1. INTRODUCTION:

An imbalance between aggressive forces, gastric acid, pepsin, and external irritants and protective elements that maintain the integrity of the mucosa causes gastric ulcer disease, a frequent pathology of the stomach that appears as discrete lesions within the gastric lining.¹ Gastric ulcer disease, which is most prevalent in adults over 60, has serious consequences in 50–170 out of every 100,000 individuals. Usage of NSAIDs and Helicobacter pylori, which causes gastrointestinal tract infections, are the most common causes of gastric ulcer disease and gastrointestinal bleeding.²According to studies, 5–10% of people worldwide suffer from peptic ulcer disease (PUD), with 10% of women and 12% of men having lifelong PUD.³ Gastric cancer, also known as gastric adenocarcinoma (GC), is a concern for world health. It is the fifth most frequent cancer worldwide and the third most common cause of cancer-related death, contributing about 800,000 cancer-related deaths every year⁴^.Despite the improvement in medical therapy, the disease still represents a major health concern due to its high occurrence, recurrence, and complication rate. Various factors have been proposed in relation to its pathogenesis; however, oxidative stress is believed to be an important contributing factor in mucosal damage and impaired repair.⁵

The imbalance between the generation of reactive oxygen species and antioxidant defense systems leads to oxidative stress. Superoxide anion, hydrogen peroxide, and hydroxyl radicals are some of the most reactive molecules produced during normal cellular metabolism, particularly from the mitochondria.⁶They are regulated at homeostatic levels and play roles in fundamental cellular processes, including signaling and immune defense. However, excessive production or inadequate detoxification causes cellular damage and dysfunction of normal biological processes.⁷The main cause of tissue and its persistence is oxidative imbalance. Membrane lipids are invaded by the reactive species, resulting in lipid peroxidation, which leads to a loss of membrane integrity, as well as increased permeability.⁸ Therefore, mucosal damage is exacerbated by enabling hydrogen ions to back diffuse. Furthermore, oxidative protein modification results in structural changes and decreased enzyme activity, both of which impair cellular function. Nuclear acid damage causes mucosal disruption, ulceration, mutagenesis, and cell death pathways.⁹

Mitochondrial dysfunction is a major endogenous source of hydrogen peroxide, particularly upon metabolic stress.¹⁰ The substantial release of reactive species by activated immune cells during host defense is a secondary mechanism of pro-inflammatory activity. This burden is further increased by external factors, such as alcohol intake, smoking behavior, nonsteroidal anti-inflammatory drugs (NSAIDs), and exposure to various environmental toxins, leading to a highly detrimental pro-tumor microenvironment.¹¹The body then resorts to its complex antioxidant defense system, which can be either an enzymatic or non-enzymatic process.^[12] However, when oxidative damage begins to accumulate in chronic situations, those defense mechanisms and baseline antioxidant levels may not be adequate. Therapy may benefit from this information on the way oxidative stress develops in stomach ulcers. While stomach acid regulation and the removal of etiological substances are the main goals of conventional therapy, there is growing evidence that novel antioxidant-based approaches should be used to give further mucosal cytoprotection and repair.¹³The present study delivers an extensive view on oxidative stress-mediated molecular mechanisms, biomarker-based diagnosis, endogenous antioxidant defense systems, and recently developed treatment strategies, including nanotechnology-drug delivery systems, in contrast to previous reviews that either only examined clinical management or generalized oxidative mechanisms in gastric ulcer development. By updating the most recent advancements in molecular biomarkers and precision-targeted antioxidant therapy, the current review provides a more comprehensive perspective on the treatment of stomach ulcers in the future.

2. Physiology of Gastric Mucosal Defense:

The mucus-bicarbonate barrier is the first and most important line of defense against luminal aggressors, such as acid, pepsin, pathogens, and xenobiotics. The gastric mucosa is protected by a well-integrated defense system. This dense bicarbonate-rich viscoelastic gel layer, which is placed by an epithelium-secreting layer, creates a pH gradient so that there is a very low pH in the gastric lumen, and there can be a neutral pH at the epithelial surface. On the contrary, excessive formation of reactive oxygen species disrupts this homeostasis with consequent lipid peroxidation of membrane phospholipids, inhibition of mucin synthesis, secretion, and inactivation of intracellular antioxidant stores such as glutathione. In addition, the increased mucosal permeability associated with oxidative damage and the infiltration of inflammatory cells reinforces tissue lesion through the release of cytokines and secondary radicals; the reduction of bicarbonate secretion, as well as the variations in the mucosal flow, not only generates loss of cytoprotective mechanisms but also assists the development of the ulcer.¹⁴ Under physiological conditions, mediators, including nitric oxide and prostaglandins, modulate vascular tone, the balance of which promotes vasodilation and endothelial protection. Leukocyte selection is also inhibited by prostaglandins. which is beneficial when the gastrointestinal (GI) mucosa is inflamed. Prostaglandin E2 (PGE2) suppresses the release of platelet-activating factor (PAF), histamine, and tumor necrosis factor-alpha (TNF-alpha) by mast cells in the intestinal mucosa and peritoneum. Additionally, NO affects both endocrine and exocrine muscle tone and secretion. NOS enzymes, which impact motility, blood flow, and secretion, are essential for healthy GI tract function. These enzymes include nNOS, iNOS, and eNOS. GI function disruptions may result from inhibiting these enzymes.¹⁵Conversely, inducible nitric oxide synthase (iNOS), which increases nitric oxide (NO) levels under specific pathological situations, causes mucosal damage and dysfunction. When NO production is suppressed, the stomach mucosa is more susceptible to harm. Furthermore, NO stops neutrophils from entering inflammatory regions.Moreover, growth hormones like transforming growth factor-α and epidermal growth factor, which drive cell migration, differentiation, and proliferation, the three processes required for the mucosa's rapid recovery from damage, also enhance the mucosal resistive capacity.¹⁶However, when an excess overproduction of reactive species occurs, the homeostatic equilibration system is disturbed, producing an endothelial dysfunction, a reduced bioavailability of nitric oxide, and vasoconstriction. The changes associated with imbibition, however, may lead to impaired perfusion, which can result in local ischemia and hypoxia, exacerbating cellular injury and further disrupting the normal tissue damage response.Changes in these enzymes can hinder fibrinolysis and healing, especially in the tissue-type plasminogen activator–inhibitor (PAI) system. The stomach epithelium produces cathepsins, which have antibacterial qualities that promote ulcer healing and protect against bacterial infection.Additionally important mediators in angiogenesis, inflammation, ulcer healing, and cell proliferation are PAI-1 and urokinase-type plasminogen activator. Additionally, through tissue remodeling, matrix metalloproteinases (MMPs) aid in the repair of stomach ulcers.¹⁷In reaction to stress, gastric epithelial cells create heat shock proteins (HSPs), which aid in mucosal healing. They help stabilize and refold broken proteins, allow the delivery of precursor proteins to vital organelles, and support cell viability by regulating enzymes involved in inflammation and ulcer repair.Gastric mucosal defense mechanisms and oxidative stress-induced breakdown of epithelial integrity are depicted in figure1.

