Modulatory effect of caffeic acid in alleviating diabetes and associated complications

Diabetes mellitus(DM)is one of the most common metabolic disorders characterized by elevated blood glucose levels.Prolonged uncontrolled hyperglycemia often leads to multi-organ damage including diabetic neuropathy,nephropathy,retinopathy,cardiovascular disorders,and diabetic foot ulcers.Excess production of free radicals causing oxidative stress in tissues is often considered to be the primary cause of onset and progression of DM and associated complications.Natural polyphenols can be used to induce or inhibit the expression of antioxidant enzymes such as glutathione peroxidase,heme oxygenase-1,superoxide dismutase,and catalase that are essential in maintaining redox balance,and ameliorate oxidative stress.Caffeic acid(CA)is a polyphenolderived from hydroxycinnamic acid and possesses numerous physiological properties including antioxidant,anti-inflammatory,anti-atherosclerotic,immune-stimulatory,cardioprotective,antiproliferative,and hepatoprotective activities.CA acts as a regulatory compound affecting numerous biochemical pathways and multiple targets.These include various transcription factors such as nuclear factor-B,tumor necrosis factor-α,interleukin-6,cyclooxygenase-2,and nuclear factor erythroid 2-related factor 2.Therefore,this review summarizes the pharmacological properties,molecular mechanisms,and pharmacokinetic profile of CA in mitigating the adverse effects of DM and associated complications.The bioavailability,drug delivery,and clinical trials of CA have also been discussed.

On-the-Fly Nonadiabatic Dynamics of Caffeic Acid Sunscreen Compound

As a widely-used sunscreen com-pound,the caffeic acid(CA)shows the strong UV absorption,while the photoinduced reaction mecha-nisms behind its photoprotection ability are not fully understood.We try to investigate the photoin-duced internal conversion dynam-ics of CA in order to explore the photoprotection mechanism.The most stable CA isomer is selected to examine its nonadiabatic dy-namics using the on-the-fly surface hopping simulations at the semi-empirical level of electronic-struc-ture theory.The dynamics starting from different electronic states are simulated to explore the dependence of the photoinduced reaction channels on the excitation wavelengths.Several S1/S0 conical intersections,driven by the H-atom detachments and the ring deformations,have been found to be responsible for the nonadiabatic decay of the CA.The simulation re-sults show that the branching ratios towards these intersections are modified by the light with different excitation energies.This provides the valuable information for the understanding of the photoprotection mechanism of the CA compound.

Caffeic acid phenethyl ester up-regulates antioxidant levels in hepatic stellate cell line T6 via an Nrf2-mediated mitogen activated protein kinases pathway

AIM To investigate the antioxidant effect of caffeic acid phenethyl ester (CAPE) in hepatic stellate cell-T6 (HSC-T6) cells cultured in vitro and the potential mechanisms. METHODS HSC-T6 cells were cultured in vitro and treated with various concentrations of CAPE for 24, 48 and 72 h, respectively. Cell proliferation was investigated using the MTT assay, and cell ultrastructural alterations were observed by transmission electron microscopy. Flow cytometry was employed to investigate the effects of CAPE on apoptosis and the levels of reactive oxygen species in HSC-T6 cells cultured in vitro. An enzyme immunoassay instrument was used to evaluate antioxidant enzyme expression. The effect on alpha-smooth muscle actin was shown using immunofluorescence. Gene and protein levels of Nrf2, related factors, and mitogen activated protein kinases (MAPKs), in HSC-T6 cells were detected using RT-PCR and Western blot, respectively. RESULTS CAPE inhibited the proliferation and activation of HSC-T6 cells cultured in vitro. CAPE increased the antioxidant levels and the translocation of Nrf2 from the cytoplasm to the nucleus in HSC-T6 cells. Moreover, the phosphorylation of MAPKs in cells decreased in response to CAPE. Interestingly, CAPE-induced oxidative stress in the cells was significantly attenuated by pretreatment with MAPKs inhibitors. CONCLUSION CAPE inhibits cell proliferation and up-regulates the antioxidant levels in HSC-T6 cells partly through the Nrf2-MAPKs signaling pathway.

