Quercetin Alleviates Intestinal Oxidative Damage Induced by H₂O₂ via Modulation of GSH: In Vitro Screening and In Vivo Evaluation in a Colitis Model of Mice

Abstract

The gastrointestinal tract is exposed to pro-oxidants from food, host immune factors, and microbial pathogens, which may induce oxidative damage. Oxidative stress has been shown to play an important role in the onset of inflammatory bowel disease. This study aimed to use a novel model to evaluate the effects of a screened natural component and explore its possible mechanism. An in vitro oxidative stress Caco2 cell model induced by H 2 O 2 was established using a realtime cellular analysis system and verified by addition of glutathione (GSH). A variety of plant components were chosen for the screening. Quercetin was the most effective phytochemical to alleviate the decreased cell index caused by H 2 O 2 among the tested plant components. Furthermore, quercetin ameliorated dextran sulfate sodium salt (DSS)-induced colitis and further increased the serum GSH. The mechanism of quercetin protection was explored in Caco2. Reversed H 2 O 2 -induced cell damage and decreased reactive oxygen species and apoptosis ratio were observed in quercetintreated cells. Also, quercetin increased expression of the glutamate-cysteine ligase catalytic subunit (GCLC), the first rate-limiting enzyme of glutathione synthesis, and increased intracellular GSH concentration under H 2 O 2 treatment. This effect was abolished by the GCLC inhibitor buthionine sulfoximine. These results indicated that quercetin can improve cell proliferation and increase intracellular GSH concentrations by upregulating transcription of GCLC to eliminate excessive reactive oxygen species (ROS). Increased extracellular H 2 O 2 concentration induced by quercetin under oxidative stress was related to the inhibition of AQP3 and upregulation of NOX1/2, which may contribute to the observed protective effects of quercetin. Moreover, the novel H 2 O 2 -induced oxidative stress cell model based on the real-time cellular analysis system was an effective model to screen natural products to deal with intestinal oxidative damage and help accelerate the discovery of new drugs for inflammatory bowel disease (IBD).

Selenium-Containing Amino Acids Protect Dextran Sulfate Sodium-Induced Colitis via Ameliorating Oxidative Stress and Intestinal Inflammation

“…The oxidative system mainly includes excessive ROS that can induce oxidative stress, trigger lipid peroxidation, attack cell membrane lipids, and cause colonic mucosal damage. 24 , 25 In response to injury, neutrophils, monocytes, eosinophils, and macrophages from the blood are activated to produce free radicals and ROS, which act as mediators that promote the inflammatory response. 26 They also have cytotoxic effects.…”

Network Pharmacology Identifies the Mechanisms of Action of Tongxie Anchang Decoction in the Treatment of Irritable Bowel Syndrome with Diarrhea Predominant

“…It suggested that TXACD has the biological characteristics of multicomponent and multitarget in treating IBS-D. Quercetin (degree � 298), kaempferol (degree � 122), 6-gingerol (degree � 95), (2R,3S)-2-(3′,4′-dihydroxyphenyl)-3-acetylamino-7-(N-acetyl-2′′-aminoethyl)-1,4-piperocycline (degree � 95), betasitosterol (degree � 74), and flavone (degree � 70) are the main active compounds of TXACD, demonstrating that they played an crucial role in the treatment of IBS-D. It was reported that quercetin could attenuate oxidative stress and DNA damage by regulating NRF2/Keap1 signaling pathway [24] and reverse cell damage induced by H 2 O 2 [25]. Kaempferol, as a flavonol, has the function of anti-inflammation and antioxidative stress by regulating the SIRT1/HMGB1/NF-kB axis [26,27].…”

Ameliorative Role of Quercetin on Intestinal Hitomorpometric, Oxidative Status and Pro-Inflammatory Changes in Hydrogen Peroxide–exposed Rats

“…A study reported that QCT ameliorate oxidative stress biomarkers such as myeloperoxidase and MAD (Hong and Piao, 2018), and the mechanism could be amelioration of T-cell mediated colitis by modulating the(HO-1) formation (Juetal, 2017). Besides, improved expression of glutamate cysteine ligase (GLC) catalytic subunit, a firstrate limiting enzyme of GSH synthesis, and elevation of intracellular GSH concentration by QCT (Patlevic et al, 2016) treatment accompanied withamelioration excessive ROS production and lipid peroxidation (MDA) product has been documented (Wiegand et al, 2009) Another mechanism for intestinal GSH elevation by QCT could be though down regulation the transcription of AOP3, an H 2 O 2 transporting protein present in the cell membrane that facilities uptake of H 2 O 2 (Thiagarajah et al, 2017), in H 2 O 2 exposed cell (in vitro) caused depression in intracellular H 2 O 2 and elevated GSH (Dong et al, 2020).Flavonoids compounds such as Quercetin are characterized by presences of one or more phenol ring and two or more hydroxyl groups linked directly to aromatic ring (Cutillo et al, 2006), have been associated with their antiproliferative, anti-inflammatory and antioxidant properties (Sarkar et al, 2016).…”

“…In Addition to its anti-inflammatory and antioxidant activity (Cebecioglu et al, 2019). The possible role of QCT in normal intestinal physiology and in sever gastrointestinal (GIT) disorder including enteropathic damage induced by non-steroidal antiinflammatory drugs (Singh et al, 2017a and b), as well as alleviation of increase intestinal permeability (Moura et al, 2015) and dextran sodium salts induced colitis (Dong et al, 2020). As others flavonoids, the antioxidant andantiinflammatory properties of QCT is the major contributor to its protective effects (Zaragoza et al, 2020).…”