3. Reactive Oxygen Species and Sources:

Gastric ulcer development has been linked to oxidative stress, a pathological condition characterized by an imbalance between the production of reactive species and the capacity of biological systems to remove or repair the associated damage. Superoxide anion (O2 –), hydrogen peroxide (H2O2), and hydroxyl radicals (OH) are examples of reactive oxygen species (ROS), which are a range of oxygen molecules with varying degrees of reactivity. Every ROS has the capacity to impair different parts of the cell. Their levels in the body are extremely low despite the fact that they are always produced during regular metabolic activities, particularly by mitochondrial respiration. When ROS are produced in excess, harmful processes such as lipid peroxidation, protein modification, and nucleic acid degradation make the cells susceptible.¹⁸Mitochondria constitute a major intracellular source, and the release of electrons from the electron transport chain during oxidative phosphorylation produces superoxide radicals, especially when respiration is impaired or during exposure to metabolic stress. Since activated neutrophils and macrophages produce enormous amounts of reactive intermediates through enzymatic systems, such as NADPH oxidase and myeloperoxidase, during host defense, inflammation is the other prime mediator. However, it can persistently cause collateral tissue damage. These species play a crucial role in defense against microbial invasion, modulation of gene expression, control of cellular homeostasis, and regulation of cell signaling pathways. Because the physiological abundance of ROS is deeply linked to their hazardous forms through an equilibrium between their creation and neutralization, redox homeostasis is crucial for maintaining cellular integrity and inhibiting the advancement of pathophysiological diseases. It causes cellular malfunction, which increases susceptibility to acid damage and is a precursor to ulceration.¹⁹Major sources and mechanisms of reactive oxygen species production in the pathogenesis of gastric ulcer are discussed in figure2.

Fig 2. Reactive Oxygen Species Generation^18-19

4. Mechanisms of Oxidative Stress in Gastric Ulcer Pathogenesis:

4.1 Cellular Damage Mechanism:

The first reaction that occurs in the development of a gastric ulcer is lipid peroxidation, where highly reactive intermediates interact with polyunsaturated fatty acids found in cellular and organelle membranes. The initiation of this chain reaction, consisting of the separation of hydrogen atoms, which produces lipid radicals, rapidly reacts with oxygen to yield lipid peroxides and secondary products such as 4-hydroxynonenal and malondialdehyde.These by-products further alter membrane structure, whereby its fluidity, permeability, and structural organization are disrupted, thus leading to the erosive loss of integrity of the stomach epithelium. In addition, when mitochondrial membranes are damaged, there is a further loss of energy production, which in turn impairs cell signalling, defence, and repair. Protein oxidation is a result of highly reactive intermediates binding to amino acid side chains, peptide backbones, and FGs crucial to biological function, and is an important element in gastric mucosal injury. These processes lead to structural alterations such as fragmentation, cross-linking, and formation of carbonyl derivatives, all contributing to loss of protein stability and activity.Because enzymes are highly sensitive to such modifications, these changes often lead to conformational changes resulting in decreased catalytic efficiency or complete inactivation, thereby interfering with fundamental cell processes such as metabolism, detoxification, and repair.DNA in gastric epithelial cells is especially vulnerable to damage by reactive intermediates, leading to modifications such as base oxidation, single- and double-strand breaks, and mutagenic adducts that bind DNA and disrupt cell function. These changes affect the fidelity of transcription and replication, affecting protein synthesis and homeostasis of the cell. When damage cannot be repaired by other pathways, such as base excision and nucleotide excision systems, cells employ mechanisms known as programmed death to eliminate damaged components. Cytochrome c release, caspase activation, and Bcl-2 family protein regulation are examples of mitochondrial signaling cascades that primarily support this mechanism, which establishes a cell's life or death status.²⁰

