Implementation and engagement of the SMART Work & Life sitting reduction intervention: an exploratory analysis on intervention effectiveness.

BACKGROUND: To enhance the impact of interventions, it is important to understand how intervention engagement relates to study outcomes. We report on the level of implementation and engagement with the SMART Work & Life (SWAL) programme (delivered with (SWAL plus desk) and without a height-adjustable desk (SWAL)) and explore the effects of different levels of this on change in daily sitting time in comparison to the control group. METHODS: The extent of intervention delivery by workplace champions and the extent of engagement by champions and participants (staff) with each intervention activity was assessed by training attendance logs, workplace champion withdrawal dates, intervention activities logs and questionnaires. These data were used to assess whether a cluster met defined criteria for low, medium, or high implementation and engagement or none of these. Mixed effects linear regression analyses tested whether change in sitting time varied by: (i) the number of intervention activities implemented and engaged with, and (ii) the percentage of implementation and engagement with all intervention strategies. RESULTS: Workplace champions were recruited for all clusters, with 51/52 (98%) attending training. Overall, 12/27 (44.4%) SWAL and 9/25 (36.0%) SWAL plus desk clusters implemented all main intervention strategies. Across remaining clusters, the level of intervention implementation varied. Those in the SWAL (n = 8 (29.6%) clusters, 80 (32.1%) participants) and SWAL plus desk (n = 5 (20.0%) clusters, 41 (17.1%) participants) intervention groups who implemented and engaged with the most intervention strategies and had the highest percentage of cluster implementation and engagement with all intervention strategies sat for 30.9 (95% CI -53.9 to -7.9, p = 0.01) and 75.6 (95% CI -103.6 to -47.7, p < 0.001) fewer minutes/day respectively compared to the control group at 12 month follow up. These differences were larger than the complete case analysis. The differences in sitting time observed for the medium and low levels were similar to the complete case analysis. CONCLUSIONS: Most intervention strategies were delivered to some extent across the clusters although there was large variation. Superior effects for sitting reduction were seen for those intervention groups who implemented and engaged with the most intervention components and had the highest level of cluster implementation and engagement. TRIAL REGISTRATION: ISRCTN11618007. Registered on 24 January 2018. https://www.isrctn.com/ISRCTNISRCTN11618007 .

The role of hydrogen sulfide in the retina.

The discovery of the hydrogen sulfide (H2S) and the transsulfuration pathway (TSP) responsible for its synthesis in the mammalian retina has highlighted this molecule's wide range of physiological processes that influence cellular signaling, redox homeostasis, and cellular metabolism. The multi-level regulatory program that influences H2S levels in the retina depends on the relative expression and activity of TSP enzymes, which regulate the abundance of competitive substrates that support or abrogate H2S synthesis. In addition, and apart from TSP, intracellular H2S levels are regulated by mitochondrial sulfide oxidizing pathways. Retinal layers natively express differing levels of TSP enzymes, which highlight the differences in the metabolite and substrate requirement. Recent studies indicate that these systems are susceptible to pathophysiologies affecting the retina. Dysregulation at any level can upset the balance of redox and signaling processes and possibly upset oxidative stress, apoptotic signaling, ion channels, and immune response within this sensitive tissue. H2S donors are a potential therapeutic in such cases and have been demonstrated to bridge the gap, positively impacting the damaged retina. Here, we review the recent findings of H2S, how its multi-level regulation impacts the retina, and how its dysregulation is implicated in retinal pathologies.

Glucose Transporter Glut1-Dependent Metabolic Reprogramming Regulates Lipopolysaccharide-Induced Inflammation in RAW264.7 Macrophages.

