Development of a non-invasive bioassay for adiponectin target engagement in mice.

Adiponectin-based therapeutic strategies are promising for managing metabolic diseases and reducing inflammation, prompting the development of adiponectin receptor agonists. However, monitoring their pharmacodynamic actions in clinical applications is challenging. This study aimed to identify peripheral biomarkers to monitor adiponectin actions using ALY688, an adiponectin receptor agonist peptide.

TRAF1 Deficiency in Macrophages Drives Exacerbated Joint Inflammation in Rheumatoid Arthritis.

The tumor necrosis factor receptor-associated factor 1 (TRAF1) plays a key role in promoting lymphocyte survival, proliferation, and cytokine production. Recent evidence showed that TRAF1 plays opposing roles in monocytes and macrophages where it controls NF-κB activation and limits pro-inflammatory cytokine production as well as inflammasome-dependent IL-1β secretion. Importantly, TRAF1 polymorphisms have been strongly linked to an increased risk of rheumatoid arthritis (RA).

A novel blood-based bioassay to monitor adiponectin signaling.

The diverse beneficial effects of adiponectin-receptor signaling, including its impact on the regulation of inflammatory processes in vivo, have resulted in development of adiponectin receptor agonists as a treatment for metabolic disorders. However, there are no established non-invasive bioassays for detection of adiponectin target engagement in humans or animal models. Here, we designed an assay using small amounts of blood to assess adiponectin action.

Ischemia-induced cardiac dysfunction is exacerbated in adiponectin-knockout mice due to impaired autophagy flux.

Strategies to enhance autophagy flux have been suggested to improve outcomes in cardiac ischemic models. We explored the role of adiponectin in mediating cardiac autophagy under ischemic conditions induced by permanent coronary artery ligation. We studied the molecular mechanisms underlying adiponectin's cardio-protective effects in adiponectin knockout (Ad-KO) compared with wild-type (WT) mice subjected to ischemia by coronary artery ligation and H9c2 cardiomyocyte cell line exposed to hypoxia.

The slow-release adiponectin analog ALY688-SR modifies early-stage disease development in the D2. mouse model of Duchenne muscular dystrophy.

Fibrosis is associated with respiratory and limb muscle atrophy in Duchenne muscular dystrophy (DMD). Current standard of care partially delays the progression of this myopathy but there remains an unmet need to develop additional therapies. Adiponectin receptor agonism has emerged as a possible therapeutic target to lower inflammation and improve metabolism in mouse models of DMD but the degree to which fibrosis and atrophy are prevented remain unknown.

Copper infused fabric attenuates inflammation in macrophages.

While inflammation is an important immune response for protection from infections, excessive or prolonged inflammation can lead to a variety of debilitating diseases including skin disease, diabetes, heart disease, stroke, autoimmune diseases and cancer. Inflammation is a graded response that is typically initiated when resident macrophages sense the presence of pathogens or damage in the tissue and produce inflammatory cytokines and chemokines to kill the pathogen, clear debris and dead tissue, and initiate tissue repair. Here we show that copper-infused fabrics can prevent inflammation by blocking the production of inflammatory cytokines from macrophages after being exposed to LPS, a component of bacterial cell wall.

Nod-like receptors in inflammatory arthritis.

Nod-like receptors (NLRs) are innate immune receptors that play a key role in sensing components from pathogens and from damaged cells or organelles. NLRs form signaling complexes that can lead to activation of transcription factors or effector caspases - by means of inflammasome activation -Inflammatory arthritis (IA) culminating in promoting inflammation. An increasing body of research supports the role of NLRs in driving pathogenesis of IA, a collection of diseases that include rheumatoid arthritis (RA), psoriatic arthritis (PsA), ankylosing spondylitis, and pediatric arthritis.

Memory impairment in the D2.mdx mouse model of Duchenne muscular dystrophy is prevented by the adiponectin receptor agonist ALY688.

