Abstract
Rheum undulatum and Glycyrrhiza uralensis have been used as supplementary ingredients in various herbal medicines. They have been reported to have anti-inflammatory and antioxidant effects and, therefore, have potential in the treatment and prevention of various liver diseases. Considering that hepatic encephalopathy (HE) is often associated with chronic liver failure, we investigated whether an R. undulatum and G. uralensis extract mixture (RG) could reduce HE. We applied systems-based pharmacological tools to identify the active ingredients in RG and the pharmacological targets of RG by examining mechanism-of-action profiles. A CCl4-induced HE mouse model was used to investigate the therapeutic mechanisms of RG on HE. We successfully identified seven bioactive ingredients in RG with 40 potential targets. Based on an integrated target–disease network, RG was predicted to be effective in treating neurological diseases. In animal models, RG consistently relieved HE symptoms by protecting blood–brain barrier permeability via downregulation of matrix metalloproteinase-9 (MMP-9) and upregulation of claudin-5. In addition, RG inhibited mRNA expression levels of both interleukin (IL)-1β and transforming growth factor (TGF)-β1. Based on our results, RG is expected to function various biochemical processes involving neuroinflammation, suggesting that RG may be considered a therapeutic agent for treating not only chronic liver disease but also HE.
Highlights
Hepatic encephalopathy (HE) is a decline in neuropsychiatric function observed in patients with acute or chronic liver diseases [1,2]
Based on our ultra-performance liquid chromatography (UPLC) results, five and three representative components were identified from the R. undulatum and G. uralensis extracts, respectively (Figure 1 and Table 1)
Given that the absorption rate is very low in the small intestine when a component enters via the oral cavity and can be converted to rhein anthrone by various enzymes associated with intestinal microorganisms [23,24], it was not necessary to consider sennoside A as a target component
Summary
Hepatic encephalopathy (HE) is a decline in neuropsychiatric function observed in patients with acute or chronic liver diseases [1,2]. There are numerous explanations of why liver dysfunction can lead to encephalopathy; the most common clinical mechanism through which HE develops is an increase in the level of blood ammonia, which could be removed by sodium benzoate [1,2,3,4]. The nitrogen-containing compounds that remain following the food digestion process are transported through the portal vein to the liver, where most such compounds are metabolized. If the liver cells or the metabolism processes are impaired, nitrogen wastes containing a large amount of ammonia can accumulate in systemic circulation. An excessively high glutamine level in astrocytes may increase osmotic pressure and the activity of the inhibitory GABA system, leading to a shortage in the energy supply to the brain [3,5]
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