The Garlic Compound <i>Z</i>‐Ajoene, <i>S</i>‐Thiolates COX2 and STAT3 and Dampens the Inflammatory Response in RAW264.7 Macrophages

Hitchcock, Jessica K.; Mkwanazi, Nonkululeko; Barnett, Christopher B.; Graham, Lisa M.; Katz, Arieh A.; Hunter, Roger; Schäfer, Georgia; Kaschula, Catherine H.

doi:10.1002/mnfr.202000854

Cited by 12 publications

(23 citation statements)

References 83 publications

(140 reference statements)

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“…In addition to allicin, its secondary metabolite Z -ajoene has also been found to have anti-inflammatory effects. Z -ajoene has been found to inhibit the pro-inflammatory cytokine (including IL-1 β, IL-12 and IL-6 β), and up regulate the anti-inflammatory cytokine (IL = 10) ( Hitchcock et al, 2021 ). Moreover, it is reported that Z -ajoene or its analogue dansyl-ajoene was found to decrease phosphorylation and nuclear translocation of STAT3, and to covalently modify the protein by S -thiolation at Cys108, Cys367, and Cys687 ( Hitchcock et al, 2021 ).…”

Section: Allicinmentioning

confidence: 99%

“…Z -ajoene has been found to inhibit the pro-inflammatory cytokine (including IL-1 β, IL-12 and IL-6 β), and up regulate the anti-inflammatory cytokine (IL = 10) ( Hitchcock et al, 2021 ). Moreover, it is reported that Z -ajoene or its analogue dansyl-ajoene was found to decrease phosphorylation and nuclear translocation of STAT3, and to covalently modify the protein by S -thiolation at Cys108, Cys367, and Cys687 ( Hitchcock et al, 2021 ). In the same study, Z -Ajoene was also found to inhibit the activity of cyclooxygenase 2 (COX2) in a dose-dependently and non-competitively manner, which may be attributed to the S -thiolation at Cys9 and Cys299 ( Hitchcock et al, 2021 ).…”

Section: Allicinmentioning

confidence: 99%

“…Moreover, it is reported that Z -ajoene or its analogue dansyl-ajoene was found to decrease phosphorylation and nuclear translocation of STAT3, and to covalently modify the protein by S -thiolation at Cys108, Cys367, and Cys687 ( Hitchcock et al, 2021 ). In the same study, Z -Ajoene was also found to inhibit the activity of cyclooxygenase 2 (COX2) in a dose-dependently and non-competitively manner, which may be attributed to the S -thiolation at Cys9 and Cys299 ( Hitchcock et al, 2021 ). It is reported that the anti-inflammatory effect of allicin is related to its anti-cancer effect ( Schäfer and Kaschula, 2014 ).…”

Section: Allicinmentioning

confidence: 99%

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Allicin in Digestive System Cancer: From Biological Effects to Clinical Treatment

Yang

Luo

et al. 2022

Front. Pharmacol.

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Allicin is the main active ingredient in freshly-crushed garlic and some other allium plants, and its anticancer effect on cancers of digestive system has been confirmed in many studies. The aim of this review is to summarize epidemiological studies and in vitro and in vivo investigations on the anticancer effects of allicin and its secondary metabolites, as well as their biological functions. In epidemiological studies of esophageal cancer, liver cancer, pancreatic cancer, and biliary tract cancer, the anticancer effect of garlic has been confirmed consistently. However, the results obtained from epidemiological studies in gastric cancer and colon cancer are inconsistent. In vitro studies demonstrated that allicin and its secondary metabolites play an antitumor role by inhibiting tumor cell proliferation, inducing apoptosis, controlling tumor invasion and metastasis, decreasing angiogenesis, suppressing Helicobacter pylori, enhancing the efficacy of chemotherapeutic drugs, and reducing the damage caused by chemotherapeutic drugs. In vivo studies further demonstrate that allicin and its secondary metabolites inhibit cancers of the digestive system. This review describes the mechanisms against cancers of digestive system and therapeutic potential of allicin and its secondary metabolites.

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Section: Allicinmentioning

confidence: 99%

Section: Allicinmentioning

confidence: 99%

Section: Allicinmentioning

confidence: 99%

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Allicin in Digestive System Cancer: From Biological Effects to Clinical Treatment

Yang

Luo

et al. 2022

Front. Pharmacol.