Effect of caffeic acid phenethyl ester on proliferation and apoptosis of colorectal cancer cells in vitro

AIM:To study the effect of caffeic add phenethyl ester (CAPE) on proliferation, cell cycle, apoptosis and expression of β-catenin in cultured human colorectal cancer (CRC) cell line HCT116. METHODS: HCT116 cells were treated with CAPE at serial concentrations of 80,40,20,10,5,2.5 mg/L. The proliferative status of HCT116 cells was measured by using methaben-zthiazuron (MTT) assay. Cell cycle was analyzed by using flow cytometry (FCM) with propidium iodide (PI) labeling method. The rate of apoptosis was detected by using FCM with annexin V-FITC and PI double labeling method, β-catenin levels were determined by Western blotting, β-catenin localization in HCT116 was determined by indirect immunofluorescence. RESULTS: After HCT116 cells were exposed to CAPE (80, 40, 20, 10, 5, and 2.5 mg/L) for 24, 48, 72, 96 h, CAPE displayed a strong growth inhibitory effect in a dose- and time-dependent manner against HCT116 cells. FCM analysis showed that the ratio of G0/G1 phase cells increased, S phase ratio decreased and apoptosis rate increased after HCT116 cells were exposed to CAPE (10, 5, and 2.5 mg/L) for 24 h. CAPE treatment was associated with decreased cytoplasmic β-catenin, nuclear p-catenin and a concurrent increase in β-catenin protein expression at cell-cell junctions. CONCLUSION: CAPE could inhibit HCT116 cell proliferation and induce cell cycle arrest and apoptosis. Decreased β-catenin protein expression may mediate the anti-proliferative effects of CAPE.

Inhibitory effect of caffeic acid phenethyl ester on the growth of SW480 colorectal tumor cells involvesβ-catenin associated signaling pathway down-regulation

AIM： To study the anti-tumor effect of caffeic acid phenethyl ester （CAPE） and the influence of CAPE on β-catenin associated signaling pathway in SW480 colorectal cancer （CRC） cells. METHODS： SW480 cells were treated with CAPE at serial concentrations. The proliferative status of cells was measured by methabenzthiazuron （MTT） assay. Cell cycle and cell apoptosis were analyzed using flow cytometry （FCM）. Western blotting assay was used to evaluate the protein level of β-catenin, c-myc and cyclinD1. β-catenin localization was determined by indirect immunofluorescence. RESULTS： CAPE displayed a strong inhibitory effect in a significant dose- and time-dependent manner on SW480 cell growth. FCM analysis showed that the ratio of G0/G1 phase cells increased, S phase ratio decreased and apoptosis rate increased after SW480 cells were exposed to CAPE for 24 h. Pretreatment of SW480 cells with CAPE significantly suppressed β-catenin, c-myc and cyclinD1 protein expression. CAPE treatment was associated with decreased accumulation of β-catenin protein in nucleus and cytoplasm, and concurrently increased its accumulation on the surface of cell membrane. CONCLUSION： CAPE can inhibit SW480 cell proliferation by inducing cell cycle arrest and apoptosis. Decreased β-catenin and the associated signaling pathway target gene expression may mediate the anti-tumor effects of CAPE.

Identification of differential proteins in colorectal cancer cells treated with caffeic acid phenethyl ester

AIM: To investigate the molecular mechanisms of the anti-cancer activity of caffeic acid phenethyl ester (CAPE).

SALVIANOLIC ACID G,A CAFFEIC ACID DIMER WITH A NOVEL TETRACYCLIC SKELETON

Salvianolic acid G,a caffeic acid dimer with a novel tetracyclic skeleton was isolated from the roots of Salvia miltiorrhiza.Its structure was elucidated by chemical and spectral analysis,especially by 2D NMR analysis.

Lipase-catalyzed Synthesis of Caffeic Acid Phenethyl Ester in Ionic Liquids： Effect of Specific Ions and Reaction Parameters

Caffeic acid phenethyl ester(CAPE)is a rare,naturally occurring phenolic food additive.This work systematically reported fundamental data on conversion of caffeic acid(CA),yield of CAPE,and reactive selectivity during the lipase-catalyzed esterification process of CA and phenylethanol(PE)in ionic liquids(ILs).Sixteen ILs were selected as the reaction media,and the relative lipase-catalyzed synthesis properties of CAPE were measured in an effort to enhance the yield of CAPE with high selectivity.The results indicated that ILs containing weakly coordinating anions and cations with adequate alkyl chain length improved the synthesis of CAPE.[Emim][Tf2N]was selected as the optimal reaction media.The optimal parameters were as follows by response surface methodology(RSM):reaction temperature,84.0°C;mass ratio of Novozym 435 to CA,14︰1;and molar ratio of PE to CA,16︰1.The highest reactive selectivity of CAPE catalyzed by Novozym 435 in[Emim][Tf2N]reached 64.55%(CA conversion 98.76%and CAPE yield 63.75%,respectively).Thus,lipase-catalyzed esterification in ILs is a promising method suitable for CAPE production.