4.2 Mitochondrial Dysfunction:

Since it can produce a variety of different reactive oxygen intermediates, O— is the most important ROS. The inner mitochondrial membrane (IM) contains a collection of enzyme complexes called the mitochondrial respiratory chain (MRC). Coenzyme Q (CoQ), cytochrome c, a peripheral protein on the outer side of the inner mitochondrial membrane, and complexes I–IV (NADH-ubiquinone oxidoreductase, succinate dehydrogenase, ubiquinol-cytochrome c oxidoreductase, and cytochrome c oxidase) comprise the MRC. Electron leakage from MRC complexes I and III reduces molecular oxygen, resulting in O^—. The final enzyme in the MRC is cytochrome c oxidase (complex IV), which uses a four-electron reduction to convert O2 into two molecules of H2O. Complex IV isn't believed to be a physiologically significant generator of ROS. However, research suggests that cytochrome c may function as an antioxidant in the mitochondria, converting O^— to O₂. Cytochrome c oxidase is in an oxidized state and consumes NO at high cellular O2 concentrations. Nevertheless, at low oxygen concentrations, cytochrome c oxidase does not utilize NO, which causes NO to accumulate in the cell.²¹

5. Oxidative Stress in Specific Etiologies of Gastric Ulcers:

5.1 Helicobacter pylori-Induced Ulcers:

Two Australian researchers first identified the spiral-shaped, motile, microaerophilic gram-negative bacillus H. pylori in 1982. It tends to be the main reason for stomach ulcers. Because they produce the effector protein known as cytotoxin-associated gene A (cagA), type I strains of H. pylori are dangerous. After being translocated into the host cell, CagA alters the morphology of the cell, increases its motility, and interferes with junctional function. Gastric ulcers and stomach cancers are caused by this pathogenic activity. Increased synthesis of cytokines like TNF-alpha is a result of H. pylori infection in gastritis. IL-1β is also overproduced when gastritis is caused by H. pylori. The infected stomach mucosa exhibits lamina propria invasion of polymorphonuclear leukocytes, lymphocytes, monocytes, and plasma cells in addition to significant epithelial neutrophil infiltration.Appropriate antibiotic treatments are used to completely resolve mucosal inflammation, effectively eliminate H. pylori infection, and lower the risk of ulcer recurrence. H. pylori 's ability to exploit antioxidants to cause a prolonged infection. Many ROS and reactive nitrogen species (RNS) are produced as a result of the intense inflammatory host response carried on by H. pylori infection, which is mediated by neutrophils and macrophages.The generation of ROS or RNS is a crucial component of the host immune response to chronic infections. Therefore, H. pylori needs to use an antioxidant protein to fight oxidative damage caused by the host immune response to establish long-term colonization.²²

5.2 NSAIDs-Induced Gastric Injury:

Anti-inflammatory, analgesic, and antipyretic qualities make NSAIDs useful medicinal substances.⁵⁶They are frequently advised for diseases like musculoskeletal problems and arthritis. However, there is a direct correlation between the use of NSAIDs and the formation of stomach ulcers; gastric ulcer disease affects about 25% of long-term users. The capacity of NSAIDs to suppress the enzyme cyclooxygenase (COX) is linked to the formation of ulcers. Typically, COX stops arachidonic acid (AA) from becoming prostaglandins (PGs). By inhibiting COX, NSAIDs undermine the protective mucosal barrier, allowing pepsin to cause corrosive damage and speeding the formation of peptic ulcers. NSAIDs also specifically inhibit COX-1, which generates endothelin-1 (ET-1), a potent vasoconstrictor that could exacerbate mucosal injury. Maity et al. demonstrated that the PPI lansoprazole also inhibits Fas-mediated apoptosis and mitochondrial pathways, hence preventing NSAID-induced gastropathy. Lansoprazole's anti-apoptotic impact is mediated by preventing NSAID-induced reductions in anti-apoptotic genes (such as Bcl and Bcl-2) while preventing increases in pro-apoptotic genes (such as Bax and Bak), Fas, and Fas ligand. Oxidative stress can be caused by xenobiotics, tobacco smoke, ionizing and non-ionizing radiation, diets, and medications. Common exogenous sources of ROS include chemicals like quinones, heavy metals including lead, arsenic, mercury, chromium, and cadmium, organic solvents, and pesticides.²³

6. Antioxidant Defense Systems in Gastric Protection

The three isoforms of superoxide dismutase found in eukaryotic cells are extracellular copper/zinc-containing SOD (EC-SOD), mitochondrial manganese-containing SOD (Mn-SOD), and cytoplasmic/nuclear copper/zinc-containing SOD (Cu, Zn-SOD), each of which also localizes to the mitochondrial intermembrane space.⁶³ Even though the SOD isoenzymes catalyze the identical dismutation mechanism that transforms superoxide anion to oxygen and hydrogen peroxide, each SOD isoform appears to have a unique role in cellular physiology; often, one SOD is inadequate for another. Manganese superoxide dismutase is produced by oxidative stress and several physiological stimuli. including growth factors, bacterial proteins, and inflammatory cytokines. Gotz et al. report of increased Mn-SOD in stomach mucosa that was positive for H. pylori. The level of Mn-SOD protein was shown to be highly linked with the degree of inflammation in the stomach mucosa.²⁴

