# Protective Effect of Ethanolic Extract of Djulis Hull on Indomethacin-Induced Gastric Injury
## 1 Introduction  
Gastric ulcer disease is a usual digestive disorder and a global public health problem, and it is thought to occur in approximately 10% of people during their lifetime [1]. Gastric ulceration is caused by an imbalance between mucosal defensive and offensive factors, including genetic factors, gastric acid, _Helicobacter pylori_, ethanol, and nonsteroidal, anti-inflammatory drugs (NSAIDs) [2]. It is associated with mucosal injury, including perforation, loss of mucosal integrity, bleeding of gastric mucosal, apoptosis of mucosal cells, and edema in the submucosal layer [3, 4, 5]. Patients with severe and frequent gastric ulcer symptoms have a high possibility of developing gastric cancer in the future [6]. The way to preventor alleviate the symptoms of gastric ulcers from various offensive factors is an important public health issue worthy of attention now.  
NSAIDs are a heterogeneous class of commercial drugs extensively used to treat pain and inflammatory diseases (such as chronic pain, osteoarthritis, and rheumatoid arthritis), and have antiinflammatory and antipyretic effects, and are the most commonly used drugs in the world [7; 8]. NSAIDs include more than 20 heterogeneous groups of drugs, such as naproxen, aspirin, ofenamic acid, sulindac, ibuprofen, and indomethacin (IND) [9]. Contradictorily, continued and excessive use of NSAIDs produces serious side effects for the stomach, including bleeding, ulceration, and perforation of the gastrointestinal system [10]. The annual incidence of peptic ulcer complications caused by NSAIDs accounts for approximately 4-8%, and it may increase year by year [11]. Among them, IND, an NSAID drug, induces stomach ulcers by inhibiting the expression of cyclooxygenase (COX), reducing the synthesis of prostaglandandins (PG) [12]. Furthermore, administration of IND stimulates the generation of reactive oxygen species (ROS), which induces oxidative stress and leads to gastric injury [13]. Oxidative stress initiates numerous transcription factors and results in various chronic diseases. It has been reported that excessive ROS produced during oxidative metabolism initiates the inflammatory process and promotes the activation of tumor necrosis factor-\(\alpha\) (TNF-\(\alpha\)) as a proinflammatory cytokine [14]. An animal model of IND-induced jejunitis suggested that that TNF-\(\alpha\) activated the transcription of diverse inflammatory genes, including inducible nitric oxide synthase (iNOS), and thereby caused tissue damage [15]. In addition, disruption of the gastric mucosal antioxidant defense system, including the reduction of glutathione (GSH) levels and superoxide dismutase (SOD) and catalase (CAT) activities was found in rats with gastric ulcers induced by IND [16].  
For the purpose of developing functional foods for the prevention or protection of gastric ulcers, the present study used djulis (_Chenopodium formsonium_ [PERSON]), a traditional edible grain used in Taiwan for hundreds of years, as the test sample. Djulis has high nutritional value and contains a high content of antioxidant components, exhibiting several health benefits such as anti-adipogenic [17], hypoglycemic [18], anticancer [19], antihypertensive [20], and antioxidant [21] properties. Although certain reports indicate that the hull of djulis contains high amounts of bioactive compounds, including phytosterols, triterpenes, and phenolic compounds [22; 23], it is often discarded during cooking or processing because of its bitter taste. Recent studies have shown that the djulis hull had several biological effects, such as antiinflammatory, insulin resistance-improving, and gut microbiota-regulating effects [24; 25]. According to the information we have, studies on the relief effects of ethanolic extract of djulis hull (EEDH) against stomach injury caused by IND are limited. Consequently, the purpose of this study was to evaluate the protective effect of EEDH on IND-induced gastric injury and to elucidate its possible mechanism of action.