Therapeutic effect of caffeic acid phenethyl ester on cerulein-induced acute pancreatitis

AIM: To evaluate the therapeutic role of caffeic acid phenethyl ester (CAPE) in a rat model of ceruleaninduced acute pancreatitis (AP).METHODS: Seventy male Wistar albino rats were divided into seven groups. Acute edematous pancreatitis was induced by subcutaneous cerulein injection (20 μg/kg) four times at 1-h intervals. CAPE (30 mg/kg) was given by subcutaneous injection at the beginning (CAPE 1 group) and 12 h after the last cerulein injection (CAPE 2 group). Serum amylase, lipase, white blood cell count, and tumor necrosis factor (TNF)-α levels were measured, and pancreatic histopathology was assessed. RESULTS: In the AP group, amylase and lipase levels were found to be elevated and the histopathological evaluation showed massive edema and inflammation of the pancreas, with less fatty necrosis when compared with sham and control groups. Amylase and lipase levels and edema formation decreased signif icantly in the CAPE therapy groups (P < 0001); especially in the CAPE 2 group, edema was improved nearly completely (P = 0001). Inflammation and fatty necrosis were partially recovered by CAPE treatment. The pathologicalresults and amylase level in the placebo groups were similar to those in the AP group. White blood cell count and TNF-α concentration was nearly the same in the CAPE and placebo groups.CONCLUSION: CAPE may be useful agent in treatment of AP but more experimental and clinical studies are needed to support our observation of benef icial effects of CAPE before clinical usage of this agent.

Oxidative stress in testicular tissues of rats exposed to cigarette smoke and protective effects of caffeic acid phenethyl ester

Aim： To show the oxidative stress after cigarette smoke exposure in rat testis and to evaluate the effects of caffeic acid phenethyl ester （CAPE）. Methods： Twenty-one rats were divided into three groups of seven. Animals in Group Ⅰ were used as control. Rats in Group Ⅱ were exposed to cigarette smoke only （4 × 30 min/d） and rats in Group Ⅲ were exposed to cigarette smoke and received daily intraperitoneal injections of CAPE （10 μmol/kg.d）. After 60 days all the rats were killed and the levels of nitric oxide （NO） and anti-oxidant enzymes such as superoxide-dismutase, catalase and glutathione peroxidase （GSH-Px） and the level of malondialdehyde were studied in the testicular tissues of rats with spectrophotometric analysis. Results： There was a significant increase in catalase and superoxide-dismutase activities in Group Ⅱ when compared to the controls, but the levels of both decreased after CAPE administration in Group Ⅲ. GSH-Px activity was decreased in Group Ⅱ but CAPE caused an elevation in GSH-Px activity in Group Ⅲ. The difference between the levels of GSH-Px in Group Ⅰ and Group Ⅱ was significant, but the difference between groups Ⅱ and Ⅲ was not significant. Elevation of malondialdehyde after smoke exposure was significant and CAPE caused a decrease to a level which was not statistically different to the control group. A significantly increased level of NO after exposure to smoke was reversed by CAPE administration and the difference between NO levels in groups Ⅰ and Ⅲ was statistically insignificant. Conclusion： Exposure to cigarette smoke causes changes in the oxidative enzyme levels in rat testis, but CAPE can reverse these harmful effects. （Asian J Andro12006 Mar; 8： 189-193）

Caffeic acid and protocatechuic acid modulate Nrf2 and inhibit Ehrlich ascites carcinomas in mice