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“…LC−MS Analysis 1 for target peptide list generation and LC−MS Analysis 2 via multiple reaction monitoring (MRM) based validation were performed according to the method previously published by Hitchcock et al 27 Statistics. All analyses were performed using GraphPad Prism v5 software (GraphPad Software, La Jolla, CA).…”

Section: ■ Materials and Methodsmentioning

confidence: 99%

Activity-Based Proteomic Identification of the S-Thiolation Targets of Ajoene in MDA-MB-231 Breast Cancer Cells

Kusza

Hunter

Schäfer

et al. 2022

J. Agric. Food Chem.

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Garlic is a medicinal plant and spice that has been used for millennia for its health-promoting effects. These medicinal properties are associated with low molecular weight organosulfur compounds, produced following the crushing of garlic cloves. One of these compounds, ajoene, is proposed to act by S-thioallylating cysteine residues on target proteins whose identification in cancer cells holds great promise for understanding mechanistic aspects of ajoene’s cancer cell cytotoxicity. To this end, an ajoene analogue (called biotin-ajoene, BA), containing a biotin affinity tag, was designed as an activity-based probe specific for the protein targets of ajoene in MDA-MB-231 breast cancer cells. BA was synthesized via a convergent “click” strategy and found to retain its cytotoxicity against MDA-MB-231 cells compared to ajoene. Widespread biotinylation of proteins was found to occur via disulfide bond formation in a dose-dependent manner, and the biotin-ajoene probe was found to share the same protein targets as its parent compound, ajoene. The biotinylated proteins were affinity-purified from the treated MDA-MB-231 cell lysate using streptavidin-coated magnetic beads followed by an on-bead reduction, alkylation, and digestion to liberate the peptide fragments, which were analyzed by liquid chromatography tandem mass chromatography. A total of 600 protein targets were identified, among which 91% overlapped with proteins with known protein cysteine modification (PCM) sites. The specific sites were enriched for those susceptible to S-glutathionylation (−SSG) (16%), S-sulfhydration (−SSH) (20%), S-sulfenylation (−SOH) (22%), and S-nitrosylation (−SNO) (31%). As target validation, both ajoene and a dansylated ajoene (DP) were found to S-thiolate the pure recombinant forms of glutathione S-transferase pi 1 (GSTP1) and protein disulfide isomerase (PDI), and the ajoene analogue DP was found to be a more potent inhibitor than 5,5-dithio-bis-(2-nitrobenzoic acid) (DTNB). Pathway analysis elucidated that ajoene targets functional and signaling pathways that are implicated in cancer cell survival, specifically cellular processes, metabolism, and genetic information processing pathways. The results of this study provide mechanistic insights into the character of the anti-cancer activity of the natural dietary compound ajoene.

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“…AGE also regulates the inflammatory process by inducing AMPK activation and down-regulating the Toll-like receptor (TLR) signaling pathway ( Miki et al, 2017 ). Z-Ajone reduces the phosphorylation and nuclear translocation of STAT3, inhibits the activity of Cyclooxygenase-2 (COX2) ( Hitchcock et al, 2021 ), and carries out S-sulfhydrylation of cysteine sulfhydryl groups in two inflammatory proteins, thus producing downstream anti-inflammatory effects.…”

Section: The Pharmacological Activity Of Garlicmentioning

confidence: 99%

Roles and mechanisms of garlic and its extracts on atherosclerosis: A review

Yun

Wang

et al. 2022

Front. Pharmacol.

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The prevention and treatment of cardiovascular diseases (CVDs) have achieved initial results, but the number of CVDs patients will increase rapidly in the next 10 years. Atherosclerosis (AS) is a significant risk factor for CVDs. The impact of lifestyle and daily diet varies considerably between different countries and continents and has been shown to affect the development of various diseases such as diabetes and CVDs. Primary and secondary prevention using alternative supplements and methods to avoid or reduce the use of traditional pharmacological drugs have also become popular. One of the reasons for this is that pharmacological drugs with lipid-lowering, and blood pressure-lowering effects cause many side effects that may negatively impact the quality of life. Patients are now emphasizing reliance on lifestyle changes to reduce cardiovascular risks. Garlic is a medicinal and edible plant that has been used for a long time. In order to reveal garlic application in the prevention and treatment of AS, reviewing the latest domestic and international studies through searching databases. The result shows that the antiatherogenic role of garlic is eximious. And the mechanisms are mainly related to hypolipidemic, antioxidant, antithrombotic, inhibiting angiogenesis, protecting endothelial cells, anti-inflammatory, anti-apoptotic, inhibiting vascular smooth muscle proliferation, and regulating gut microbiota. The main signaling pathways involve AMPK/TLRs, Keap1/Nrf2, PI3K/AKT, PPARγ/LXRα, GEF-H1/RhoA/Rac, etc. The antiatherogenic actions and molecular mechanism of garlic were reviewed in this study to obtain a robust evidence basis for the clinical application and mechanistic study and provide a theoretical basis for further utilization of garlic.

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The Garlic Compound Z‐Ajoene, S‐Thiolates COX2 and STAT3 and Dampens the Inflammatory Response in RAW264.7 Macrophages

Cited by 12 publications

References 83 publications

Allicin in Digestive System Cancer: From Biological Effects to Clinical Treatment

Allicin in Digestive System Cancer: From Biological Effects to Clinical Treatment

Activity-Based Proteomic Identification of the S-Thiolation Targets of Ajoene in MDA-MB-231 Breast Cancer Cells

Roles and mechanisms of garlic and its extracts on atherosclerosis: A review

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