The primary non-protein thiol in cells, glutathione (gamma-L-glutamyl-L-cysteinylglycine), is only produced in the cytosol in two ATP-dependent stages. The process begins with the enzyme gamma-glutamylcysteine synthetase's specific coupling of glutamic acid's gamma-carboxylic acid to cysteine. Afterwards, GSH synthetase utilized ATP, gamma-glutamylcysteine, and glycine as substrates to produce GSH. Gamma-glutamylcysteine production, a response inhibited by GSH, is the rate-limiting reaction in GSH synthesis that regulates the quantity of GSH in cells.Vitamin C can have pro-oxidant activity by lowering heavy metal ions (Fe, Cu) that can generate free radicals through the Fenton reaction, despite its major function as an antioxidant^.Vitamin E, of which α-tocopherol is the most physiologically active form, is a vital and abundant antioxidant that shields cell membranes against lipid peroxidation (LPO).^[25]α-tocopherol inhibits the activity of LPO by scavenging lipid peroxyl radicals (LOO·), but in the process, it becomes a reactive radical. Additionally, α-tocopherol can reduce Fe or Cu because it is a pro-oxidant. There is significant interest in the restoration of non-enzymatic protections of these pathways through dietary supplements or pharmaceutical support.

7. Biomarkers of Oxidative Stress in Gastric Ulcer Disease:

7.1 Oxidative DNA and Protein Damage Biomarkers:

Malondialdehyde is another reactive aldehyde that is produced from the degradation of lipid hydroperoxides, undergoes reaction with nucleic acids and proteins, and causes cellular damage by disrupting cellular function and structural integrity.Similarly, TBARS are a heterogeneous species and provide integrated information about ongoing peroxidative damage resulting from lipid degradation, as different by-products appear throughout the process. Increased levels of these markers in gastric tissue or biological fluids have been associated with a higher extent of membrane damage, increased permeability, and loss of epithelial integrity, facilitating ulcer development and progression.For oxidative damage of the stomach mucosa, it is crucial to identify biological markers of in vivo oxidative DNA damage, such as 8-hydroxy-2'-deoxyguanosine, and well-known lipid peroxidation markers, such as malondialdehyde (MDA) and 4-hydroxy-2-nonenal (HNE). High-performance liquid chromatography, mass spectrometry, and electron paramagnetic resonance are among the advanced techniques used to identify free radicals and reactive oxygen species or their metabolites. The HPLC methods are used for both the electrochemical detection of DNA oxidation products and the electrochemical assessment of protein oxidation products, especially nitrotyrosine and dityrosine. This enzyme's decreased activity increases the mucus' susceptibility to erosion, inhibits its ability to repair, and increases the risk of ulcers. A crucial regulator of gastric physiology, nitric oxide protects mucosal blood flow, promotes barrier function, and controls inflammatory responses, especially through inducible nitric oxide synthase, which stimulates the synthesis of highly reactive derivatives, such as peroxynitrite, that alter and even destroy lipids, proteins, and nucleic acids. Meanwhile, leukocyte infiltration and activity in stomach tissue are indicated by myeloperoxidase (MPO), which is strongly elevated in neutrophils. These combined assessments of myeloperoxidase activity and nitric oxide also show a balance between the ulcer's oxidative imbalance, immunological response, and vascular regulation.²⁶

7.2 Emerging Molecular Biomarkers:

At the genomic and proteomic levels, novel molecular biomarkers provide a deeper phenotype of the gastric injury, inflammation, and oxidative stress of gastric ulcers, which may provide some of the multifactorial mechanisms of gastric ulcer pathogenesis. Finding protein and molecular indicators of human aging has gained focus in clinical studies of supplements or other anti-aging treatments. Human aging has been linked to some well-known molecular markers, these markers are related to premature human aging diseases. A few of the more precise biological age indicators that have been produced in genetic model systems and are more specifically associated with the aging process were confirmed in individuals. Highly recognized post-transcriptional regulators of gene expression, microRNAs (miRNAs) have unique expression patterns that are linked to inflammatory signaling, healing impairment, and mucosal injury. Disturbances in cellular energy metabolic pathways have also been linked to altered production of mitochondrial respiratory chain proteins or alterations in the number of copies of mitochondrial DNA.[27] An extended duration of organ pathogenic signals is suggested by markers of chronic tissue injury, such as targeted pro-inflammatory mediators and transcription factors. Furthermore, these composite biomarkers allow for the early diagnosis of mucosal modification and the monitoring of scar-free disease, and they are more sensitive and specific than any index. The oxidative stress biomarkers for gastric ulcer disease are shown in the following table.

Table 1: Biomarkers of Oxidative Stress in Gastric Ulcer Disease

S. No.	Biomarker	Category	Source	Significance of Gastric Ulcer	References
1	Malondialdehyde (MDA)	Lipid peroxidation	Membrane lipids	Exhibits oxidative membrane damage	[28]
2	4-Hydroxynonenal (4-HNE)	Lipid peroxidation	Polyunsaturated fatty acids	Modification of proteins	[29]
3	Isoprostanes	Lipid peroxidation	Arachidonic acid	Reliable oxidative stress marker	[30]
4	Protein carbonyls	Protein oxidation	Oxidized proteins	Indicates protein damage	[31]
5	Nitrotyrosine	Protein oxidation	Peroxynitrite reaction	Nitrosative stress marker	[32]
6	8-OHdG	DNA damage	Oxidized guanine	DNA injury indicator	[33]
7	Comet assay	DNA damage	Nuclear DNA	Measures strand breaks	[34]
8	Superoxide dismutase (SOD)	Enzymatic antioxidant	Cytosol/mitochondria	Defense status	[35]
9	Catalase	Enzymatic antioxidant	Peroxisomes	Detoxifies H₂O₂	[36]
10	Glutathione peroxidase (GPx)	Enzymatic antioxidant	Cytosol	Reduces peroxides	[37]
11	Reduced glutathione (GSH)	Non-enzymatic	Intracellular	Maintains redox balance	[38]
12	Oxidized glutathione (GSSG)	Redox marker	Intracellular	Indicates oxidative load	[39]
13	Nitric oxide (NO)	Reactive nitrogen species	NOS enzymes	Dual role (protective/damaging)	[40]
14	Myeloperoxidase (MPO)	Inflammatory enzyme	Neutrophils	Indicates inflammation	[41]