Objective:To assess the nuclear factor-erythroid 2-related factor-2(Nrf2)modulatory effect of caffeic acid and protocatechuic acid and determine the anti-tumor activity of these phenolic compounds against Ehrlich ascites carcinoma growth in mice.Methods:Antioxidant activity of protocatechuic acid and caffeic acid was assessed using ferric reducing antioxidant power(FRAP)and 2,2-diphenyl-1-picrylhydrazyl(DPPH).Nrf2 activation potential of phenolic compounds was tested by quantitative realtime polymerase chain reaction,and luciferase complementation reporter assays.In vivo efficacy was tested using the Ehrlich ascites carcinoma model.Results:FRAP and DPPH radical scavenging assays showed that caffeic acid and protocatechuic acid were more potent compared with cinnamic acid and benzoic acid.Luciferase complementation reporter assays identified caffeic acid and protocatechuic acid as the activators of Nrf2.Both caffeic acid and protocatechuic acid upregulated the expression of Nrf2 target genes heme oxygenase-1(HO-1),glutamate-cysteine ligase catalytic subunit(GCLC),and glutamate-cysteine ligase modifier subunit(GCLM)and the activity of NAD(P)H:quinone oxidoreductase 1(NQO1)when tested on HCT-116 cells using a cell-based assay system at 9 h.In addition,intraperitoneal administration of caffeic acid and protocatechuic acid to Ehrlich ascites carcinoma bearing mice suppressed tumor growth and angiogenesis.Conclusions:Caffeic acid and protocatechuic acid can modulate Nrf2 and inhibit Ehrlich ascites carcinoma cells.

Extraction Process and Content Determination of Caffeic Acid in Laggera alata from Different Production Areas of Guangxi

[Objectives] To establish a method for determining the content of Laggera alata( D. Don) Sch. Bip. Ex Oliv. using caffeic acid the target component,and to compare the content of caffeic acid in the medicinal materials of L. alata in different production areas of Guangxi.[Methods]The content was determined by Inertsil~ODS-3 chromatographic column C_(18)( 4. 60 mm × 250 mm,5 μm,mobile phase: acetonitrile-0. 1% phosphoric acid( 22∶ 78),detection wavelength: 320 nm,flow rate: 1. 0 m L/min,column temperature: 30℃,and injection volume: 10 μL. [Results] The caffeic acid showed a good linear relationship in the range of injection volume of 0. 025 92-0. 259 2 μg( R =0. 999 5). The average recovery rate was 98. 33%( RSD = 1. 85%). L. alata in different production areas of Guangxi contained the caffeic acid,and there was a great difference in the caffeic acid. L. alata in Baise had the highest content of caffeic acid,while that in Guilin had the lowest content of caffeic acid. [Conclusions]This method can accurately determine the content of caffeic acid and is expected provide a scientific basis for the development and utilization of herbal medicine L. alata.

Effects of caffeic acid phenethyl ester on proliferation of vascular smooth muscle cells in rats

Objective： To investigate the inhibitory effect of caffeic acid phenethyl ester（CAPE） on the proliferation of vascular smooth muscle cells （VSMC） activated by lipopolysaccharide （LPS） and to clarify its mechanism. Methods： VSMC activated by LPS （1 mg-L^-1） were treated with CAPE at different concentrations. The inhibitory effecfs of CAPE on the proliferation of VSMC were determined by methabenzthiazuron（MTT） colorimetry. The effects of CAPE on the expression of proliferating cell nuclear antigen （PCNA） and Survivin protein in VSMC were evaluated by immunocytochemistry staining technique （SABC method）. Cell cycle was analyzed by flow cytometry（FCM） with propidiumiodide （PI） labeling method. The relative expression level of Survivin mRNA was measured with real-time quantified RT-PCR technique. Results. CAPE exerted significant inhibitory effects on. proliferation of VSMC at concentrations ranging from 5 mg·L^-1 to 80 mg·L^-1, decreased the rate of cells positive for PCNA and Survivin protein and repressed the expressioh of Survivin mRNA in a dose- and time-dependent manner （P 〈 0.05）. FCM analysis displayed that CAPE up-regulated the ratio of G0/G1 stages and reduced the percentage of VSMC in S stage （P 〈 0.05）. Conclusion： CAPE can significantly inhibit the proliferation of VSMC activated by LPS in a dose- and time-dependent manner, which may be carded out through regulating cell cycle and repressing the expression of PCNA and Survivin.