This study investigated the critical role of Glut1-mediated glucose metabolism in the inflammatory response of macrophages, which are energy-intensive cells within the innate immune system. Inflammation leads to increased Glut1 expression, ensuring sufficient glucose uptake to support macrophage functions. We demonstrated that using siRNA to knock down Glut1 reduces the expression of various pro-inflammatory cytokines and markers, such as IL-6, iNOS, MHC II/CD40, reactive oxygen species, and the hydrogen sulfide (H2S)-producing enzyme cystathionine γ-lyase (CSE). Glut1 activates a pro-inflammatory profile through a nuclear factor (NF)-κB, while silencing Glut1 can prevent lipopolysaccharide (LPS)-induced IκB degradation, blocking NF-κB activation. Glut1's role in autophagy, an essential process for macrophage functions such as antigen presentation, phagocytosis, and cytokine secretion, was also measured. The findings show that LPS stimulation decreases autophagosome formation, but Glut1 knockdown reverses this effect, increasing autophagy beyond control levels. The study highlights Glut1's importance in macrophage immune responses and its regulation of apoptosis during LPS stimulation. Knocking down Glut1 negatively impacts cell viability and mitochondrial intrinsic pathway signaling. These findings collectively suggest that targeting macrophage glucose metabolism through Glut1 could potentially serve as a target for controlling inflammation.

From Gasotransmitter to Immunomodulator: The Emerging Role of Hydrogen Sulfide in Macrophage Biology.

Hydrogen sulfide (H2S) has been increasingly recognized as a crucial inflammatory mediator in immune cells, particularly macrophages, due to its direct and indirect effects on cellular signaling, redox homeostasis, and energy metabolism. The intricate regulation of endogenous H2S production and metabolism involves the coordination of transsulfuration pathway (TSP) enzymes and sulfide oxidizing enzymes, with TSP's role at the intersection of the methionine pathway and glutathione synthesis reactions. Additionally, H2S oxidation mediated by sulfide quinone oxidoreductase (SQR) in mammalian cells may partially control cellular concentrations of this gasotransmitter to induce signaling. H2S is hypothesized to signal through the posttranslational modification known as persulfidation, with recent research highlighting the significance of reactive polysulfides, a derivative of sulfide metabolism. Overall, sulfides have been identified as having promising therapeutic potential to alleviate proinflammatory macrophage phenotypes, which are linked to the exacerbation of disease outcomes in various inflammatory conditions. H2S is now acknowledged to have a significant influence on cellular energy metabolism by affecting the redox environment, gene expression, and transcription factor activity, resulting in changes to both mitochondrial and cytosolic energy metabolism processes. This review covers recent discoveries pertaining to the involvement of H2S in macrophage cellular energy metabolism and redox regulation, and the potential implications for the inflammatory response of these cells in the broader framework of inflammatory diseases.

Cystathionine γ-lyase and hydrogen sulfide modulates glucose transporter Glut1 expression via NF-κB and PI3k/Akt in macrophages during inflammation.

Macrophages play a crucial role in inflammation, a defense mechanism of the innate immune system. Metabolic function powered by glucose transporter isoform 1 (Glut1) is necessary for macrophage activity during inflammation. The present study investigated the roles of cystathionine-γ-lyase (CSE) and its byproduct, hydrogen sulfide (H2S), in macrophage glucose metabolism to explore the mechanism by which H2S acts as an inflammatory regulator in lipopolysaccharide- (LPS) induced macrophages. Our results demonstrated that LPS-treated macrophages increased Glut1 expression. LPS-induced Glut1 expression is regulated via nuclear factor (NF)-κB activation and is associated with phosphatidylinositol-3-kinase PI3k activation. Small interfering (si) RNA-mediated silencing of CSE decreased the LPS-induced NF-κB activation and Glut1 expression, suggesting a role for H2S in metabolic function in macrophages during pro-inflammatory response. Confoundingly, treatment with GYY4137, an H2S-donor molecule, also displayed inhibitory effects upon LPS-induced NF-κB activation and Glut1 expression. Moreover, GYY4137 treatment increased Akt activation, suggesting a role in promoting resolution of inflammation. Our study provides evidence that the source of H2S, either endogenous (via CSE) or exogenous (via GYY4137), supports or inhibits the LPS-induced NF-κB activity and Glut1 expression, respectively. Therefore, H2S may influence metabolic programming in immune cells to alter glucose substrate availability that impacts the immune response.