Andrographolide derivative AL-1 reduces intestinal permeability in dextran sulfate sodium (DSS)-induced mice colitis model
Introduction
Ulcerative colitis (UC) is a chronic and irregulated inflammatory disease of the gastrointestinal tract, which is characterized by series of relapses separated by remissions. An important pathological feature of UC is the leaky intestinal epithelial barrier [1,2]. Current drugs for the UC treatment are 5-aminosalicylic acid (5-ASA), corticosteroids, immuno-suppressants and biological agents or their derivatives [3]. These drugs are focused on remission of patients' symptoms, while no curative treatment against UC has been found yet. Although the exact mechanism underlying the development of UC is unclear, an increased intestinal permeability will lead to the translocation of luminal antigens and microorganisms and induce intestinal dysbiosis, which in turn promotes the development of intestine inflammation and exacerbates the disease progression [4]. The normal epithelial barrier function is provided by the mucus layers and the tight junctions (TJs) [5]. It has been reported that defect in either of these two elements can trigger or aggravate the intestinal inflammation [1,6].
Mucus is present in almost all mucosal layers and it moisturizes, lubricates and protects the underlying epithelium [7]. In the colon, mucus layers are formed by secretory mucins, which are synthesized in intestinal goblet cells and the most abundantly expressed secretory mucin is the mucin-2 (MUC-2). Tight junction is another important element that helps maintaining the intestinal homeostasis. The tight junction proteins such as claudins, junctional adhesion molecule 1 (JAM-A) and zonula occludens-1 (ZO-1) form seals between adjacent epithelial cells near the lateral membranes [8,9]. ZO proteins have been found to link claudin protein family and JAM protein family to the per-junctional actin-myosin ring (PAMR), which is a cytoskeletal ring of actin and myosin [10,11]. Myosin light chain kinase (MLCK) regulates the phosphorylation levels of myosin regulatory light chain II (MLC2), which is a biochemical marker of actomyosin contraction [12]. Phosphorylation of MLC2 by MLCK could lead to cytoskeletal structure alteration, which is an essential factor to the disturbance of TJs expression level and break-down of the intestinal epithelial barrier function [[13], [14], [15]].
Andrographolide (Andro), the major active compound of the medicinal plant Andrographis paniculata, has multiple pharmacological activities such as immunoregulatory [14] and anti-inflammatory effects [15]. Lipoic acid (LA) has a wide range of effects on mitigating oxidative stress diseases [16]. Andro derivative (AL-1) is an andrographolide-lipoic acid conjugate [17]. Although our previous study showed that AL-1 ameliorated trinitrobenzenesulfonic acid (TNBS)-induced colitis in mice [17], the protective effect mediated by modulating the intestinal barrier function has not been elucidated. To assess this, we investigated the therapeutic effects of AL-1 and its underlying mechanisms in DSS-induced mice colitis. The results indicated that AL-1 alleviated the DSS-induced colitis and protected the intestinal mucosal barrier function through inhibition of the MLCK-pMLC2 pathway.
Section snippets
Animals
Seven-week-old C57BL/C mice (male, 18–22 g) were purchased from Guangzhou University of Traditional Chinese Medicine. The mice were kept at room temperature of 23 ± 3 °C and humidity of 60% ± 15% for a week to adapt to the environment before starting the experiment. The mice were given free access to food and water. All animal experimental procedures strictly followed the regulations of the Experimental Animal Ethics Committee of Guangzhou University of Traditional Chinese Medicine.
Induction of colitis
Mice were
AL-1 promoted DSS-induced mice colitis recovery
Male C57BL/6 mice were treated with drinking water containing 2.5% DSS for 7 consecutive days. Body weight was significantly reduced from day 6 in the model group as compared to the normal control group (P < 0.05). However, AL-1 (15 mg/kg and 45 mg/kg) markedly prohibited the DSS-induced weight loss. In addition, the disease activity index (DAI) was determined. The DSS-treated mice group had a higher disease activity index (DAI) score as compared to the control mice group. Compared with animals
Discussion
In this study, we investigated the effect of AL-1 on DSS-induced intestinal barrier defects in male C57BL/6 mice. The results suggested that AL-1 could prevent the increase of intestinal permeability in the DSS-induced experimental colitis model through suppressing of MLCK regulated phosphorylation of MLC2.
DSS-induced mice colitis presented similar pathologic features as human UC, which were characterized by weight loss, blood diarrhea, with pathological changes of epithelial cell loss and
Conclusion
In summary, AL-1 promoted DSS-induced mice colitis recovery and attenuated histopathological changes of DSS-induced colitis in mice. In addition, AL-1 ameliorated the increased expression of the pro-inflammatory cytokines in colon tissue and preserved the mucus secretion. The results indicated that the effect of AL-1 was superior to the 5-ASA. Maintaining the normal mucus secretion and preserving tight junction complex may be the possible underlying mechanisms of its protective effects on the
Author contribution to study
Nan Jiang: Conceptualization, Methodology, Formal Analysis, Writing – Original Draft
Yuke Wei: Validation, Writing – Original Draft, Formal Analysis
Yun Cen: Investigation
Luchen Shan: Resources
Zaijun Zhang: Resources
Pei Yu: Resources
Yuqiang Wang: Conceptualization
Lipeng Xu: Conceptualization, Methodology, Writing – Review & Editing, Project Administration
Declaration of competing interest
The authors declare that there are no conflicts of interest.
Acknowledgments
This work is supported by grants from the National Natural Science Foundation of China (No. 81673496) and the Science and Technology Planning Project of Guangdong Province, China (2015B020211011). We would like to thank Bin Zheng, Jinxin Jiang and Mei Jing for language editing.
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