Effect of caffeic acid derivatives on polychlorinated biphenyls induced hepatotoxicity in male mice

Chronic exposure to coplanar polychlorinated biphenyls（PCBs）,a potent inducer of toxic reactive oxygen species（ROS）,in the environment and food can cause liver diseases.It remains unknown whether caffeic acid derivatives（CADs） exerted protective effect on PCB-induced hepatotoxicity.We sought to evaluate the activities of 3CADs on PCB169-induced oxidative stress and DNA damage in the liver.Male ICR mice were administered with1 μmol/mL PCB169 at 5 mL/kg body weight for 2 weeks.The mice were given CADs by gastric gavage for 3weeks.We found that PCB169 decreased the growth rate and reduced the levels of superoxide dismutase（SOD）,glutathione（GSH） and GSH peroxidase（GPx）.It increased the liver weight,malondialdehyde（MDA）and 8-hydroxy-2＇-deoxyguanosine（8-OHdG） levels and CYPlAl activity in the liver tissues and plasma of mice（P〈0.05）.Pretreatment of mice with CADs restored the above parameters to normal levels.There was a synergistic protective effect between CADs in preventing MDA and 8-OHdG formation and inducing CYPlAl and phase II metabolism enzyme（SOD,GPx） activities（P〈0.05）.In conclusion,PCB169 induced hepatotoxicity and pretreatment with CADs had synergistic protective effects on liver damage.

A single dose of caffeic acid phenethyl ester prevents initiation in a medium-term rat hepatocarcinogenesis model

AIM： To study of the effect of caffeic acid phenethyl ester （CAPE） on the initiation period in a medium-term assay of hepatocarcinogenesis. METHODS： Male Wistar rats were subjected to a carcinogenic treatment （CT） and sacrificed at 25^th d; altered hepatic foci （AHF） were generated efficiently. To a second group of rats a single 20 mg/kg doses of CAPE was given 12 h before initiation with CT and were sacrificed at 25^th d. We evaluated the expression of preneoplastic markers as Y-glutamyltranspeptidase （GGT） and glutathione S-transferase type pi protein （GSTp） by histochemistry, RT-PCR and Western blot analyses, respectively. We measured thiobarbituric acid reactive substances （TBARS） in homogenates of liver and used Unscheduled DNA Synthesis （UDS） assay by incorporation of [^3H] thymidine （^3HdT） in primary hepatocyte cultures （PHC）. RESULTS： At 25^th d after CT CAPE reduced the observed increase of GGT^＋AHF by 84% and liver expression ofggt mRNA by 100%. In case of the GSTp protein, the level was reduced by 90%. As indicative of oxidative stress generated by diethylnitrosamine （DEN） 12 h after its administration, we detected a 68% increase of TBARS. When CAPE was administered before DEN, it completely protected from liver TBARS induction. To have an indication of the sole effect of CAPE on initiation, two carcinogens were tested in a UDS assay in PHC, we used methyl-n-nitrosoguanidine as a direct carcinogen and DEN, as indirect carcinogen. In this assay, genotoxic damage caused by carcinogens was abolished at 5μM CAPE concentration. CONCLUSION： Our results demonstrated that CAPE possesses anti-genotoxic and antineoplastic capabilities, by an anti-oxidative and free-radical scavenging mechanism.

A facile electrochemical synthesis of caffeic acid derivatives in the presence of acetylacetone or methyl acetoacetate in aqueous medium

The anodic oxidation of caffeic acid in the presence of acetylacetone or methyl acetoacetate in aqueous solution has been studied by cyclic voltammetry and controlled-potential electrolysis techniques. The result showed that caffeic acid was oxidized to the corresponding o-benzoquinone, which underwent further Michael-addition with acetylacetone or methyl acetoacetate to produce caffeic acid derivative 3,4-dihydroxy-6-(1-acetylacetone)-yl cinnamic acid 4a or 3,4-dihydroxy-6-(1-acetyl-methylacetate)-yl cinnamic acid 4b.

Effect of Caffeic acid on the Tumor Cells U937 Evaluated by an Electrochemical Voltammetric Method

Electrochemical voltammetric method can;be used to monitor cell health state during its growth. Here we studied the effect of caffeic acid on leukemia cells U937 by the voltammetric behavior of the cells. The result showed that this drug had a negative influence on cell health. which suggests that caffeic acid may be used in inhibition of tumor cells.

