceptions indirectly decrease behaviour frequency via a mediated relationship with societal risk perceptions. Conclusion: The findings highlight the import of governmental authorities analysing and communicating about the range of risk perceptions citizens might have about a "total social fact" such as COVID-19.

The Relationship Between Barriers and Drivers of COVID-19 Protective Behaviors in Germany and the UK.

Objectives: To explore and evaluate the impact of factors including public risk perceptions on COVID-19 protective behaviors across the UK and Germany. Methods: We used survey data collected from a representative sample for Germany and the UK (total N = 1,663) between April and May 2021. Using a Structural Equation Model, we evaluate the role of personal health risk perceptions, official message quality, source of news, age and political orientation on COVID-19 protective behaviors in the context of German and UK risk communication strategies. Results: Personal health risk perceptions had a significant positive influence on protective behaviors. Economic risk perceptions had a negative direct influence on protective behaviors, particularly in Germany, as well as a positive indirect influence. Official message quality, use of official news sources and age had positive impacts on risk perceptions and protective behaviors. Left-wing political orientation was linked to greater likelihood of undertaking protective behaviors. Conclusion: For future pandemics, more attention should be paid to evaluating and conceptualizing different varieties of risk perceptions, risk communication strategies, and demographic variables alongside their impacts on undertaking protective behaviors.

Exosomes and their cargo are important regulators of cell function in endometriosis.

Endometriosis is a chronic oestrogen-dependent gynaecological disorder characterized by non-menstrual pelvic pain, infertility and the extrauterine growth of endometrial-like glands and stroma. It has been noted that the eutopic endometrium of women with endometriosis is functionally distinct from that of women without endometriosis. Moreover, ectopic endometrial implants are functionally different from the eutopic endometrium of women with endometriosis. However, the mechanisms directing these differences are ill-defined. It is proposed here that small membrane-bound extracellular vesicles called exosomes are important vehicles in the protection and transport of signalling molecules central to the dysregulation of endometrial function in women with endometriosis. Therefore, a critical review of the literature linking exosomes and their cargo to the pathobiology of endometriosis was conducted. Circulating peritoneal fluid and endometrial cell exosomes contained long non-coding RNA, miRNA and proteins involved in histone modification, angiogenesis and immune modulation that differed significantly in women with endometriosis compared with controls. Moreover, experimental evidence supports a role for exosomes and their cargo in angiogenesis, neurogenesis, immune modulation and endometrial stromal cell invasion. It is therefore suggested that exosomes play an important role in the pathophysiology of endometriosis.