Curcumin Oxidation Is Required for Inhibition of Helicobacter pylori Growth, Translocation and Phosphorylation of Cag A

Abstract

Curcumin is a potential natural remedy for preventing Helicobacter pylori-associated gastric inflammation and cancer. Here, we analyzed the effect of a phospholipid formulation of curcumin on H. pylori growth, translocation and phosphorylation of the virulence factor CagA and host protein kinase Src in vitro and in an in vivo mouse model of H. pylori infection. Growth of H. pylori was inhibited dose-dependently by curcumin in vitro. H. pylori was unable to metabolically reduce curcumin, whereas two enterobacteria, E. coli and Citrobacter rodentium, which efficiently reduced curcumin to the tetra- and hexahydro metabolites, evaded growth inhibition. Oxidative metabolism of curcumin was required for the growth inhibition of H. pylori and the translocation and phosphorylation of CagA and cSrc, since acetal- and diacetal-curcumin that do not undergo oxidative transformation were ineffective. Curcumin attenuated mRNA expression of the H. pylori virulence genes cagE and cagF in a dose-dependent manner and inhibited translocation and phosphorylation of CagA in gastric epithelial cells. H. pylori strains isolated from dietary curcumin-treated mice showed attenuated ability to induce cSrc phosphorylation and the mRNA expression of the gene encoding for IL-8, suggesting long-lasting effects of curcumin on the virulence of H. pylori. Our work provides mechanistic evidence that encourages testing of curcumin as a dietary approach to inhibit the virulence of CagA.

Oxidative Products of Curcumin Rather Than Curcumin Bind to Helicobacter Pylori Virulence Factor VacA and Are Required to Inhibit Its Vacuolation Activity

“…Curcumin, a natural polyphenolic compound, has an inhibitory effect on H. pylori growth. H. pylori , unlike other bacteria such as E. coli , fails to evade the inhibitory effects of curcumin due to its inability to reduce this compound [ 5 ]. This is attributed to the absence of the reductase enzyme CurA, suggesting that curcumin reduction may contribute to its inactivity [ 17 ].…”

“…While reduction of curcumin is associated with its reduced activity, oxidation of curcumin has been implicated in its enhanced biological activity. Recently we have shown that curcumin oxidation is essential for inhibiting H. pylori growth, phosphorylation, and translocation of one of its major virulence factors, CagA [ 5 ].…”

“…Curcumin engages with several cell-signaling pathways and inhibits cancer cell proliferation. Recently, it has been seen that curcumin undergoes an autoxidative transformation at physiological pH leading to the generation of oxidative derivatives of curcumin [ 4 ] We have shown that the oxidation of curcumin is an essential step for its inhibitory effects against CagA, one of the major H. pylori virulence factors [ 5 ]. This study indicated that short-lived oxidative products of curcumin are active compounds against CagA.…”

“…The CagA protein has a molecular weight of 120–140-kDa and is translocated in to the host cell via the type IV secretion system after bacterial adhesion [ 8 ]. It has been recently shown that oxidation of curcumin is required for inhibition of CagA translocation and phosphorylation [ 5 ].…”

Effect of polyphenol compounds onHelicobacter pylorieradication: a systematic review with meta-analysis

“…13 Several studies indicate that these polyphenol compounds positively affect H. pylori eradication. [14][15][16][17][18][19][20][21] However, several experimental and clinical studies have shown different results. 22 23 There are no known meta-analyses concerning the effects of polyphenol compounds on H.pylori infection.…”