Protective Effect of Iridoid Glycosides of the Leaves of Syringa oblata Lindl. on Dextran Sulfate Sodium-Induced Ulcerative Colitis by Inhibition of the TLR2/4/MyD88/NF-κB Signaling Pathway

Abstract

Iridoid glycoside (IG) is the major active fraction extracted from the leaves of Syringa oblata Lindl. In view of its antimicrobial and antidiarrheal potential, it could be beneficial for the treatment of ulcerative colitis (UC). In the present study, IG (20, 40, and 80 mg/kg) was administered orally for 14 days to dextran sulfate sodium- (DSS-) induced colitis rats. The anti-inflammatory effects of IG on DSS-induced UC were evaluated by comparing observations in DSS-induced colitis and drug-treated groups using disease activity index (DAI), macroscopic score, histological analysis, and apoptosis assay. To elucidate the antioxidant mechanisms of IG on NOX-dependent ROS production, the activities of 8-OHdG, NOX1, and NOX2 in DSS-induced colitis were determined. The levels of proinflammatory cytokines such as IL-2, IL-4, IL-5, IL-12p40, and IL-13 were detected. The inflammation-associated protein and mRNA expressions of TLR-2, TLR-4, MyD88, and NF-κBp65 were assessed by immunohistochemistry and real-time quantitative PCR, respectively. The results suggested that IG treatment significantly reduced DAI, macroscopic score, and histological damage compared to untreated animals (p<0.01), whereas administration of IG remarkably attenuated the upregulation of 8-OHdG, NOX1, and NOX2 and the expression of proinflammatory cytokines such as IL-2, IL-4, IL-5, IL-12p40, and IL-13 in DSS-treated rats in a concentration-dependent manner. In addition, IG treatment could dose dependently suppress the protein and mRNA levels of TLR-2, TLR-4, MyD88, and NF-κBp65. The dose of IG that produced the most significant protective effect was 80 mg/kg. The above results demonstrate that IG exerts its inhibitory effect on cell apoptosis, oxidative stress, and proinflammatory cytokines in DSS-induced colitis through modulation of the TLR2/4/MyD88/NF-κB signaling pathway.

Dual Functional Eudragit® S100/L30D-55 and PLGA Colon-Targeted Nanoparticles of Iridoid Glycoside for Improved Treatment of Induced Ulcerative Colitis

“…Iridoid glycosides (IG) were extracted from the leaves of Syringa oblata Lindl., and purified by macroporous resin under the guidance of our previously established procedure. 2 PLGA (DL-lactide/Glycolide 50:50 copolymer) was synthesized by solid phase polycondensation reaction as our previous work. 28 Methacrylic acid copolymers, EL30D-55 and ES100 were supplied by Röhm GmbH (Darmstadt, Germany).…”

“… 1 The incidence of UC is increasing during the past three decades worldwide, which may progress to colorectal cancer. 2 The symptoms of UC range from diarrhea, fecal blood and weight loss to ulceration and complete obstruction of the gastrointestinal tract (GIT), which can negatively affect daily life of patients. 3 , 4 However, the therapeutic effect of many currently marketed formulations (tablets and capsules) remain unsatisfactory for its clinical treatment, most often due to their low oral bioavailability attributed to the lack of targeted delivery of drugs specifically to the inflamed colon tissue.…”

“… 7 , 8 Our previous studies have reported the protective effects of IG on UC because of its anti-inflammatory, anti-apoptotic, anti-oxidative and immunomodulatory properties. 2 , 9 The capsules and tablets of IG have been developed in Drug Standard by Ministry of Health of People’s Republic of China (PRC). 4 Despite the role of IG in chemotherapy, the beneficial effect of IG on colonic tissue is constrained by its conventional oral formulations due to the nonspecific drug release in the upper GIT and rapid metabolism, 10 which lead to low oral bioavailability of IG.…”

“…UC is a chronic intestinal inflammation with complex pathogenesis, which was triggered by numerous inflammatory mediators and cytokines. 2 , 23 In the inflammatory process, lots of inflammatory mediators and cytokines, such as NADPH oxidases (NOXs), cyclooxygenase ( COX)-2 , matrix metalloprotein-9 ( MMP-9 ), tumor necrosis factor-α (TNF-α), interleukin 17 (IL-17) and IL-23 involved in the immune response. 24 , 25 Oxidative stress has been identified as a major factor that contributes to the pathogenesis and progression of IBD, and NADPH oxidases (NOXs) are the main sources of ROS.…”

“… 24 , 25 Oxidative stress has been identified as a major factor that contributes to the pathogenesis and progression of IBD, and NADPH oxidases (NOXs) are the main sources of ROS. 2 Growing evidence suggests that there is a positive correlation between upregulated NADPH oxidase (NOX) expression and gastrointestinal inflammation. 26 Prostaglandin E2 (PGE2) is also another important inflammatory mediator produced from arachidonic acid metabolites catalyzed by COX-2 in inflammatory responses.…”