Sishen Wan® Ameliorated Trinitrobenzene-Sulfonic-Acid-Induced Chronic Colitis via NEMO/NLK Signaling Pathway

Abstract

The nuclear factor (NF)-κB signaling pathway plays an important role in the initialization and development phase of inflammatory injuries, including inflammatory bowel disease (IBD). Sishen Wan (SSW) is a classic Chinese patent medicine listed in the Chinese Pharmacopoeia, which is usually used to treat chronic colitis; however, it is unclear whether SSW can treat IBD via the NF-κB signaling pathway. In the present study, the therapeutic effect of SSW was demonstrated by the decreased index of colonic weight, macroscopic and microscopic score, and pathological observation in chronic colitis induced by trinitrobenzene sulfonic acid. In colonic mucosa of rats with chronic colitis, SSW reduced the levels of calprotectin and eliminated oxidative lesions; downregulated expression of interferon-γ, interleukin (IL)-1β and IL-17; increased expression of IL-4; and suppressed expression of NF-κB p65, and NF-κB essential modulator (NEMO)-like kinase (NLK). Furthermore, SSW inhibited ubiquitinated NEMO, ubiquitin-activated enzyme, and E2i activation, and phosphorylation of downstream proteins (cylindromatosis protein, transforming growth factor-β-activated kinase and P38). These results show that the therapeutic effects of SSW in chronic colitis were mediated by inhibiting the NEMO/NLK signaling pathway to suppress NF-κB activation.

Sishen Pill Treatment of DSS-Induced Colitis via Regulating Interaction With Inflammatory Dendritic Cells and Gut Microbiota

“…The nine major bioactive components of SSP, deoxyschizandrin, γ-schizandrin, schizandrin, schizandrol B, schisantherin A, psoralen, isopsoralen, evodiamine, and rutaecarpine, have been analyzed by high performance liquid chromatography (HPLC) coupled with electrospray tandem mass spectrometry (ESI-MS/MS; Zhang et al, 2018). Our previous studies have shown that SSP attenuates the symptoms of trinitrobenzene-sulfonic-acid induced colitis by restraining nuclear factor-κB activation via inhibiting the NEMO/NLK signaling pathway (Wang et al, 2019), indicating that SSP had certain effect on colitis, but whether it affected the development of ulcerative colitis by another way has not been known. However, it is unknown whether SSP is active against experimental colitis by regulating the balance between inflammatory DCs and gut microbiota.…”

Regulatory Effect of Sishen Pill on Tfh Cells in Mice With Experimental Colitis

“…In China, Sishen Pill (SSP) is the classic prescription of traditional Chinese medicine (TCM) for 1,000 years, and frequently-used to treat IBD, allergic colitis, chronic colitis, irritable bowel syndrome (IBS), and so on (Wang et al, 2019a). In clinic, SSP is widely accepted by IBD patients for definite therapeutic effect, little adverse reaction, and lower recurrence rate (Lu et al, 2011).…”

Poly‐pharmacokinetic strategy represented the synergy effects of bioactive compounds in a traditional Chinese medicine formula, Si Shen Wan and its separated recipes to normal and colitis rats

“…7.81−500 ng/mL for 17 and 20; 1.61−103.13 ng/mL for 4; 1.46−93.75 ng/mL for 7; 1.95−125 ng/mL for 0.98−62.50 ng/mL for the other compounds. For the method validation, the low, middle, and highquality control (QCL, QCM, QCH) samples were prepared by mix appropriate aliquots of 26 stock solutions in MeOH:…”

“…from Beijing John Long Technology Development (Beijing, China) and Chengdu Push Biotechnology (Chengdu, China), respectively. (-)-Licarin-B (2) [30], isopsoralen (8), psoralen (9), psoralidin (1), lespecyrtin B1 (3), isobavachromene (4), isobavachalcone (5), psorachalcone A (6), bavachin (7), neobavaisoflavone (15) [18,20,21,[31][32][33], 10-methoxywuchuyuamide I (10), dehydroevodiamine (11), wuchuyuamide-I (12), wuchuyuamide-III (14), evodiame (16), rutaecarpine (19), evocarpine (23), 1-methyl-2-decyl-4(1H)-quinolone (26) [34][35][36] were isolated from PC, MF, EF in our laboratory with the purity ≥98% which the structure identification were completed by 1 H-NMR, 13 C-NMR, and TOF-MS spectral analyses as described in our previous reports. Carbamazepine (Internal standard, IS, Cat No.…”

“…In the long‐term maintainable remission research, the recurrence rate of SSW was 8.1% within half a year, whereas the patients treated with mesalazine relapsed at a rate of 23.3% [6]. SSW can suppress inflammatory injuries by inhibited the NEMO/MLK signaling pathway [7], and exhibit protective effects against colonic mucosa via suppressed the p38 MAPK [8] and pi3K/Akt signal pathway [9]. In addition, SSW could maintain the immune homeostasis influenced by Pro‐ and Anti‐inflammatory cytokine [10] and the imbalance of intestinal flora [10].…”