New Findings: What is the central question of this study? Can adiponectin receptor agonism improve recognition memory in a mouse model of Duchenne muscular dystrophy? What is the main finding and its importance? Short-term treatment with the new adiponectin receptor agonist ALY688 improves recognition memory in D2.mdx mice. This finding suggests that further investigation into adiponectin receptor agonism is warranted, given that there remains an unmet need for clinical approaches to treat this cognitive dysfunction in people with Duchenne muscular dystrophy.

Moderate exercise induces trained immunity in macrophages.

Despite its importance in protecting the host from infections and injury, excessive inflammation may lead to serious human diseases including autoimmune disorders, cardiovascular diseases, diabetes, and cancer. Exercise is a known immunomodulator; however, whether exercise causes long-term changes in inflammatory responses and how these changes occur are lacking. Here, we show that chronic moderate-intensity training of mice leads to persistent metabolic rewiring and changes to chromatin accessibility in bone marrow-derived macrophages (BMDMs), which, in turn, tempers their inflammatory responses.

Autophagy deficiency exacerbates iron overload induced reactive oxygen species production and apoptotic cell death in skeletal muscle cells.

Iron overload is associated with various pathological changes which contribute to metabolic syndrome, many of which have been proposed to occur via damaging tissue through an excessive amount of reactive oxygen species (ROS) production. In this study, we established a model of iron overload in L6 skeletal muscle cells and observed that iron enhanced cytochrome c release from depolarized mitochondria, assayed by immunofluorescent colocalization of cytochrome c with Tom20 and the use of JC-1, respectively. This subsequently elevated apoptosis, determined via use of a caspase-3/7 activatable fluorescent probe and western blotting for cleaved caspase-3.

Cutting Edge: Negative Regulation of Inflammasome Activation by TRAF1 Can Limit Gout.

Secretion of IL-1β, a potent cytokine that plays a key role in gout pathogenesis, is regulated by inflammasomes. TRAF1 has been linked to heightened risk to inflammatory arthritis. In this article, we show that TRAF1 negatively regulates inflammasome activation to limit caspase-1 and IL-1β secretion in human and mouse macrophages.

Role of Mitochondrial Iron Overload in Mediating Cell Death in H9c2 Cells.

Iron overload (IO) is associated with cardiovascular diseases, including heart failure. Our study's aim was to examine the mechanism by which IO triggers cell death in H9c2 cells. IO caused accumulation of intracellular and mitochondrial iron as shown by the use of iron-binding fluorescent reporters, FerroOrange and MitoFerroFluor.

The Acute Effects of Milk Consumption on Systemic Inflammation after Combined Resistance and Plyometric Exercise in Young Adult Females.

High-intensity/impact exercise elicits a transient increase in inflammatory biomarkers. Consuming nutrient-dense wholefoods, like milk, following exercise may modulate post-exercise inflammation and aid recovery. We examined the effect of post-exercise skim milk consumption (versus an isoenergetic, isovolumetric carbohydrate [CHO] drink) on acute exercise-induced inflammation in untrained females.

Scientific meeting report: International Biochemistry of Exercise 2022.

Exercise is one of the only nonpharmacological remedies known to counteract genetic and chronic diseases by enhancing health and improving life span. Although the many benefits of regular physical activity have been recognized for some time, the intricate and complex signaling systems triggered at the onset of exercise have only recently begun to be uncovered. Exercising muscles initiate a coordinated, multisystemic, metabolic rewiring, which is communicated to distant organs by various molecular mediators.

Mitochondrial protein import stress regulates the LC3 lipidation step of mitophagy through NLRX1 and RRBP1.

Protein import into mitochondria is a highly regulated process, yet how cells clear mitochondria undergoing dysfunctional protein import remains poorly characterized. Here we showed that mitochondrial protein import stress (MPIS) triggers localized LC3 lipidation. This arm of the mitophagy pathway occurs through the Nod-like receptor (NLR) protein NLRX1 while, surprisingly, without the engagement of the canonical mitophagy protein PINK1.

