The Cytokine Release Inhibitory Drug CRID3 Targets ASC Oligomerisation in the NLRP3 and AIM2 Inflammasomes

Background: The Inflammasomes are multi-protein complexes that regulate caspase-1 activation and the production of the pro-inflammatory cytokine IL-1 beta. Previous studies identified a class of diarylsulfonylurea containing compounds called Cytokine Release Inhibitory Drugs (CRIDs) that inhibited the post-translational processing of IL-1 beta. Further work identified Glutathione S-Transferase Omega 1 (GSTO1) as a possible target of these CRIDs. This study aimed to investigate the mechanism of the inhibitory activity of the CRID CP-456,773 (termed CRID3) in light of recent advances in the area of inflammasome activation, and to clarify the potential role of GSTO1 in the regulation of IL-1 beta production

NLRP3 inflammasome inhibition with MCC950 improves insulin sensitivity and inflammation in a mouse model of frontotemporal dementia

Acknowledgments: This study was supported by ARUK project grant PG2017B-11 and ARUK summer scholarship funding from the Scottish ARUK network. The authors would like to thank Prof. Gernot Riedel for his support of the in vivo experimentation.Peer reviewedPostprin

A systematic evaluation of physical activity and diet policies in Scotland : results from the 2021 Active Healthy Kids Report Card

Acknowledgements The authors are grateful to the stakeholders who appraised and provided feedback on the policy evaluation and grade (within the Report Card) prior to publication of the Report Card.Peer reviewe

Antimicrobial octapeptin C4 analogues active against Cryptococcus species

Resistance to antimicrobials is a growing problem in both developed and developing countries. In nations where AIDS is most prevalent, the human fungal pathogen Cryptococcus neoformans is a significant contributor to mortality, and its growing resistance to current antifungals an ever-expanding threat. We investigated octapeptin C4, from the cationic cyclic lipopeptide class of antimicrobials, as a potential new antifungal. Octapeptin C4 was a potent, selective inhibitor of this fungal pathogen with minimum inhibitory concentration of 1.56 μg/mL. Further testing of octapeptin C4 against 40 clinical isolates of C. neoformans var. grubii or neoformans showed MIC 1.56-3.13 μg/mL while 20 clinical isolates of C. neoformans var. gattii had MIC 0.78-12.5 μg/mL. In each case MIC values for octapeptin C4 were equivalent to, or better than, current antifungal drugs fluconazole and amphotericin B. The negatively charged polysaccharide capsule of C. neoformans influences the pathogens sensitivity to octapeptin C4 while degree of melanisation had little effect. Testing synthetic octapeptin C4 derivatives provided insight into the structure activity relationships, revealing that the lipophilic amino acid moieties are more important to the activity than the cationic diaminobutyric acid groups. Octapeptins have promising potential for development as anticryptococcal therapeutic agents

A framework to explore micronutrient deficiency in maternal and child health in Malawi, Southern Africa

<p>Abstract</p> <p>Background</p> <p>Global food insecurity is associated with micronutrient deficiencies and it has been suggested that 4.5 billion people world-wide are affected by deficiencies in iron, vitamin A and iodine. Zinc has also been identified to be of increasing concern. The most vulnerable are young children and women of childbearing age. A pilot study has been carried out in Southern Malawi, to attempt to link the geochemical and agricultural basis of micronutrient supply through spatial variability to maternal health and associated cultural and social aspects of nutrition. The aim is to establish the opportunity for concerted action to deliver step change improvements in the nutrition of developing countries.</p> <p>Results</p> <p>Field work undertaken in August 2007 and July/August 2008 involved the collection of blood, soil and crop samples, and questionnaires from ~100 pregnant women. Complex permissions and authorisation protocols were identified and found to be as much part of the cultural and social context of the work as the complexity of the interdisciplinary project. These issues are catalogued and discussed. A preliminary spatial evaluation is presented linking soil quality and food production to nutritional health. It also considers behavioural and cultural attitudes of women and children in two regions of southern Malawi, (the Shire Valley and Shire Highlands plateau). Differences in agricultural practice and widely varying soil quality (e.g. pH organic matter, C/N and metal content) were observed for both regions and full chemical analysis of soil and food is underway. Early assessment of blood data suggests major differences in health and nutritional status between the two regions. Differences in food availability and type and observations of life style are being evaluated through questionnaire analysis.</p> <p>Conclusion</p> <p>The particular emphasis of the study is on the interdisciplinary opportunities and the barriers to progress in development support in subsistence communities. Engaging at the community level and the balance of expectations from both study subjects and research team highlight the merit of careful and detailed planning and project delivery.</p

NLRP3-inflammasome inhibition prevents high fat and high sugar diets-induced heart damage through autophagy induction

