Helicobacter pylori inhabits more than 50 % ofworld population and is a major cause of gastric cancer. Gastric ulcers, adenocarcinomas, and mucosa-associated lymphoid tissue (MALT) lymphoma are major pathological conditions associated with H. pylori infection [1]. Oxidative stress and altered immune responses associated with these pathological conditions are hallmarks of H. pylori pathogenesis. Reactive oxygen species (ROS) and reactive nitrogen species (RNS)are highly reactive biochemical free radical species which have important role in normal physiological functioning but when produced in excess during oxidative stress cause tissue and cell damage and hence also enhance inflammation [2].Nicotinamide adenine dinucleotide phosphate (NADPH) oxidases (NOX) are membrane bound protein complexes which help in ROS production especially in immune cells [3] similarly RNS are mainly produced during amino acid l-arginine metabolism by nitric oxide synthase (NOS) enzyme [2].H. pylori not only survive the killing of ROS and RNS produced by infiltrated immune cells at infection site, but also triggers the releaseof these oxidative species [4], [5]. Excess release of ROS/RNS further damage surrounding cells which enhance inflammation.As an extracellular bacterium, the pathogenicity of H. pylori depends on either surface exposed virulence factor or its secretory proteins.H. pylori secrets a plethora of secretory proteins from which cytotoxin associated gene A (CagA), vacuolating cytotoxin A (VacA), neutrophil activating protein (NAP), heat shock protein B (HspB),duodenal ulcer promoting factor A (DupA), outer inflammatory protein A (OipA) and high temperature requirement A (HtrA) are main which have role in oxidative stress [6]. These virulence factors not only stimulatefree radicals’ production but also protect H. pylori from these species. CagA and VacAare highly studied virulence factors which also have role in oxidative stress as they inhibit autophagy which further enhances ROS production [6], [7]. ROS produced in excess further stimulates genomic DNA damage which is also a cause of gastric carcinogenesis [5]. H. pylori survives the killing from ROS and RNS through chemotactically sensing ROS gradient byTlpDprotein [8].It alsoinhibits RNS production by downregulatingNOSwiththe depletion of cellular l-arginine [9]. Studies also showed nitric oxide synthase 2 (NOS2) dependent presence of NO in gastric epithelial and phagocyte cells during H. pylori pathogenesis [18]. NOS2-dependent NO production and related RNS are associated with DNA damage and modification of the nucleic acid base guanine to 8-nitoguanine, which is also a potent mutagen [19], [20]. H. pylori-induced NO also found to restrict Th1 and innate immune responses related IFN-γ-induced apoptosis in gastric epithelial cells [19], [21]. Although NO can restrictH. pylori growth, it is also regulated by H. pylori for its survival. H. pylori depletes cellular l-arginine which is a NOS2 substrateand it also induces asymmetric dimethylarginine expression which is a NOS2 inhibitor [22], [23]. H. pylori also deploys its two-component system CrdS-CrdR, NADPH-dependent NO reductase of H. pyloriand S-nitrosoglutathione reductase FrxA in the defense against host NO and related nitrosative species [24], [25].

Myeloperoxidase (MPO) enzyme is an innate immune defense to kill bacteria by phagocytes, primarily through neutrophils. MPO catalyzed NADPH oxidase stimulates superoxide ions to produce bactericidal HOCl[26]. The higher expression of MPO during H. pylori pathogenesis was found stimulated by HP-NAP [27]. MPO gene polymorphism, which leads to low expression of this enzyme, is also found associated with increased pathogenesis of H. pylori [28], [29]. H. pylori survives the killing from HOCl through sensing its molar concentration gradients by transducer-like protein Tlp D and chemotactically avoids higher concentration [30].

H. pylori-induced ROS is also responsible for macrophage polarization from pro-inflammatory M1 phenotype to cancer-associated M2 phenotype [10], [11]. Proinflammatory cytokine interleukin 1 beta (IL-1β) high expression and gene polymorphism are associated with H. pylori pathogenesis [12]. IL-1β inhibits gastric acid secretion and increases the production of IL-8 and nitric oxide (NO) through mitogen-activated protein kinase and ROS signaling [13]. Nuclear organization domain (NOD) like receptor protein 3 (NLRP3) inflammasome assembly regulates IL-1β secretion through the activation of caspase-1 [14]. H. pylori stimulates innate immune cells to secrete IL-1β through NLRP3 activation [15], [16] whereas reports also showed its downregulation by H. pylori [17]. Role of H. pyloriin NLRP3 inflammasome regulation and macrophage polarization is not well understood. TRPM2 deficiency in mice led to increased inflammation and decreased bacterial colonization during H. pylori infection, suggesting a potential link between oxidative stress and macrophage polarization [11]. However, the specific role of H. pylori-induced oxidative stress in NLRP3 inflammasome regulation and macrophage polarization remains unclear. Further research is needed to elucidate the molecular mechanisms underlying these processes.

Keeping in mind that oxidative stress plays a vital role during H. pylori pathogenesis, it is important to study oxidative stress primary makers ROS, NO, MPO, lipid peroxidation and protein carbonylation. Virulence genes variance among different strains and host genetic diversity are key challenges in defining a clear role of H. pylori genes in oxidative stress. Bacterial pathogen-associated molecular patterns (PAMPs) produce cellular organelle damage and ROS which activate NLRP3 and IL-1β release through an unknown mechanism [14]. Similar mechanisms during H. pylori pathogenesis are not studied yet. In current study, H. pylori secretory proteins induced oxidative stress role is defined in the regulation of NLRP3 inflammasome and macrophage polarization.