O-GlcNAcylation is an atypical, reversible, and dynamic glycosylation that plays a critical role in maintaining the normal physiological functions of cells by regulating various biological processes such as signal transduction, proteasome activity, apoptosis, autophagy, transcription, and translation. It can also respond to environmental changes and physiological signals to play the role of “stress receptor” and “nutrition sensor” in a variety of stress responses and biological processes. Even, a homeostatic disorder of O-GlcNAcylation may cause many diseases. Therefore, O-GlcNAcylation and its regulatory role in stress response are reviewed in this paper.

Ambient air temperature is a key factor affecting human health. Long-term exposure to a cold environment can cause various diseases, while the impact on the intestine, the organ which has the largest contact area with the external environment, cannot be ignored. In this study, we investigated the effect of chronic cold exposure on the colon and its preliminary mechanism of action. Mice were exposed to 4°C for 3 hours a day for 10 days. We found that cold exposure damaged the morphology and structure of the colon, destroyed the tight junctions of the colonic epithelial tissue, and promoted inflammation of the colon. At the same time, cold exposure also activated the unfolded protein response (UPR) in the colon and promoted apoptosis in intestinal epithelial cells. Chronic cold exposure induced oxidative stress in vivo, but also significantly enhanced the response of the Nrf2 pathway that promotes an anti-oxidant effect. Furthermore, we demonstrated that chronic cold exposure promoted p65 acetylation to aggravate the inflammatory response by inhibiting SIRT1. Similar results were observed following SIRT1 knock-down by shRNA in Caco-2 cells treated with Thapsigargin (Tg). Knock-down of SIRT1 promoted nuclear localization of Nrf2, and increased the level of Nrf2 acetylation. Taken together, our study indicates that cold exposure may aggravate endoplasmic reticulum stress and damage epithelial tight junctions in the colon by inhibiting SIRT1, which promotes nuclear localization of Nrf2 and induces an anti-oxidant response to maintain intestinal homeostasis. These findings suggest that SIRT1 is a potential target for regulating intestinal health under cold exposure conditions.

Cold stress can induce neuroinflammation in the hippocampal dentate gyrus (DG), but the mechanism underlying neuronal apoptosis induced by cold stress is not well-understood. To address this issue, male and female C57BL/6 mice were exposed to a temperature of 4 °C for 3 h per day for 1 week, and glial cell activation, neuronal apoptosis, and neuroinflammation were evaluated by western blotting, immunofluorescence, terminal deoxynucleotidyl transferase 2’-deoxyuridine 5’-triphosphate (dUTP) nick end labeling, Nissl staining, and immunohistochemistry. Additionally, BV2 cells were treated with different concentrations of cortisol (CORT) for 3 h to mimic stress and molecular changes were assessed by western blotting, immunofluorescence, and co-immunoprecipitation. We found that excess CORT activated glial cells and increased neuroinflammation in the DG of mice exposed to cold temperatures, which was associated with increased acetylation and nuclear factor-κB signaling. These effects were mediated by the acetylation of lysine 9 of histone 3 and lysine 310 of p65, which resulted in increased mitogen-activated protein kinase phosphorylation, nuclear translocation of p65, microglia activation, and acetylation of high-mobility group box 1. Neuroinflammation was more severe in male compared to female mice. These findings provide new insight into the mechanisms of the cold stress response, which can inform the development of new strategies to combat the effects of hypothermia.

The main danger of cold stress to animals in cold regions is systemic metabolic changes and protein synthesis inhibition. Cold-induced RNA-binding protein is a cold shock protein that is rapidly up-regulated under cold stimulation in contrast to the inhibition of most proteins and participates in multiple cellular physiological activities by regulating targets. Therefore, this study was carried out to investigate the possible mechanism of CIRP-mediated glucose metabolism regulation and survival promotion in skeletal muscle after acute cold exposure. Skeletal muscle and serum from mice were obtained after 0, 2, 4 and 8 h of acute hypothermia exposure. Subsequently, the changes of CIRP, metabolism and apoptosis were examined. Acute cold exposure increased energy consumption, enhanced glycolysis, increased apoptosis, and up-regulated CIRP and phosphorylation of AKT. In addition, CIRP overexpression in C2C12 mouse myoblasts at each time point under 37°C and 32°C mild hypothermia increased AKT phosphorylation, enhanced glucose metabolism, and reduced apoptosis. CIRP knockdown by siRNA interference significantly reduced the AKT phosphorylation of C2C12 cells. Wortmannin inhibited the AKT phosphorylation of skeletal muscle after acute cold exposure, thereby inhibiting glucose metabolism and aggravating apoptosis. Taken together, acute cold exposure up-regulates CIRP in mouse skeletal muscle, which regulates glucose metabolism and maintains energy balance in skeletal muscle cells through the AKT signaling pathway, thus slowing down the apoptosis of skeletal muscle cells.