Dataset Information

Huang-Lian-Jie-Du Decoction Ameliorates Acute Ulcerative Colitis in Mice via Regulating NF-?B and Nrf2 Signaling Pathways and Enhancing Intestinal Barrier Function.

ABSTRACT: Evidence shows that intestinal inflammation, oxidative stress, and injury of mucosal barrier are closely related to the pathogenesis of ulcerative colitis (UC). Huang-lian-Jie-du Decoction (HLJDD) is a well-known prescription of traditional Chinese medicine with anti-inflammatory and antioxidative activities, which may be used to treat UC. However, its therapeutic effect and mechanism are still unclear. In this study, the UC model of BABL/c mice were established by DSS [3.5% (w/v)], and HLJDD was given orally for treatment at the same time. During the experiment, the clinical symptoms of mice were scored by disease activity index (DAI). Besides, the effects of HLJDD on immune function, oxidative stress, colon NF-?B and Nrf2 signaling pathway, and intestinal mucosal barrier function in UC mice were also investigated. The results showed that HLJDD could alleviate body weight loss and DAI score of UC mice, inhibit colonic shortening and relieve colonic pathological damage, and reduce plasma and colon MPO levels. In addition, HLJDD treatment significantly up-regulated plasma IL-10, down-regulated TNF-? and IL-1? levels, and inhibited the expression of NF-?B p65, p-I?K?/?, and p-I?B? proteins in the colon. Moreover, NO and MDA levels in colon tissues were significantly reduced after HLJDD treatment, while GSH, SOD levels and Nrf2, Keap1 protein expression levels were remarkably elevated. Additionally, HLJDD also protected intestinal mucosa by increasing the secretion of mucin and the expression of ZO-1 and occludin in colonic mucosa. These results indicate that HLJDD could effectively alleviate DSS-induced mice UC by suppressing NF-?B signaling pathway, activating Nrf2 signaling pathway, and enhancing intestinal barrier function.

SUBMITTER: Yuan Z

PROVIDER: S-EPMC6900672 | biostudies-literature | 2019

REPOSITORIES: biostudies-literature

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Huang-Lian-Jie-Du Decoction Ameliorates Acute Ulcerative Colitis in Mice <i>via</i> Regulating NF-κB and Nrf2 Signaling Pathways and Enhancing Intestinal Barrier Function.

Yuan Ziwen Z Yang Lihong L Zhang Xiaosong X Ji Peng P Hua Yongli Y Wei Yanming Y

Frontiers in pharmacology 20191121

Evidence shows that intestinal inflammation, oxidative stress, and injury of mucosal barrier are closely related to the pathogenesis of ulcerative colitis (UC). Huang-lian-Jie-du Decoction (HLJDD) is a well-known prescription of traditional Chinese medicine with anti-inflammatory and antioxidative activities, which may be used to treat UC. However, its therapeutic effect and mechanism are still unclear. In this study, the UC model of BABL/c mice were established by DSS [3.5% (w/v)], and HLJDD wa ...[more]

PMID: 31849642

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Project description:Huang-Lian-Jie-Du Decoction (HLJDD) is a "Fangji" made up of well-designed Chinese herb array and widely used to treat ischemic stroke. Here we aimed to investigate pharmacological mechanism by introducing an inter-module analysis to identify an overarching view of target profile and action mode of HLJDD. Stroke-related genes were obtained from OMIM (Online Mendelian Inheritance in Man). And the potential target proteins of HLJDD were identified according to TCMsp (Traditional Chinese Medicine Systems Pharmacology Database and Analysis Platform). The two sets of molecules related to stroke and HLJDD were respectively imported into STRING database to construct the stroke network and HLJDD network, which were dissected into modules through MCODE, respectively. We analyzed the inter-module connectivity by quantify "coupling score" (CS) between HLJDD-modules (H-modules) and stroke-modules (S-module) to explore the pharmacological acting pattern of HLJDD on stroke. A total of 267 stroke-related proteins and 15 S-modules, 335 HLJDD putative targeting proteins, and 13 H-modules were identified, respectively. HLJDD directly targeted 28 proteins in stroke network, majority (16, 57.14%) of which were in S-modules 1 and 4. According to the modular map based on inter-module CS analysis, H-modules 1, 2, and 8 densely connected with S-modules 1, 3, and 4 to constitute a module-to-module bridgeness, and the enriched pathways of this bridgeness with top significance were TNF signaling pathway, HIF signaling pathway, and PI3K-Akt signaling pathway. Furthermore, through this bridgeness, H-modules 2 and 4 cooperatively work together to regulate mitochondrial apoptosis against the ischemia injury. Finally, the core protein in H-module 4 account for mitochondrial apoptosis was validated by an in vivo experiment. This study has developed an integrative approach by inter-modular analysis for elucidating the "shotgun-like" pharmacological mechanism of HLJDD for stroke.

Project description:Huang-Lian-Jie-Du Decoction (HLJDD) is a classical Traditional Chinese Medicine (TCM) formula with heat-dissipating and detoxifying effects. It is used to treat inflammation-associated diseases. However, no systematic pharmacokinetic (PK) and pharmacodynamic (PD) data concerning the activity of HLJDD under inflammatory conditions is available to date. In the present study, the concentration-time profiles and the hepatic clearance rates (HCR) of 41 major components in rat plasma in response to the oral administration of a clinical dose of HLJDD were investigated by LC-QqQ-MS using a dynamic multiple reaction monitoring (DMRM) method. Additionally, the levels of 7 cytokines (CKs) in the plasma and the body temperature of rats were analyzed. Furthermore, a PK-PD model was established to describe the time course of the hemodynamic and anti-inflammatory effects of HLJDD. As one of the three major active constituents in HLJDD, iridoids were absorbed and eliminated more easily and quickly than alkaloids and flavonoids. Compared with the normal controls, the flavonoids, alkaloids and iridoids in inflamed rats exhibited consistently changing trends of PK behaviors, such as higher bioavailability, slower elimination, delays in reaching the maximum concentration (Tmax) and longer substantivity. The HCR of iridoids was different from that of alkaloids and flavonoids in inflamed rats. Furthermore, excellent pharmacodynamic effects of HLJDD were observed in inflamed rats. The levels of tumor necrosis factor-? (TNF-?), interleukin-6 (IL-6), IL-1?, IL-10, and macrophage inflammatory protein-2 (MIP-2) and body temperature significantly decreased after the administration of HLJDD. Based on PK-PD modeling with the three-phase synchronous characterization of time-concentration-effect, flavonoids exhibited one mechanism of action in the anti-inflammatory process, while iridoids and alkaloids showed another mechanism of action. Taken together, the results demonstrated that HLJDD may restrain inflammation synergistically via its major constituents (alkaloids, flavonoids and iridoids). A correlation between the exposure concentration of different types of compounds and their anti-inflammatory effects in the body was shown. This study provides a comprehensive understanding of the anti-inflammatory activity of HLJDD.

Dataset Information

Huang-Lian-Jie-Du Decoction Ameliorates Acute Ulcerative Colitis in Mice via Regulating NF-?B and Nrf2 Signaling Pathways and Enhancing Intestinal Barrier Function.

Publications

Huang-Lian-Jie-Du Decoction Ameliorates Acute Ulcerative Colitis in Mice <i>via</i> Regulating NF-κB and Nrf2 Signaling Pathways and Enhancing Intestinal Barrier Function.

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