Detection of ASC Oligomerization by Western Blotting.

Apoptosis-associated speck-like protein containing a caspase-recruitment domain (ASC) is an adaptor protein that is essential for the activation of several inflammasome complexes. Activation of inflammasomes leads to pathogenic clearance and inflammatory cell death called pyroptosis. Upon inflammasome activation, ASC oligomerization leads to the recruitment and activation of caspase-1, which in turn converts pro-inflammatory cytokines (e.

Measurement of Inflammasome-Induced Mitochondrial Dysfunction by Flow Cytometry.

A growing body of work has recently highlighted the pivotal role of mitochondria in the initiation and modulation of inflammasome activation. Specifically, mitochondrial dysfunction can induce NLRP3 inflammasome activation, where loss of mitochondrial potential leads to production of reactive oxygen species (ROS) and release of Ca, which in turn trigger inflammasome assembly. Therefore, several measures of mitochondrial parameters and components are routinely utilized in studies assessing mechanisms of inflammasome activation.

Regulation of the NLRP3 Inflammasome by Posttranslational Modifications.

Inflammasomes are important in human health and disease, whereby they control the secretion of IL-1β and IL-18, two potent proinflammatory cytokines that play a key role in inflammatory responses to pathogens and danger signals. Several inflammasomes have been discovered over the past two decades. NLRP3 inflammasome is the best characterized and can be activated by a wide variety of inducers.

The PKN1- TRAF1 signaling axis as a potential new target for chronic lymphocytic leukemia.

TRAF1 is a pro-survival adaptor molecule in TNFR superfamily (TNFRSF) signaling. TRAF1 is overexpressed in many B cell cancers including refractory chronic lymphocytic leukemia (CLL). Little has been done to assess the role of TRAF1 in human cancer.

Innate immunity drives pathogenesis of rheumatoid arthritis.

Rheumatoid arthritis (RA) is an autoimmune disease affecting ∼1% of the general population. This disease is characterized by persistent articular inflammation and joint damage driven by the proliferating synovial tissue fibroblasts as well as neutrophil, monocyte and lymphocyte trafficking into the synovium. The factors leading to RA pathogenesis remain poorly elucidated although genetic and environmental factors have been proposed to be the main contributors to RA.

Dicer regulates activation of the NLRP3 inflammasome.

Inflammation plays a critical role in initiation of adaptive immunity, pathogen clearance and tissue repair. Interleukin (IL)-1β is a potent pro-inflammatory cytokine and therefore its production is tightly regulated: its secretion requires the assembly of a macromolecular protein complex, termed the inflammasome. Aberrant activation of the inflammasome has been linked to debilitating human diseases including chronic inflammatory and autoimmune diseases.

The Evolving Role of TRAFs in Mediating Inflammatory Responses.

TRAFs [tumor necrosis factor (TNF) receptor associated factors] are a family of signaling molecules that function downstream of multiple receptor signaling pathways and play a pivotal role in the biology of innate, and adaptive immune cells. Following receptor ligation, TRAFs generally function as adapter proteins to mediate the activation of intracellular signaling cascades. With the exception of TRAF1 that lacks a Ring domain, TRAFs have an E3 ubiquitin ligase activity which also contributes to their ability to activate downstream signaling pathways.

TRAF1 Signaling in Human Health and Disease.

Tumor necrosis factor receptor (TNFR) associated factor 1 (TRAF1) is a signaling adaptor first identified as part of the TNFR2 signaling complex. TRAF1 plays a key role in pro-survival signaling downstream of TNFR superfamily members such as TNFR2, LMP1, 4-1BB, and CD40. Recent studies have uncovered another role for TRAF1, independent of its role in TNFR superfamily signaling, in negatively regulating Toll-like receptor and Nod-like receptor signaling, through sequestering the linear ubiquitin assembly complex, LUBAC.