Peptic ulcer, an acid-induced lesion in the digestive tract, predominantly occurs in the stomach or proximal duodenum, marked by mucosal denudation extending into the submucosa or muscularis propria [1]. The general population's prevalence is 5–10 %, but recent studies note a decline, attributed to improved hygiene and new therapies reducing Helicobacter pylori infections [2]. Traditionally, hypersecretory acid environments, dietary factors, and stress were considered causes. Risk factors behind this condition include H. pylori infection, alcohol/tobacco use, non-steroidal anti-inflammatory drugs (NSAIDs), and Zollinger–Ellison syndrome [2]. The severe complications of H. pylori and the over usage of NSAID are the main risks for gastric and duodenal ulcers [[3], [4], [5]]. However, only a small proportion of infected or NSAID-using individuals develop peptic ulcer, highlighting individual susceptibility. Genetic polymorphisms in cytokine genes, like interleukin 1β (IL1B), play a role. It was observed that such complications are four times more likely in NSAID users and two times in aspirin users. The concurrent use with anticoagulants, corticosteroids, and Selective serotonin reuptake inhibitors (SSRIs) increases upper gastrointestinal bleeding risk. A meta-analysis suggests independent risks for NSAIDs, aspirin, and H. pylori infection. H. pylori-negative, NSAID-negative, aspirin-negative peptic ulcers, classified as idiopathic, constitute about one-fifth of cases [[6], [7], [8], [9]].

Current clinical treatments for gastric ulcers have high recurrence rates. Natural products for peptic ulcer prevention and treatment are not uncommon, with societies using plant parts historically [10]. A vast portion of plant diversity remains unexplored for medicinal potential. Antiulcer properties in medicinal plants show promise, and various experimental models evaluate their effects [10]. To assess the preventive effects of plants and drugs on ulcers, it is crucial to employ valid experimental models. These models serve as valuable tools for comprehending the pathophysiological mechanisms of wounds and the antioxidant properties of essential drugs or substances with anti-ulcer attributes. Numerous models exist for evaluating anti-ulcer drugs, making the selection of an appropriate model challenging. Each model comes with its own set of advantages and disadvantages, and the choice is often influenced by local resources, study objectives, test hypotheses, or the researcher's questions [10]. Choosing the right experimental model demands a meticulous evaluation among the various existing models, posing a time-consuming, costly, and information-intensive challenge for inexperienced researchers.

This review aims to provide a comprehensive overview of current understanding of synthetic and natural metabolites with gastroprotective activity.

Peptic ulcers are notably more prevalent in smokers compared to non-smokers, with smoking-induced ulcers attributed to various factors such as increased acid secretion and alterations in blood flow [10]. Other contributing factors in smokers include bile reflux induction and a reduction in prostaglandin production. Genetics also play a significant role in the development and progression of peptic ulcers. Reports indicate an autosomal dominant inheritance of hyperpepsinogenemia I in patients with duodenal ulcers. Additionally, several rare genetic abnormalities, including familial amyloidosis, gastrocutaneous syndrome, stiff man syndrome, and tremor nystagmus ulcer syndrome, have been associated with peptic ulcer disease. H. pylori, prevalent in almost half the global population, is a significant contributor to peptic ulcer disease [10]. Typically acquired in unsanitary and crowded childhood environments with lower socioeconomic status, H. pylori triggers severe epithelial cell degeneration in the antrum through an inflammatory response involving neutrophils, lymphocytes, plasma cells, and macrophages.

The precise mechanism behind H. pylori-induced gastroduodenal mucosal lesions remains unclear. H. pylori infection can result in either hypochlorhydria or hyperchlorhydria, determining the type of peptic ulcer [10]. Cytokines play a crucial role by inhibiting parietal cell secretion, and direct effects on the H+/K+-ATPase α-subunit, activation of calcitonin gene-related peptide (CGRP) sensory neurons, or inhibition of gastrin production are observed. Eradicating H. pylori decreases gastrin mRNA expression and increases somatostatin mRNA expression. NSAID-induced gastroduodenal mucosal damage primarily arises from systemic inhibition of cyclooxygenase-1 (COX-1), reducing prostaglandin synthesis. This leads to decreased mucosal blood flow, low mucus and bicarbonate secretion, and inhibition of cell proliferation [10]. In a concentration-dependent manner, NSAIDs disrupt mucus phospholipids and initiate mucosal damage by uncoupling mitochondrial oxidative phosphorylation. Their physicochemical properties allow protonation in acidic gastric juice, facilitating entry into epithelial cells, ionization, release of H+, and impairment of cellular integrity. Co-administration of exogenous prostaglandins and cyclooxygenase-2 (COX-2)-selective NSAIDs mitigates mucosal damage and lowers the risk of ulcers. Fig. 1 illustrates the molecular mechanisms involved in regulation of acid secretion from parietal cells.