Table 2: Drugs Used in the Treatment of Gastric Ulcers

S. No.	Drug Name	Drug Class	Mechanism of Action	Therapeutic Use	References
1	Omeprazole	Proton Pump Inhibitor	Irreversibly inhibits H⁺/K⁺ ATPase	Peptic ulcer, GERD	[44]
2	Pantoprazole	Proton Pump Inhibitor	Suppresses gastric acid secretion	Ulcer healing	[45]
3	Esomeprazole	Proton Pump Inhibitor	Inhibits proton pump	H. pylori therapy	[46]
4	Rabeprazole	Proton Pump Inhibitor	Blocks acid secretion	Gastric ulcers	[47]
5	Lansoprazole	Proton Pump Inhibitor	Inhibits H⁺/K⁺ ATPase	Ulcer treatment	[48]
6	Famotidine	H2 Receptor Antagonist	Blocks histamine H2 receptors	Mild ulcers	[49]
7	Ranitidine	H2 Receptor Antagonist	Reduces gastric acid secretion	Acid-related disorders	[50]
8	Cimetidine	H2 Receptor Antagonist	Inhibits H2 receptors	Ulcer management	[51]
9	Sucralfate	Cytoprotective Agent	Forms a protective barrier on the ulcer	Mucosal healing	[52]
10	Misoprostol	Prostaglandin Analog	Increases mucus & bicarbonate	NSAID-induced ulcers	[53]
11	Bismuth subsalicylate	Bismuth Compound	Coats ulcer, antimicrobial	H. pylori therapy	[54]
12	Amoxicillin	Antibiotic	Inhibits the bacterial cell wall	H. pylori eradication	[55]
13	Clarithromycin	Antibiotic	Inhibits protein synthesis	Triple therapy	[56]
14	Metronidazole	Antibiotic	Causes DNA damage in bacteria	Resistant H. pylori	[57]
15	Tetracycline	Antibiotic	Inhibits protein synthesis	Quadruple therapy	[58]

9. Nanotechnology-Based Approaches in Gastric Ulcer Management:

The study involves the use of different nanoformulations, e.g., nanoparticles, nanoemulsions, liposomes, and lipid-based carriers, having advantages of resolving the stability, solubility, and bioavailability challenges for higher local gastric drug concentrations with controlled and site-specific release. As a result, these systems can entrap antioxidants, anti-inflammatory agents, and cytoprotective agents against degradation and release them with sustained activity at the injury site. Nano-carriers, by enabling specificity in their delivery, can minimize systemic side effects while promoting therapeutic efficacy, which is particularly important in disease states with excessive production of reactive intermediates.⁵⁹ Some nanomaterials also possess radical-scavenging properties and, therefore, minimize cellular injury in a dose-dependent manner. More penetration and adhesion over the gastric mucosa enhances their retention time and longer interaction with the damaged part of the stomach, thus promoting healing. Moreover, these systems have responsive features towards specific physiological stimuli (pH, enzymatic action), which release the drug at the optimal site. Therefore, nanotechnology formulations are an excellent progress in protection against oxidative injury through selective therapy and improved pharmacokinetics and related consequences, and can provide a novel approach for the management and improvement of gastric ulcer disease.⁵⁹

10. Future Perspectives and Emerging Trends:

Research on gastric ulcer is gradually changing from simple experimental approaches to integrated and precision-based approaches that may solve the complex nature of mucosal injury. Newer omics technologies, such as proteomics, metabolomics, and genomics, reveal the complex molecular events associated with redox imbalance, inflammation, and restoration of function.⁶⁰ Ultimately, this might result in the discovery of fresh therapeutic targets and individualized treatment choices. Although nanotechnology-translated formulations and antioxidant methods have demonstrated enormous potential in the experimental setting, there will be numerous challenges to overcome before antioxidant-based medicines may be used in clinical settings. Large-scale clinical validations, long-term toxicity assessment, nanoformulation repeatability, regulatory approval issues, economic effectiveness, and difficulties with targeted stomach distribution under various physiological situations are some of these. Additionally, this may be linked to significant interindividual variation in oxidative stress-related indicators and patients' reactions to them, making the development of a clear therapy prescription more difficult. Determining the safety, effectiveness, and practical application of this approach will require further translational research and multicenter clinical trials.

11. CONCLUSION:

Oxidative stress is the main cause of the imbalance that arises in gastric ulcer disease as a result of a breakdown in the balance between endogenous and exogenous aggressive forces and the defensive mucosal mechanisms. Overproduction of reactive species impairs the integrity of the stomach mucosa, slowing the healing process, and damages cellular macromolecules, including lipids, proteins, and nucleic acids, as well as reproductive cells. This condition is complicated by a variety of factors, including inflammatory responses, mitochondrial malfunction, and the environment. Even while there is an active antioxidant defense system, abnormal circumstances can surpass it, requiring the development of therapeutic approaches. Normal pharmaceuticals suppress acid secretion in gastric ulcer disease, which is a recurrent disorder caused by oxidative damage. However, their effectiveness is limited to the period of normal medication use. Therefore, the introduction of antioxidant-based methods, such as natural agents, synthetic agents, and modern drug delivery systems, would be a more suitable process of treatment.

