Salubrinal-mediated activation of eIF2α signaling improves oxidative stress-induced BMSCs senescence and senile osteoporosis

Integrated Stress Response (ISR) Pathway: Unraveling Its Role in Cellular Senescence

“…In this model, the knockdown of PERK or IRE1α increased the number of senescent cells, while salubrinal attenuated this process. Thus, activation of the ISR signaling reduced senescence in this model [206].…”

“…Although salubrinal maintains the activity of the Bcl2 protein, which normally protects cells from apoptosis, this pro-apoptotic effect is likely to be a result of excessive ISR activation. Interestingly, in the same experiment, treatment of BMSCs with AMG44, a PERK kinase inhibitor, suppressed ISR signaling but did not affect the senescent state of these cells [206]. The anti-senescent effect of salubrinal has been demonstrated not only in a model of H 2 O 2 -induced senescence but also in a more complex system where senescence was induced by suppressing the expression of the autophagy receptor gene NBR1 using siRNA.…”

“…In cultures of senescent BMSCs, salubrinal reduced the number of SA-βGAL-positive cells by 34.8% and significantly enhanced the proliferative activity of approximately 28.5% of the cells. However, exposure to salubrinal also led to an increase in the number of early apoptotic cells by 6.2% [206]. Although salubrinal maintains the activity of the Bcl2 protein, which normally protects cells from apoptosis, this pro-apoptotic effect is likely to be a result of excessive ISR activation.…”

Undersized telomeres in regulatory T cells link to the pathogenesis of allergic rhinitis

“…Salubrinal has been used in the studies of ER stress inhibition. It can improve cardiac hypertrophy, 11 osteoporosis, 12 arthritis, 13 and inhibition of TNF-α-triggered NF-κB activation. 14 Current data indicate that administration of Salubrinal also can attenuate experimental airway allergy by improving the abundance of Tregs in the airway tissues.…”

“…ER stress-related overproduction of X-box binding protein-1 (XBP1) can cause disruption in dendritic cell homeostasis and reduce their ability to fight tumors. 10 Proline-rich receptor-like protein kinase (PERK) and eukaryotic initiation factor 2-α (eIF2a) are also ER stress-associated molecules, which are involved in regulating many biochemical processes, such as cardiac hypertrophy, 11 osteoporosis, 12 arthritis, 13 and inhibition of tumor necrosis factor alpha (TNF-α)-triggered nuclear factor κB (NF-κB) activation. 14 However, the detailed mechanism by which eIF2a regulates Treg’s destiny remains unknown.…”