TL;DR
The β-clamp protein is identified as a therapeutic target and CID 546,407 as a promising lead for drug development, driven by robust Van der Waals forces, which avoids the massive entropic penalties hindering other compounds.
ABSTRACT The rising prevalence of antibiotic-resistant Helicobacter pylori (H. pylori) underscores the urgent need for alternative treatment strategies. By producing ammonia to neutralize gastric acid, the key virulence factor urease is essential for H. pylori acid tolerance, thereby representing a promising therapeutic target. In this study, we identified luteolin as a potent urease inhibitor (IC50 = 30.50 μg/mL) from a screening of over 200 natural compounds. Further investigation through molecular docking, dynamics simulations, cellular thermal shift assay, and enzyme kinetics studies confirmed its competitive binding to the Ni2+-centered catalytic site of H. pylori urease (HPU). Luteolin exhibited potent anti-H. pylori activity under standard and simulated gastric conditions, and showed low propensity for resistance development over 14 serial passages. Proteomic and metabolomic analyses revealed that luteolin inhibited HPU activity, and the consequent ammonia restriction triggered severe metabolic dysfunction, characterized by disruptions in nucleotide, amino acid biosynthesis and TCA cycle. In GES-1 cells, luteolin protected against H. pylori-induced damage. In a mouse model of H. pylori-induced peptic ulcer, luteolin treatment significantly reduced the bacterial load, with concomitant alleviation of gastric mucosal pathology and suppression of inflammatory responses. In contrast to antibiotic-induced gastric microbial dysbiosis, microbial diversity analysis indicated that luteolin treatment had minimal impact on the resident gastric microbiota. In summary, as a urease inhibitor, luteolin suppresses H. pylori by blocking ammonia production, thereby disrupting acid neutralization and inducing metabolic dysfunction, which collectively alleviates gastric damage and inflammation while minimizing microbiota disruption and resistance risk.
It is demonstrated that HEP exerts gastroprotective effects against CAG through coordinated anti-inflammatory, antioxidant, and structure-dependent NF-κB inhibitory actions, supporting its potential as a promising natural agent for CAG intervention.
Findings indicate that ELKL exerts significant anti-inflammatory effects through the multi-component and multi-target regulation of inflammatory signaling pathways, thereby supporting its therapeutic potential in preventing the progression of CAG and IM.
ETHNOPHARMACOLOGICAL RELEVANCE Helicobacter pylori (H. pylori) infection is a leading risk factor for chronic gastritis, peptic ulcers, and gastric cancer. The escalating antibiotic resistance of H. pylori and adverse effects arising from standard antibiotic regimens have underscored an urgent need for natural, food-complementary therapeutic alternatives. Terminalia chebula Retz., commonly named "Hezi" in traditional Chinese medicine and "Haritaki" in Ayurveda, is a well-recognized edible fruit with a long history of use in alleviating gastrointestinal disorders. AIM OF THE STUDY While it has been traditionally recognized for its anti-inflammatory and antimicrobial properties, its anti-adhesive efficacy against H. pylori and the metabolic mechanisms underlying its in vivo effects remain largely unexplored. MATERIALS AND METHODS This study adopted multiple analytical and experimental approaches: ultra-high-performance liquid chromatography-tandem mass spectrometry (UPLC-MS/MS), RNA-seq, cell viability and adhesion assays, western blotting, hematoxylin and eosin (H&E) staining, enzyme-linked immunosorbent assay (ELISA), metabolomics, and proteomics. RESULTS In this study, 15 primary compounds in T. chebula aqueous extract were identified, predominantly tannins. Multi-omics analyses (transcriptomics, metabolomics, and proteomics) revealed that T. chebula aqueous extract significantly inhibited H. pylori adhesion and enriched the lysine degradation pathway. Notably, N-alpha-acetyl-L-lysine was characterized as a key metabolite in fecal metabolomic profiling, which was associated with glycosphingolipid biosynthesis, ferroptosis, HIF-1 signaling, lysosomal function, and arginine metabolism. In vitro assays confirmed that N-alpha-acetyl-L-lysine reduced H. pylori adhesion to GES-1 cells, reversed H. pylori-induced cellular damage, and suppressed the secretion of pro-inflammatory cytokines (IL-6 and TNF-α). In vivo, T. chebula aqueous extract administration markedly alleviated H. pylori-induced gastric inflammation by downregulating IL-6, IL-1β, TNF-α, TGF-β, and IFN-γ. Collectively, these findings demonstrate that T. chebula aqueous extract exerts anti-H. pylori effects by regulating lysine metabolism, with N-alpha-acetyl-L-lysine serving as a key metabolite via fecal metabolomics. CONCLUSION These findings highlight T. chebula's promising potential as a functional food ingredient or adjunctive therapy for H. pylori-related diseases, providing a natural, mechanism-based option for clinical intervention.
Background: Peptic ulcer disease (PUD) remains a global health burden with limitations of current therapies including side effects of proton pump inhibitors and rising antibiotic resistance against Helicobacter pylori. Medicinal plants offer multi-targeted gastroprotective alternatives. Objective: To investigate the phytochemical profile and in-vitro anti-ulcer activity of Bombax ceiba stem bark and Coptis japonica rhizomes. Methods: Aqueous, hydroalcoholic, methanolic, and ethanolic extracts were prepared. Qualitative and quantitative phytochemical analyses (total phenolic, flavonoid, alkaloid, and tannin content) were performed. In-vitro anti-ulcer activity was evaluated using acid-neutralizing capacity (ANC), H⁺/K⁺-ATPase (proton pump) inhibition assay, pepsin inhibition assay, and cytoprotective activity against ethanol-induced damage in human gastric epithelial (AGS) cells. Omeprazole and sodium bicarbonate served as standards. Results: Hydroalcoholic extract of B. ceiba showed highest total phenolic (186.4 mg GAE/g) and flavonoid (112.5 mg QE/g) content, while methanolic extract of C. japonica exhibited highest alkaloid content (245.8 mg/g). In ANC, B. ceiba hydroalcoholic extract (18.6 mEq/g) was comparable to sodium bicarbonate (21.2 mEq/g). For H⁺/K⁺-ATPase inhibition, C. japonica methanolic extract (IC₅₀ = 28.4 µg/mL) showed potent activity approaching omeprazole (12.6 µg/mL). Both plants demonstrated concentration-dependent pepsin inhibition and significant cytoprotection in AGS cells (up to 82% viability at 200 µg/mL). Conclusion: Bombax ceiba exhibits excellent acid-neutralizing and cytoprotective effects attributed to phenolics and tannins, whereas Coptis japonica is a potent natural H⁺/K⁺-ATPase inhibitor due to its high alkaloid (berberine) content. Both plants possess multi-target anti-ulcer mechanisms, supporting their traditional use and offering potential as safer, alternative or adjunctive therapies for peptic ulcer disease.