12. CONFLICT OF INTEREST:

The author(s) declared no conflict of interest.

13. REFERENCES:

1. Malik TF, Gnanapandithan K, Singh K. Peptic ulcer disease. In: StatPearls. Treasure Island (FL): StatPearls Publishing; 2026 Jan–. Updated 2023 Jun 5.

2. Zullo A, Hassan C, Campo SMA, Morini S. Bleeding peptic ulcer in the elderly: risk factors and prevention strategies. Drugs Aging. 2007; 24(10): 815–828.

3. Huang CY, Lai WY, Sun MF, et al. Prescription patterns of traditional Chinese medicine for peptic ulcer disease in Taiwan: a nationwide population-based study. J Ethnopharmacol. 2015; 176: 311–320.

4. Menon G, El-Nakeep S, Babiker HM. Gastric cancer. In: StatPearls. Treasure Island (FL): StatPearls Publishing; 2026 Jan–. Updated 2024 Oct 28.

5. Dash UC, Bhol NK, Swain SK, Samal RR, Nayak PK, Raina V, et al. Oxidative stress and inflammation in the pathogenesis of neurological disorders: mechanisms and implications. Acta Pharm Sin B. 2025; 15(1): 15–34. doi:10.1016/j.apsb.2024.10.004.

6. Pizzino G, Irrera N, Cucinotta M, Pallio G, Mannino F, Arcoraci V, et al. Oxidative stress: harms and benefits for human health. Oxid Med Cell Longev. 2017; 2017: 8416763. doi:10.1155/2017/8416763.

7. Sabir S, Jan A. Physiology, immune response. In: StatPearls. Treasure Island (FL): StatPearls Publishing; 2026 Jan–. Updated 2025 Dec 1.

8. Vadivelan R, Dhanabal SP, Raja Rajeswari, Shanish A, Elango K, Suresh B. Oxidative stress in diabetes—A key therapeutic agent. Res J Pharmacol Pharmacodyn. 2010; 2(3): 221–227.

9. Pathade PA, Ahire YS, Bairagi VA, Abhang DR. Antioxidant therapy in cognitive dysfunction associated with diabetes mellitus: an overview. Res J Pharmacol Pharmacodyn. 2011; 3(2): 39–44.

10. Zong Y, Li H, Liao P, Chen L, Pan Y, Zheng Y, et al. Mitochondrial dysfunction: mechanisms and advances in therapy. Signal Transduct Target Ther. 2024; 9(1): 124. doi:10.1038/s41392-024-01839-8.

11. Chen L, Deng H, Cui H, Fang J, Zuo Z, Deng J, et al. Inflammatory responses and inflammation-associated diseases in organs. Oncotarget. 2017; 9(6): 7204–7218. doi:10.18632/oncotarget. 23208.

12. Mahurkar N, Hasan SMU, Malpani A, Manjunath C. Evaluation of gastroprotective influence of vitamin C, melatonin, rabeprazole, and their combination in ethanol-induced ulcer model. Res J Pharmacol Pharmacodyn. 2013; 5(3): 155–161.

13. Cherrada N, Chemsa AE, Gheraissa N, Laib I, Gueboudji Z, El-Shazly M, et al. Gastroprotective efficacy of North African medicinal plants: a review on their therapeutic potential for peptic ulcers. Food Sci Nutr. 2024; 12(11): 8793–8824. doi:10.1002/fsn3.4536.

14. Wang F, Liu J, Hu X, Zhong Y, Wen F, Tang X, et al. The influence on oxidative stress markers, inflammatory factors, and intestinal injury-related molecules in the Wahui pigeon induced by lipopolysaccharide. PLoS One. 2021; 16(5): e0251462. doi:10.1371/journal.pone.0251462.

15. Bilski J, Konturek PC, Konturek SJ, Cieszkowski M, Czarnobilski K. Role of endogenous nitric oxide in the control of gastric acid secretion, blood flow, and gastrin release in conscious dogs. Regul Pept. 1994; 53(3): 175–184. doi:10.1016/0167-0115(94)90166-X.

16. Tarnawski AS, Jones MK. The role of epidermal growth factor (EGF) and its receptor in mucosal protection, adaptation to injury, and ulcer healing: involvement of EGF-R signal transduction pathways. J Clin Gastroenterol. 1998; 27 Suppl 1: S12–S20. doi:10.1097/00004836-199800001-00004.

17. Kim HS, Hwang KY, Chung IK, et al. Tissue plasminogen activator and plasminogen activator inhibitor type 1 gene polymorphism in patients with gastric ulcer complicated with bleeding. J Korean Med Sci. 2003; 18(1): 58–64. doi:10.3346/jkms.2003.18.1.58.

18. Damayanthi D, Prasad KVSRG. Evaluation of antidiabetic and antioxidant activity of n-cinnamoyl metformin analogues. Res J Pharmacol Pharmacodyn. 2017; 9(2): 81–87.

19. Sies H, Jones DP. Reactive oxygen species (ROS) are pleiotropic physiological signalling agents. Nat Rev Mol Cell Biol. 2020; 21(7): 363–383. doi:10.1038/s41580-020-0230-3.

