Metformin has anti-inflammatory effects and induces immunometabolic reprogramming via multiple mechanisms in hidradenitis suppurativa.

BACKGROUND: Targeting immunometabolism has shown promise in treating autoimmune and inflammatory conditions. Hidradenitis suppurativa (HS) is a chronic inflammatory skin disease involving painful lesions in apocrine gland-bearing skin. Therapeutic options for HS are limited and often ineffective; thus, there is a pressing need for improved treatments. To date, metabolic dysregulation has not been investigated in HS. As HS is highly inflammatory, we hypothesized that energy metabolism is dysregulated in these patients. Metformin, an antidiabetic drug, which is known to impact on cellular metabolic and signalling pathways, has been shown to have anti-inflammatory effects in cancer and arthritis. While metformin is not licensed for use in HS, patients with HS taking metformin show improved clinical symptoms. OBJECTIVE: To assess the effect and mechanism of action of metformin in HS. METHODS: To assess the effect of metformin in vivo, we compared the immune and metabolic profiles of peripheral blood mononuclear cells (PBMCs) of patients with HS taking metformin vs. those not taking metformin. To examine the effect of metformin treatment ex vivo, we employed a skin explant model on skin biopsies from patients with HS not taking metformin, which we cultured with metformin overnight. We used enzyme-linked immunosorbent assays, multiplex cytokine assays and quantitative real-time polymerase chain reaction (RT-PCR) to measure inflammatory markers, and Seahorse flux technology and quantitative RT-PCR to assess glucose metabolism. RESULTS: We showed that metabolic pathways are dysregulated in the PBMCs of patients with HS vs. healthy individuals. In metformin-treated patients, these metabolic pathways were restored and their PBMCs had reduced inflammatory markers following long-term metformin treatment. In the skin explant model, we found that overnight culture with metformin reduced inflammatory cytokines and chemokines and glycolytic genes in lesions and tracts of patients with HS. Using in vitro assays, we found that metformin may induce these changes via the NLR family pyrin domain containing 3 (NLRP3) inflammasome and the AMP-activated protein kinase (AMPK)-mammalian target of rapamycin (mTOR) pathway, which is linked to glycolysis and protein synthesis. CONCLUSIONS: Our study provides insight into the mechanisms of action of metformin in HS. The anti-inflammatory effects of metformin support its use as a therapeutic agent in HS, while its effects on immunometabolism suggest that targeting metabolism is a promising therapeutic option in inflammatory diseases, including HS.

Inflammation in the pathogenesis of depression: a disorder of neuroimmune origin.

There are several hypotheses concerning the underlying pathophysiological mechanisms of major depression, which centre largely around adaptive changes in neuronal transmission and plasticity, neurogenesis, and circuit and regional connectivity. The immune and endocrine systems are commonly implicated in driving these changes. An intricate interaction of stress hormones, innate immune cells and the actions of soluble mediators of immunity within the nervous system is described as being associated with the symptoms of depression. Bridging endocrine and immune processes to neurotransmission and signalling within key cortical and limbic brain circuits are critical to understanding depression as a disorder of neuroimmune origins. Emergent areas of research include a growing recognition of the adaptive immune system, advances in neuroimaging techniques and mechanistic insights gained from transgenic animals. Elucidation of glial-neuronal interactions is providing additional avenues into promising areas of research, the development of clinically relevant disease models and the discovery of novel therapies. This narrative review focuses on molecular and cellular mechanisms that are influenced by inflammation and stress. The aim of this review is to provide an overview of our current understanding of depression as a disorder of neuroimmune origin, focusing on neuroendocrine and neuroimmune dysregulation in depression pathophysiology. Advances in current understanding lie in pursuit of relevant biomarkers, as the potential of biomarker signatures to improve clinical outcomes is yet to be fully realised. Further investigations to expand biomarker panels including integration with neuroimaging, utilising individual symptoms to stratify patients into more homogenous subpopulations and targeting the immune system for new treatment approaches will help to address current unmet clinical need.

Conserving diversity in Irish plant-pollinator networks.

Beneficial insects provide valuable services upon which we rely, including pollination. Pollinator conservation is a global priority, and a significant concern in Ireland, where over half of extant bee species have declined significantly in recent decades. As flower-visiting insects rely on flowering plants, one way to conserve and promote pollinator populations is to protect high-quality habitat. We analyzed the structure of insect-flower interactions from multiple habitat categories in a large database of interactions from Ireland. Our primary goals were to compare spatial and temporal variation in Irish network structures, compare Irish networks to published networks from other countries, and provide evidence-based recommendations for pollinator conservation in Ireland by identifying well-visited plant species that may promote high pollinator diversity, abundance, and functional complementarity. Habitat types within Ireland differed substantially: seminatural grasslands had the highest pollinator species richness and largest number of unique pollinator species, while intensively managed habitats exhibited negative asymmetry (more plant than pollinator species). This negative asymmetry is notable because most plant-pollinator networks exhibit a positive asymmetry. Within intensively managed habitats, agricultural and urban habitats differed. Urban habitats had the highest number of non-native plant species while agricultural habitats had the lowest pollinator species richness. We also found Irish networks varied across the growing season, where July had the highest plant and insect species richness. When comparing Irish networks to published networks from other countries, we found Irish networks had a higher ratio of plant species to pollinator species, and that this difference was most evident in agricultural habitats. This ratio means the typical network asymmetry (more pollinator than plant species) was flipped (more plant than pollinator species) in the Irish network. We conclude that conserving seminatural grasslands in Ireland will be an essential component of pollinator conservation and identify thirty-five plant species important for restoring seminatural habitats.

ERS International Congress, Madrid, 2019: highlights from the Allied Respiratory Professionals' Assembly.

This article provides an overview of outstanding sessions that were (co)organised by the Allied Respiratory Professionals' Assembly during the European Respiratory Society International Congress 2019 in Madrid, Spain. Session content was mainly targeted at allied respiratory professionals such as respiratory physiologists, respiratory physiotherapists and respiratory nurses, and is summarised in this document. Short take-home messages related to pulmonary function testing highlight the importance of quality control. Furthermore, novel findings regarding the assessment of functional status call attention to bodily factors that can affect functional status. Regarding pulmonary rehabilitation, data were presented about the use of equipment and type of exercise training in COPD and lung cancer. Recent developments in physical activity-related research give insight in enablers of physical activity after hospital admission. The importance of integrated respiratory care was also highlighted, with the occupational therapist, nurse, and nutritional and psychological counsellor playing a pivotal role, which relates directly to research in the field of respiratory nursing that formulates the need for more nursing led-interventions in the future. To conclude, this review provides readers with valuable insight into some of the emerging and future areas affecting clinical practice of allied healthcare professionals.