Modulation of Pancreatic Islets' Function and Survival During Aging Involves the Differential Regulation of Endoplasmic Reticulum Stress by p21 and CHOP

Abstract

Aims: Although endoplasmic reticulum (ER) stress is recognized as a major mechanism causing pancreatic dysfunction in diabetes, little is known on how aging modulates the process. Here, we compared the response with ER stress, viability, and insulin release from pancreatic islets of young (6 weeks) or aged (14 months) mice. Results: Islets from aged mice were more sensitive to ER stress than their younger counterparts; they exhibited more pronounced unfolded protein response (UPR) and caspase activation and displayed compromised insulin release after high-glucose stimulation. Genetic ablation of p21 sensitized the islets to ER stress, especially in the aged group, whereas CHOP ablation was protective for islets from both aged and younger animals. Ciclopirox (CPX), an iron chelator that stimulates p21 expression, protected islets from glucotoxicity and mice from dietinduced diabetes, especially in the aged group in a manner that was both p21 and CHOP dependent. Innovation: For the first time, the study shows that age-dependent susceptibility to diet-induced diabetes is associated with the activity of p21 and CHOP in pancreatic islets and that CPX protects islets from glucotoxicity and mice from diabetes in an age-dependent manner. Conclusions: Our results identify ER stress as an age-dependent modifier of islet survival and function by mechanisms implicating enhancement of CHOP activity and inhibition of the protective activity of p21. These findings suggest that interventions restoring the homeostatic activity of ER stress, by agents such as CPX, may be particularly beneficial for the management of diabetes in the elderly. Antioxid. Redox Signal. 27,[185][186][187][188][189][190][191][192][193][194][195][196][197][198][199][200]

Superior efficacy of the antifungal agent ciclopirox olamine over gemcitabine in pancreatic cancer models

“…In view of the ability of CPX to scavenge ROS [ 30 ], we evaluated the levels of 8-hydroxy-2’ -deoxyguanosine (8-OHdG) in the pancreas tissue of human pancreatic tumor xenograft models that have been administrated to CPX alone or gemcitabine alone or in combination with CPX (Figure 6A ). As shown in Figure 6D gemcitabine single agent caused a strong induction of ROS accumulation significantly (for BxPC-3, PANC-1; P < 0.05, for MIA-PACA-2; P < 0.01), whereas CPX single agent did not affect ROS accumulation.…”

“…Also, we have shown in vitro that CPX can enhance gemcitabine's cytotoxicity, suggesting that ROS generation destroys malignant cells by CPX-induced apoptosis. Noteworthy the ROS scavenging activity of CPX inhibits the ROS production of the pancreatic tissues, underlying the beneficial properties of CPX in healthy tissues [ 30 ]. We further investigated the role of CPX in ROS generation, in mouse pancreatic tissues followed CPX monotherapy, in vivo .…”

“…Next, the tissues were frozen in liquid nitrogen and stored at −80°C until analyzed. Subsequently, for cell cultures and pancreatic tissues, oxidative damage 8-OHdG was quantified with the highly sensitive 8-OHdG check enzyme-linked immunosorbent assay (ELISA) kit (Genox Corp., Baltimore, MD) in agreement with the manufacturer's instructions, as described in [ 30 ].…”

Retracted: Cell‐autonomous cytotoxicity of type I interferon response via induction of endoplasmic reticulum stress

“…Thus, we exposed WT, p21KO, p53KO, and CHOPKO fibroblasts to 5-aza alone or in combination with TUDCA or 4-PBA and monitored BiP and CHOP expression and cell survival. For this experiment, we also used CPX, an iron chelator and ER stress inhibitor (23,24). TUDCA significantly increased survival in WT, p53KO, and p21KO fibroblasts, whereas CPX was effective in p53KO fibroblasts ( Fig.…”

Endoplasmic Reticulum Unfolded Protein Response, Aging and Exercise: An Update

“…Several studies have shown decreased BiP levels in different tissues from aged mice and rats (Rabek et al, 2003; Erickson et al, 2006; Gavilán et al, 2006; Hussain and Ramaiah, 2007; Naidoo et al, 2008; Mihailidou et al, 2017). Other researches have indicated that BiP levels are not compromised in aged flies (Brown et al, 2014), several tissues from mice (Wu et al, 2010; Naidoo et al, 2011; Jiao et al, 2012; Torres-González et al, 2012) or rats (O'Leary et al, 2013; Baehr et al, 2016), and human muscle (Ogborn et al, 2014).…”