Citrus aurantium L. and Its Flavonoids Regulate TNBS-Induced Inflammatory Bowel Disease through Anti-Inflammation and Suppressing Isolated Jejunum Contraction

Abstract

Inflammatory bowel disease (IBD) is a serious digestive system disease, for which the clinical therapeutic choices remain limited. Dried fruits of Citrus aurantium L. (CAL) are a traditional medicine used for regulation of the digestive system. The aim of this study was to identify the regulatory effects of CAL on IBD and to clarify the mechanism of the active compounds. In trinitrobenzene sulfonic acid-induced IBD rats, 125 to 500 mg/kg of oral CAL significantly alleviated weight loss and diarrhea, decreased colitis inflammatory cell infiltration, and inhibited pro-inflammatory cytokine production. The mechanisms of characteristic flavonoids in CAL were evaluated involving inflammation and intestine contraction aspects. Naringenin, nobiletin, and hesperetin showed anti-inflammatory effects on lipopolysaccharide-induced RAW cells. The mechanism may be related to the inhibition of the tumor necrosis factor-α (TNF-α)-induced nuclear factor kappa-light-chain-enhancer of activated B cells (NF-κB) pathway to suppress cyclooxygenase-2 (COX-2) and inducible nitric oxide synthase (iNOS) expressions. Naringenin and nobiletin showed inhibitory effects on isolated jejunum contraction. The mechanism of naringenin is partly related to COX, NOS, inositol triphosphate (IP3), and finally, to decreased jejunum motility. This study demonstrated that CAL, and its flavonoids’ regulatory effects on IBD through anti-inflammation and inhibition of intestine muscle contraction, can provide basic information on developing new drugs or supplements against IBD based on CAL.

Chemical profiling and pharmaco‐toxicological activity ofOriganum sipyleumextracts: Exploring for novel sources for potential therapeutic agents

“…Nonetheless, ethyl acetate extract revealed the highest content in flavonoids, which have been demonstrated to exert protective effects via multiple mechanisms. Actually, the blunting effects induced by ethyl acetate extract on the selected pro‐inflammatory and pro‐oxidant biomarkers could be due, albeit partially, to flavonoid‐induced inhibitory effects on LDH, COX‐2, 5‐HT3 receptor, and i‐NOS, whose upregulation have been causally related to inflammatory conditions and tissue damage (Chandel, Rawal, & Kaur, ; He et al, ; Herbrechter et al, ; Mousavizadeh et al, ; Zhang et al, ). The observed downregulating effects on the tested biomarkers could be also consistent with extract content in gentisic acid, rosmarinic acid, and phloridzin (Table ).…”

“…Overall, extracts downregulated all tested biomarkers of oxidative stress and inflammation, thus supporting a protective role in the colon. (Chandel, Rawal, & Kaur, 2018;He et al, 2018;Herbrechter et al, 2015;Mousavizadeh et al, 2009;Zhang et al, 2018). The ob-…”

Targeting NF-κB pathway for treating ulcerative colitis: comprehensive regulatory characteristics of Chinese medicines

“…Research reveals that Citrus aurantium L. and its flavonoids (Naringenin, nobiletin, and hesperetin) (125, 250 and 500 mg/kg) suggests anti-inflammatory effects on TNBS-induced IBD and LPS-induced RAW cells, which is related to the inhibition of TNF-α-induced NF-κB pathway [114].…”

“…Qi-regulating medicine Norisoboldine DSS-induced colon tissues Inhibit phosphorylation, nuclear translocation and DNA-binding activity of NF-κBp65 [113] Citrus aurantium L. TNBS-induced colon tissues Inhibit the NF-κB pathway [114] RAW264.7 cells Inhibit the protein expressions of NF-κB [114] Tonifying medicine Eclipta Prostrata HT-29 cells Reduce the nuclear translocation of NF-κB [115] Astragalus polysaccharide DSS-induced colonic tissues Reduce NF-κB DNA phosphorylation activity [116] Astragaloside IV CCD-18Co cells Inhibit the phosphorylation of NF-κBp65 [117] Licochalcone A DSS-induced colonic tissues Reverse the increased expression of p65 NF-κB [118] Diammonium glycyrrhizinate AA-induced colonic tissues Suppress the positive percentage and density of NF-κBp65 [119] Vanillic acid DSS-induced colon tissues Suppress the activation of transcription NF-κBp65 [120] Paeoniflorin TNBS-induced colon tissues Inhibit the expressions of p-NF-κB [121] The fruit of Ziziphus jujuba Mill.…”

Effects of Allium mongolicum Regel and Its Flavonoids on Constipation

“…Mice intestinal tissue (containing jejunum and ileum) preparation and isometric measurements were performed as described previously [21]. Shortly, mice were sacrificed by cervical dislocation after fasting 24 h. The intestinal tissue section was isolated and approximately 1 cm section was cut down.…”