High-dose vitamin C alleviates pancreatic injury via the NRF2/NQO1/HO-1 pathway in a rat model of severe acute pancreatitis

Abstract

Background: Oxidative stress plays a pivotal role in the progress of severe acute pancreatitis (SAP).Vitamin C (VC) is the most important antioxidant in plasma. However, the effects of an intravenous administration of high-dose VC and the mechanisms by which it exerts its antioxidant function in an experimental model of SAP have not been determined.Methods: Sodium taurocholate was used to induce rat pancreatic injury and AR42J cells injury. After the establishment of SAP model, SAP rat and injured AR42J cells were treated with VC. For the injured AR42J cells, small interfering RNA-mediated knockdown of NRF2 was conducted after VC treatment.The histopathological characteristics, the apoptosis of pancreatic acinar cells, oxidative stress markers and levels of enzymes, biochemical indicators, and inflammatory cytokines were examined in vivo and in vitro.Furthermore, the mortality of rats was assessed.Results: In vivo and in vitro results demonstrated that VC treatment ameliorated apoptosis of pancreatic acinar cells, as evidenced by the increase in Bcl-2, Bcl-XL, and MCL-1 expressions and decrease in Bax and cleaved caspase-3 expression along with decreased TUNEL-positive cells. Also, we found that the elevation of MDA and decrease of SOD, GPx, GSH/GSSG, and T-AOC induced by SAP were reversed by VC treatment in vivo and in vitro, and VC treatment increased expressions of Nrf2, NQO1, and HO-1 in SAP model at protein and gene level, indicating that VC attenuated oxidative stress via the NRF2/NQO1/HO-1 pathway. Meanwhile, it was found that sodium taurocholate significantly induced the release of amylase, lipase, IL-1β, and IL-6 in rat plasma and AR42J cells, which were declined by VC treatment. In vitro results also revealed that these alterations in sodium taurocholate-injured AR42J cells due to VC treatment was attenuated by NRF2 knockdown. In addition, VC at a dose of 500 mg/kg decreased the levels of lactic acid, Cre, NGAL, AST, and ALT in the plasma of SAP rats, suggesting the improvement of renal and pancreatic injury and liver function of SAP rats. Furthermore, the mortality of SAP rats was 50%, which declined to 30% after VC treatment. Conclusions:The present study suggests that high-dose of VC ameliorate pancreatic injury of SAP via the NRF2/NQO1/HO-1 pathway to inhibit oxidative stress.

Vitamin C for sepsis intervention: from redox biochemistry to clinical medicine

“…In a rat model of severe acute pancreatitis and an in vitro model of taurocholate-induced injury in AR42J rat pancreatic acinar cells, vitamin C has been shown to attenuate pancreatic cell injury likely via activating the Nrf2/NQO1/HO-1 pathway [46]. Notably, the protective effects of vitamin C on taurocholate-induced AR42J cell injury was attenuated by Nrf2 knockdown [46], suggesting a causal role for Nrf2 signaling in mediating vitamin C cytoprotection. Presently, how vitamin C activates Nrf2 signaling remains unclear though an early study suggested a possible involvement of phosphoinositide 3-kinase [47].…”

“…Nrf2 is a major regulator of cellular antioxidative and other cytoprotective genes [45]. In a rat model of severe acute pancreatitis and an in vitro model of taurocholate-induced injury in AR42J rat pancreatic acinar cells, vitamin C has been shown to attenuate pancreatic cell injury likely via activating the Nrf2/NQO1/HO-1 pathway [46]. Notably, the protective effects of vitamin C on taurocholate-induced AR42J cell injury was attenuated by Nrf2 knockdown [46], suggesting a causal role for Nrf2 signaling in mediating vitamin C cytoprotection.…”

The Challenges and Effects of Ascorbic Acid Treatment of Acute Pancreatitis: A Systematic Review and Meta-Analysis of Preclinical and Clinical Studies

“…Four studies that did not report main outcomes of interest were excluded (32)(33)(34)(35), and two studies reported overlapping data, so one of them was excluded (36). Finally, four studies were included in the metaanalysis for clinical trials (37)(38)(39)(40) and nine articles (41)(42)(43)(44)(45)(46)(47)(48)(49) in the meta-analysis for preclinical studies (Figure 1).…”

A narrative review of a type of pancreatitis worthy of attention: acute pancreatitis associated with pancreatic tumors—current problems and future thinking

“…The cellular events important to the pathogenesis of AP include pathological calcium signaling (10)(11)(12), premature trypsinogen activation within macrophages and acinar cells (13)(14)(15), mitochondrial dysfunction (16,17), endoplasmic reticulum (ER) stress (18,19), impaired autophagy, and impaired unfolded protein response (UPR) (17). These events are caused by usual acinar cell toxins, such as nicotine, alcohol, and bile acids.…”