Fralin Biomedical Research Institute

This meta-review aimed to synthesize the evidence of the effects of exercise on anxiety and depression symptoms amongst adults with cancer, and cancer-survivors, comparing effects sizes between meta-analysis.

Major databases were searched up to February 9, 2024 for meta-analyses evaluating the effects of exercise, using anxiety and/or depression scales. Effect size (ES) values were calculated as standardized differences in the means and expressed as the Standardized Mean Difference (SMD) with the 95% confidence interval (95%CI). A total of eight unique meta-analyses were included.

Among meta-analyses examining both anxiety and depression symptoms overall, a small beneficial effect of exercise was shown [SMD = 0.41 (0.25-0.57); p < 0.0001]. Subgroup analyses revealed that exercise has a small effect on decreasing anxiety [SMD = 0.42 (0.04-0.79); p = 0.027], and depressive symptoms [SMD = 0.38 (0.21-0.56); p < 0.0001]. In addition, aerobic exercise has a moderate effect on reducing depressive symptoms [SMD = 0.54 (0.16-0.93); p = 0.005], whereas resistance exercise has no effect. Subgroup analyses by type of cancer observed a moderate effect on decreasing depressive symptoms in patients with breast cancer [SMD = 0.51 (0.27-0.74); p < 0.0001].

Exercise (specifically aerobic) should be considered by healthcare professionals as a strategy to treat/manage symptoms of anxiety and depression amongst adults with cancer and cancer-survivors.

Reactive oxygen species (ROS) are critical mediators of cellular signaling that regulate metabolic homeostasis, including lipid uptake, synthesis, and storage. NADPH oxidase 4 (NOX4), a significant enzymatic source of ROS, has been identified as a redox-sensitive regulator of glucose and lipid metabolism. However, its contribution to sex-specific metabolic regulation remains poorly defined. This study compared how NOX4 knock-out (NOX4 KO) shifted systemic and tissue-specific metabolic phenotypes between male and female mice fed with a high-fat diet (HFD) for 20-weeks. We observed that male NOX4 mice on HFD exhibited reduced adiposity, diminished liver lipid accumulation, and improved glucose and insulin tolerance compared to male WT mice on HFD. In contrast, female NOX4 KO mice developed increased adiposity and lipid accumulation in peripheral adipose depots, accompanied by impaired glucose tolerance. Gene expression profiling in skeletal muscle and liver revealed distinct, sex-specific patterns of changes in genes related to lipid uptake, synthesis, and storage, possibly implicating differential activation of PPAR signaling pathways supportive of in vivo data. These findings identify NOX4 as a central regulator of sexually dimorphic lipid metabolism, acting through redox-sensitive transcriptional networks to shape divergent metabolic responses to HFD.

Toll-like receptor 4 (TLR4), a pattern-recognition receptor located on the plasma membrane, senses extracellular danger signals to initiate inflammatory immune responses. It is initially synthesized in the endoplasmic reticulum (ER), undergoes N-linked glycosylation, and is subsequently transported to the Golgi before ultimately reaching the plasma membrane. However, the mechanisms underlying the processing and maturation of TLR4 in the ER remain elusive. Through whole genome-wide CRISPR screening, CCDC134 was identified as a critical and essential factor for TLR4-dependent inflammatory response. Localization of CCDC134 in the ER lumen rather than its exosome-mediated secretion is required for its role in TLR4 signaling. Loss of CCDC134 results in the retention of TLR4 in the ER for subsequent ER-associated degradation, and thus blockade of TLR4 maturation and plasma membrane trafficking. Defects in TLR4 processing and maturation in the ER in CCDC134-depleted cells are caused by aberrant hyperglycosylation and destabilization of glycoprotein 96 (gp96), a key chaperone of TLR4. These results suggest that CCDC134 controls gp96 glycosylation to facilitate TLR4 maturation in the ER.