Caffeic acid 3,4-dihydroxyphenethyl ester prevents colorectal cancer through inhibition of multiple cancer-promoting signal pathways in 1,2-Dimethylhydrazine/dextran sodium sulphate mouse model

OBJECTIVE:To elucidate the potential feature and mechanism of the caffeic acid 3,4-dihydroxyphenethyl ester(CADPE)molecule,which can prevent colorectal cancer(CRC)in the 1,2-Dimethylhydrazine(DMH)/dextran sodium sulphate(DSS)-induced mouse model.METHODS:Institute of cancer research(ICR)male mice were injected with 20 mg/kg DMH for a week.After that,2%DSS was administered in the drinking water for another 7 d.The CADPE treatment was given to the DMH/DSS induced male mice at three different periods until their sacrifice.Histopathological examination was used for observing the CRC development at colonic mucosa.Immunohistochemistry(IHC),blood cells smearing and crypt damage scoring methods were used for investigating the anti-inflammation feature of CADPE related to CRC.The reversing targets searching method was applied with artificial intelligence(AI),computeraided drug designing(CADD)and Ingenuity Pathway Analysis(IPA)techniques for predicting the potential targets and mechanism of CADPE highly related to CRC.RESULTS:The data indicated that CADPE inhibited CRC tumor development in the colitis-associated DMH/DSS induced mouse model after giving the early treatment.CADPE also impeded the acute inflammation by decreasing the infiltration of neutrophils significantly during the initial stage of CRC development.Finally,our data showed that CADPE prevented CRC by blocking active sites of three pivotal protein targets including epidermal growth factor receptor(EGFR),extracellular signal-regulated kinase(ERK)and mammalian target of rapamycin(m TOR)in two major cancer development pathways.CONCLUSIONS:CADPE effectively prevented CRC at early stage of tumor germination in the DMH/DSS mouse model highly likely due to its anti-acute inflammation characteristic and the ability of blocking EGFR,ERK and m TOR activities in two highly related CRC developing pathways.

Correlation between Polyphenol Contents and Antioxidant Activities in Different Echinacea Purpurea Varieties

Objective:Polyphenols are complex compounds containing multiple phenolic hydroxyl groups.They are widely distributed in plants and have antioxidant activities.Whether the antioxidant activities of the cultivated varieties of Echinacea are similar to or better than those of the wild ones and the relationship between the accumulation of polyphenols and their antioxidant activities are still not clear.Methods:Folin-Ciocalteu method,high performance liquid chromatography(HPLC),2,2-diphenyl-1-picrylhydrazyl(DPPH)radical scavenging assay,ferric ion reducing antioxidant power(FRAP)assay,2,2'-azino-bis(3-ethylbenzothiazoline-6)-sulfonic acid(ABTS)radical scavenging assay,and Fe^(2+)chelating ability assay were used,respectively,to detect the total polyphenols and 5 kinds of caffeic acid derivatives(chicoric acid,caffeic acid,caftaric acid,chlorogenic acid,and 1,5-dicaffeoylquinic acid)in the roots,stems,leaves,and flowers,and the antioxidant activities of 3 varieties of Echinacea:E.purpurea L.,cultivar E.purpurea'Aloha',and E.purpurea'White Swan'.Results:E.purpurea L.had the highest contents of total polyphenols,5 caffeic acid derivatives and antioxidant activities,followed by E.purpurea'White Swan'and E.purpurea'Aloha',respectively.E.purpurea'White Swan'had the strongest ability to remove the DPPH,ABTS·^(+)and free radicals,and to chelate Fe^(2+);E.purpurea L.had the strongest ability to reduce FRAP.The correlation analyses revealed that the contents of total polyphenols and caffeic acid derivatives of E.purpurea L.and E.purpurea'White Swan'were correlated with their antioxidant activities.Conclusion:E.purpurea L.was the most appropriate material for the development of medicinal plants.E.purpurea'White Swan'could be used as a substitute for E.purpurea L.in terms of its antioxidant activity.

Electronic Aspects of the Synergistic Antioxidant Interaction of Various Pairs “Phenolic Food Acid and Glutathione” in Their Reactions with the Stable Radical Cation ABTS+·

In the present work, for the first time, the main details of the electronic mechanism of the synergistic antioxidant interaction between different pairs: phenolic food acid and glutathione and the stable radical cation ABTS+· were revealed on the basis of a rigorous analysis of the DFT calculated data. It was shown that among all the studied food acids, only caffeic acid exhibits a clear-cut significant synergistic effect with glutathione. It established the electronic and structural factors underlying the mechanism of the synergistic interaction of the mixture caffeic acid and glutathione in its reaction with ABTS+·. The main causes of this considered synergistic effect are, firstly, the presence of the 3-OH and 4-OH hydroxyl groups in the structure of caffeic acid, secondly, the greater stability of its anion which contains the deprotonated 4-OH hydroxyl group. All other phenolic food acids under study do not possess the given structural particularity and therefore do not show such synergistic effects with glutathione.