Optimizing PDIA1 Inhibition as a Strategy to Inhibit NLRP3 Inflammasome Activation and Activity.

The NLRP3 inflammasome is a protein complex that promotes pro-inflammatory signaling as part of the innate immune response. Hyperactivation of the NLRP3 inflammasome has been implicated in many inflammatory and neurodegenerative diseases, leading to significant effort in developing strategies to limit its activation to intervene in these disorders. We previously showed that pharmacologic inhibition of endoplasmic reticulum (ER)-localized protein disulfide isomerase PDIA1 suppresses NLRP3 activation and activity, identifying PDIA1 as a potential therapeutic target to mitigate hyperactive NLRP3 activity.

Skeletal Muscle Fatigue in Rats Is More Consistently Related to Increased Inorganic Phosphate Concentration Than Acidosis.

Aim: Distinguish the relative importance of intramuscular acidosis (hydrogen ion) and inorganic phosphate in skeletal muscle fatigue in vivo in rats.

Methods: We used direct sciatic nerve electrical stimulations to evoke twitches at different frequencies of contraction (0.25-, 0.

Drug Repurposing Screen Identifies an HRI Activating Compound that Promotes Adaptive Mitochondrial Remodeling in MFN2-deficient Cells.

Pathogenic variants in the mitochondrial outer membrane GTPase MFN2 cause the peripheral neuropathy Charcot-Marie-Tooth Type 2A (CMT2A). These mutations disrupt MFN2-dependent regulation of diverse aspects of mitochondrial biology including organelle morphology, motility, mitochondrial-endoplasmic reticulum (ER) contacts (MERCs), and respiratory chain activity. However, no therapies currently exist to mitigate the mitochondrial dysfunction linked to genetic deficiencies in MFN2.

Patterns of care in the management of high-risk COPD in Australia (2015-2019): an observational study for the CONQUEST quality improvement program.

Background: We compared the management of patients with 'high-risk' COPD in Australia to national/international guidelines and quality standards, including the COllaboratioN on QUality improvement initiative for achieving Excellence in STandards of COPD care (CONQUEST).

Methods: Eligible patients in the Optimum Patient Care Research Database Australia were categorized as newly diagnosed (≤12 months after diagnosis), already diagnosed, or patients with potential undiagnosed COPD, in each year from 2015 to 2019. 'High-risk' patients had ≥2 COPD exacerbations/exacerbation-like events in the last 24 months.

Inhibition of NF-κB Signaling by the Reactive Glycolytic Metabolite Methylglyoxal.

The NF-κB family of transcription factor complexes are central regulators of inflammation, and their dysregulation contributes to the pathology of multiple inflammatory disease conditions. Accordingly, identifying pharmacological mechanisms that restrain NF-κB overactivation remains an area of key importance. Here, we demonstrate that inhibition of the glycolytic enzyme phosphoglycerate kinase 1 (PGK1) with the small molecule inhibitor CBR-470-2 results in attenuated NF-κB signaling, decreasing transcriptional output in response to several canonical NF-κB activating stimuli.