20. Brunelle JK, Letai A. Control of mitochondrial apoptosis by the Bcl-2 family. J Cell Sci. 2009; 122(Pt 4): 437–441. doi:10.1242/jcs. 031682.

21. Babu VNK, Khurana N. A review on mitochondrial dysfunction and oxidative stress due to complex I in Parkinson's disease. Res J Pharmacol Pharmacodyn. 2021; 13(4): 167–170.

22. Alexander A, Tripathi DK, Ajazuddin, Singh M, Sahu M, Swarna. Multidose therapy (MDT) treatment for Helicobacter pylori infection leading to gastric ulcer and carcinoma: a review. Res J Pharmacol Pharmacodyn. 2011; 3(3): 140–147.

23. Maity P, Bindu S, Choubey V, et al. Lansoprazole protects and heals gastric mucosa from NSAID-induced gastropathy by inhibiting mitochondrial and Fas-mediated death pathways with concurrent induction of mucosal cell renewal. J Biol Chem. 2008; 283: 14391–14401.

24. Gotz JM, Veenendaal RA, Biemond I, Muller ES, Veselic M, Lamers CB. Serum gastrin and mucosal somatostatin in Helicobacter pylori-associated gastritis. Scand J Gastroenterol. 1995; 30(11): 1064–1068.

25. Gangoni A, Suneetha B, Sunanda S, Ravindrababu S. Hypolipidemic and antioxidant activity of methanolic leaf extract of Ochna obtusata on high-fat diet-induced obesity in rats. Res J Pharmacol Pharmacodyn. 2015; 7(1): 1–4.

26. Rizo-Téllez SA, Sekheri M, Filep JG. Myeloperoxidase: regulation of neutrophil function and target for therapy. Antioxidants (Basel). 2022; 11(11): 2302. doi:10.3390/antiox11112302.

27. Zhang W, Zhong R, Qu X, Xiang Y, Ji M. Effect of 8-hydroxyguanine DNA glycosylase 1 on the function of immune cells. Antioxidants (Basel). 2023; 12(6): 1300. doi:10.3390/antiox12061300.

28. Cordiano R, Di Gioacchino M, Mangifesta R, Panzera C, Gangemi S, Minciullo PL. Malondialdehyde as a potential oxidative stress marker for allergy-oriented diseases: an update. Molecules. 2023; 28(16): 5979. doi:10.3390/molecules28165979.

29. Gnatyuk O, Skorokhod O, Damin A, Chaika M, Naeimaeirouhani F, Pica L, et al. Structural impact of 4-hydroxynonenal modification on human cytochrome CYP4F11. Chem Med Chem. 2026; 21(2): e202500935. doi:10.1002/cmdc. 202500935.

30. Cracowski JL, Durand T, Bessard G. Isoprostanes as a biomarker of lipid peroxidation in humans: physiology, pharmacology and clinical implications. Trends Pharmacol Sci. 2002; 23(8): 360–366.

31. Nyström T. Role of oxidative carbonylation in protein quality control and senescence. EMBO J. 2005; 24(7): 1311–1317. doi:10.1038/sj.emboj.7600599.

32. Bandookwala M, Sengupta P. 3-Nitrotyrosine: a versatile oxidative stress biomarker for major neurodegenerative diseases. Int J Neurosci. 2020; 130(10): 1047–1062.

33. Goriuc A, Cojocaru KA, Luchian I, Ursu RG, Butnaru O, Foia L. Using 8-hydroxy-2'-deoxyguanosine (8-OHdG) as a reliable biomarker for assessing periodontal disease associated with diabetes. Int J Mol Sci. 2024; 25(3): 1425. doi:10.3390/ijms25031425.

34. Collins AR. The comet assay for DNA damage and repair: principles, applications, and limitations. Mol Biotechnol. 2004; 26(3): 249–261.

35. Biradar KV, Patil CB, Chivde BV, Malipatil MH, Biradar SD. Effect of superoxide dismutase mimetic tempol on dexamethasone-induced insulin resistance—role of oxidative stress. Res J Pharmacol Pharmacodyn. 2011; 3(3): 134–137.

36. Nandi A, Yan LJ, Jana CK, Das N. Role of catalase in oxidative stress- and age-associated degenerative diseases. Oxid Med Cell Longev. 2019; 2019: 9613090. doi:10.1155/2019/9613090.

37. Pei J, Pan X, Wei G, Hua Y. Research progress of glutathione peroxidase family (GPX) in redox. Front Pharmacol. 2023;14:1147414. doi:10.3389/fphar. 2023.1147414.

38. Georgiou-Siafis SK, Tsiftsoglou AS. The key role of GSH in keeping the redox balance in mammalian cells: mechanisms and significance of GSH in detoxification via formation of conjugates. Antioxidants (Basel). 2023; 12(11): 1953. doi:10.3390/antiox12111953.

39. Zitka O, Skalickova S, Gumulec J, Masarik M, Adam V, Hubalek J, et al. Redox status expressed as the GSH: GSSG ratio as a marker for oxidative stress in paediatric tumour patients. Oncol Lett. 2012; 4(6): 1247–1253. doi:10.3892/ol.2012.931.

40. Mijatović S, Savić-Radojević A, Plješa-Ercegovac M, Simić T, Nicoletti F, Maksimović-Ivanić D. The double-faced role of nitric oxide and reactive oxygen species in solid tumors. Antioxidants (Basel). 2020; 9(5): 374. doi:10.3390/antiox9050374.