The NLRP3-inflammasome complex has emerged as an important component of inflammatory processes in metabolic dysfunction induced by high-caloric diets. In this study, we investigate the molecular mechanisms by which NLRP3 inhibition may attenuate diet-induced cardiac injury. Here we show the cardiac damage induced by high sugar diet (HSD), high fat diet (HFD) or high sugar/fat diet (HSFD) over 15 weeks. Genetic ablation of NLRP3 protected against this damage by autophagy induction and apoptotic control. Furthermore, NLRP3 inhibition by the selective small molecule MCC950 resulted in similar autophagy induction and apoptotic control in hearts after diets. These data were reproduced in THP-1 cells treated with MCC950 and cultured in media supplemented with serum from mice dosed with MCC950 and fed with diets. NLRP3 inhibition exerted beneficial metabolic, and autophagic adaptations in hearts from obesogenic diets. The inhibition of NLRP3 activation may hold promise in the treatment of metabolic and cardiovascular diseases.Junta de Andalucía CTS113Junta de Andalucia PI-0036-201

Bacillus cereus non-haemolytic enterotoxin activates the NLRP3 inflammasome

Inflammasomes are important for host defence against pathogens and homeostasis with commensal microbes. Here, we show non-haemolytic enterotoxin (NHE) from the neglected human foodborne pathogen Bacillus cereus is an activator of the NLRP3 inflammasome and pyroptosis. NHE is a non-redundant toxin to haemolysin BL (HBL) despite having a similar mechanism of action. Via a putative transmembrane region, subunit C of NHE initiates binding to the plasma membrane, leading to the recruitment of subunit B and subunit A, thus forming a tripartite lytic pore that is permissive to efflux of potassium. NHE mediates killing of cells from multiple lineages and hosts, highlighting a versatile functional repertoire in different host species. These data indicate that NHE and HBL operate synergistically to induce inflammation and show that multiple virulence factors from the same pathogen with conserved function and mechanism of action can be exploited for sensing by a single inflammasome

Compromised NLRP3 and AIM2 inflammasome function in autoimmune NZB/W F1 mouse macrophages

Inflammasomes are protein complexes activated by infection and cellular stress that promote caspase-1 activation and subsequent inflammatory cytokine processing and cell death. It has been anticipated that inflammasome activity contributes to autoimmunity. However, we previously showed that macrophages from autoimmune New Zealand Black (NZB) mice lack NLRP3 inflammasome function, and their AIM2 inflammasome responses are compromised by high expression of the AIM2 antagonist protein p202. Here we found that the point mutation leading to lack of NLRP3 expression occurred early in the NZB strain establishment, as it is shared with the related obese strain NZO, but not with the unrelated New Zealand White (NZW) strain. The first cross progeny of NZB and NZW mice develop more severe lupus nephritis than the NZB strain. We have compared AIM2 and NLRP3 inflammasome function in macrophages from NZB, NZW and NZB/W F1 mice. The NZW parental strain showed strong inflammasome function, whilst the NZB/W F1 have haploinsufficient expression of NLRP3 and show reduced NLRP3 and AIM2 inflammasome responses, particularly at low stimulus strength. It remains to be established whether the low inflammasome function could contribute to loss of tolerance and the onset of autoimmunity in NZB and NZB/W F1. However, with amplifying inflammatory stimuli through the course of disease, the NLRP3 response in the NZB/W F1 may be sufficient to contribute to kidney damage at later stages of disease. This article is protected by copyright. All rights reserved

A systematic evaluation of physical activity and diet policies in Scotland: Results from the 2021 Active Healthy Kids Report Card

Background Policymaking regarding physical activity (PA) and diet plays an important role in childhood health promotion. This study provides a detailed examination of Scottish government and policy for child and adolescent PA and diet and discusses strengths and areas for improvement. Methods Scottish policy documents (n = 18 [PA]; n = 10 [diet])—published in 2011–20—were reviewed for grading using an adapted version of the Health-Enhancing Physical Activity Policy Audit Tool Version 2. Results There is clear evidence of leadership and commitment to improving PA and diet and tackling obesity in children and adolescents. The allocation of funds and resources for policy implementation has increased substantially over the past decade. Progress through early key stages of public policymaking—policy agenda and formation—has improved. However, there is limited information on later key stages, including policy monitoring and evaluation. Conclusions Childhood PA and diet are a clear priority in Scotland, and PA and diet policies clearly support the desire to achieve other goals, including reducing inequalities and increasing active travel in Scotland. Nonetheless, future policies should be further strengthened through clear(er) plans of implementation, and monitoring and evaluation to support their societal impact

A systematic evaluation of physical activity and diet policies in Scotland : results from the 2021 Active Healthy Kids Report Card

Background: Policymaking regarding physical activity (PA) and diet plays an important role in childhood health promotion. This study provides a detailed examination of Scottish government and policy for child and adolescent PA and diet and discusses strengths and areas for improvement. Methods: Scottish policy documents (n = 18 [PA]; n = 10 [diet])—published in 2011–20—were reviewed for grading using an adapted version of the Health-Enhancing Physical Activity Policy Audit Tool Version 2. Results: There is clear evidence of leadership and commitment to improving PA and diet and tackling obesity in children and adolescents. The allocation of funds and resources for policy implementation has increased substantially over the past decade. Progress through early key stages of public policymaking—policy agenda and formation—has improved. However, there is limited information on later key stages, including policy monitoring and evaluation. Conclusions: Childhood PA and diet are a clear priority in Scotland, and PA and diet policies clearly support the desire to achieve other goals, including reducing inequalities and increasing active travel in Scotland. Nonetheless, future policies should be further strengthened through clear(er) plans of implementation, and monitoring and evaluation to support their societal impact