41. Siraki AG. The many roles of myeloperoxidase: from inflammation and immunity to biomarkers, drug metabolism, and drug discovery. Redox Biol. 2021; 46: 102109. doi:10.1016/j.redox.2021.102109.

42. Jaydeokar AV, Bandawane DD, Nipate SS, Chaudhari PD. Natural antioxidants: a review on therapeutic applications. Res J Pharmacol Pharmacodyn. 2012; 4(1): 55–61.

43. Johnson DB, Gorle A, Paleti SK, Javvadi A. Anti-gastric ulcer studies on certain Siddha drugs. Res J Pharmacol Pharmacodyn. 2011; 3(3): 123–128.

44. Shah N, Gossman W. Omeprazole. In: StatPearls. Treasure Island (FL): StatPearls Publishing; 2026 Jan–. Updated 2023 Feb 7.

45. Fornai M, Colucci R, Antonioli L, Ghisu N, Tuccori M, Blandizzi C, et al. Effects of pantoprazole on ulcer healing delay associated with NSAID treatment. Naunyn Schmiedebergs Arch Pharmacol. 2009; 379(3): 305–313. doi:10.1007/s00210-008-0355-y.

46. Laine L. Esomeprazole in the treatment of Helicobacter pylori. Aliment Pharmacol Ther. 2002;16 Suppl 4: 115–118. doi:10.1046/j.1365-2036.16.s4.13.x.

47. Langtry HD, Markham A. Rabeprazole: a review of its use in acid-related gastrointestinal disorders. Drugs. 1999; 58(4): 725–742. doi:10.2165/00003495-199958040-00014.

48. Croom KF, Scott LJ. Lansoprazole in the treatment of gastro-oesophageal reflux disease in children and adolescents. Drugs. 2005; 65(15): 2129–2137. doi:10.2165/00003495-200565150-00005.

49. Patel P, Ahlawat R. Famotidine. In: StatPearls. Treasure Island (FL): StatPearls Publishing; 2026 Jan–. Updated 2025 Sep 14.

50. Nugent CC, Falkson SR, Terrell JM. H2 blockers. In: StatPearls. Treasure Island (FL): StatPearls Publishing; 2026 Jan–. Updated 2024 Aug 11.

51. Pino MA, Azer SA. Cimetidine. In: StatPearls. Treasure Island (FL): StatPearls Publishing; 2026 Jan–. Updated 2023 Mar 6.

52. Kudaravalli P, Patel P, John S. Sucralfate. In: StatPearls. Treasure Island (FL): StatPearls Publishing; 2026 Jan–. Updated 2024 Feb 28.

53. Krugh M, Patel P, Maani CV. Misoprostol. In: StatPearls. Treasure Island (FL): StatPearls Publishing; 2026 Jan–. Updated 2024 Dec 11.

54. Graham DY, Lee SY. How to effectively use bismuth quadruple therapy: the good, the bad, and the ugly. Gastroenterol Clin North Am. 2015; 44(3): 537–563. doi:10.1016/j.gtc.2015.05.003.

55. Shih C, Wu I, Wu D, Lei W, Tsay F, Tsai T. Evolution of amoxicillin-based mono-antibiotic regimens for Helicobacter pylori eradication: from ineffectiveness to innovation—a systematic review. 2026:1–17.

56. Vieira RR, Fontes LES, Pacheco RL, Fernandes MAP, Malta PP, Riera R. Proton pump inhibitor- and clarithromycin-based triple therapies for Helicobacter pylori eradication. Cochrane Database Syst Rev. 2020; 9: CD013734. doi:10.1002/14651858.CD013734.

57. Sisson G, Jeong JY, Goodwin A, Bryden L, Rossler N, Lim-Morrison S, et al. Metronidazole activation is mutagenic and causes DNA fragmentation in Helicobacter pylori and in Escherichia coli containing a cloned H. pylori RdxA(+) gene. J Bacteriol. 2000; 182(18): 5091–5096. doi:10.1128/JB.182.18.5091-5096.2000.

58. Sun YC, Zhu MJ, Chen XQ, Yue L, Zhao YR, Wang XJ, et al. Efficacy and safety of modified tetracycline dosing in a quadruple therapy for Helicobacter pylori: a retrospective single-center study. World J Gastroenterol. 2023; 29(22): 3508–3518. doi:10.3748/wjg.v29.i22.3508.

59. Petrovic S, Bita B, Barbinta-Patrascu ME. Nanoformulations in pharmaceutical and biomedical applications: green perspectives. Int J Mol Sci. 2024; 25(11): 5842. doi:10.3390/ijms25115842.

60. Sivadasan D, Sultan MH, Alqahtani SS, Javed S. Cubosomes in drug delivery: a comprehensive review on their structural components, preparation techniques, and therapeutic applications. Biomedicines. 2023; 11(4): 1114. doi:10.3390/biomedicines11041114.

61. Dai X, Shen L. Advances and trends in omics technology development. Front Med (Lausanne). 2022; 9: 911861. doi:10.3389/fmed. 2022.911861.

62. Moratilla-Rivera I, Sánchez M, Valdés-González JA, Gómez-Serranillos MP. Natural products as modulators of the Nrf2 signaling pathway in neuroprotection. Int J Mol Sci. 2023; 24(4): 3748. doi:10.3390/ijms24043748.

Received on 05.04.2026 Revised on 27.04.2026

Accepted on 15.05.2026 Published on 10.07.2026

Available online from July 14, 2026

Res.J. Pharmacology and Pharmacodynamics.2026;18(3):229-237.

DOI: 10.52711/2321-5836.2026.00031

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