Influence Of Red Pepper Spice And Turmeric On Inflammation .
Plant Foods Hum Nutr (2012) 67:415–421DOI 10.1007/s11130-012-0325-xORIGINAL PAPERInfluence of Red Pepper Spice and Turmericon Inflammation and Oxidative Stress Biomarkersin Overweight Females: A Metabolomics ApproachDavid C. Nieman & Lynn Cialdella-Kam &Amy M. Knab & R. Andrew ShanelyPublished online: 14 November 2012# Springer Science Business Media New York 2012Abstract Red pepper spice (RP) and turmeric (TM) are usedas flavorings in foods and for medicinal purposes. Utilizing arandomized, doubled-blinded, placebo-controlled, crossoverdesign (2-week washout), 4-week supplementation with RP(1 g/d) or TM (2.8 g/d) was tested for influences on inflammation and oxidative stress in 62 overweight/obese (bodymass index 27 kg/m2) females (40–75 years) with systemicinflammation (C-reactive protein, CRP 2 mg/l). Overnight,fasted blood samples were collected pre- and postsupplementation, and analyzed for oxidative stress (F2-isoprostanes, oxidized low density lipoprotein), inflammation(CRP and seven inflammatory cytokines), and metabolic profiles using gas chromatography–mass spectrometry with multivariate partial least square discriminant analysis (PLS-DA).Pre- to post-supplementation measures of inflammation andoxidative stress for both RP and TM did not differ whencompared to placebo (all interaction effects, P 0.05), andglobal metabolic difference scores calculated through PLSDA were non-significant (both spices, Q2Y 0.40). These dataindicate that 4-week supplementation with RP or TM at culinary levels does not alter oxidative stress or inflammation inoverweight/obese females with systemic inflammation, orcause a significant shift in the global metabolic profile.D. C. Nieman : L. Cialdella-Kam : A. M. Knab : R. A. ShanelyHuman Performance Lab, North Carolina Research Campus,Appalachian State University,Kannapolis, NC 28081, USAD. C. Nieman (*)North Carolina Research Campus,600 Laureate Way,Kannapolis, NC 28081, USAe-mail: niemandc@appstate.eduKeywords Capsaicin . Curcumin . F2-isoprostanes .Cytokines . Metabolites . Augmentation indexAbbreviationsAIx@75 Augmentation index normalized for a heart rateof 75 beats/minANOVA Analysis of varianceBMIBody mass indexCRPC-reactive proteinCVCoefficient of varianceGC-MS Gas chromatography mass spectrometryILInterleukinIFNγInterferon gammaLDLLow-density lipoproteinPCAPrincipal component analysisPLS-DA Partial least square discriminant analysisRPRed pepperTMTurmericTNFαTumor necrosis factor alphaTRPV1Transient potential receptor vanilloid 1IntroductionSpices and aromatic herbs are used as flavor enhancers,colorants, preservatives, and as potential medicinal agentsin the prevention and treatment of disease [1, 2]. Cell cultureand animal experiments support multiple nutraceutical rolesfor spices including antioxidant, anti-inflammatory, antipathogenic, hypolipidemic, anticancerigenic, thermogenic,vascular function, and antidiabetic influences [3]. The underlying mechanisms of spice-related activities are diverseand may involve the regulation of transcription factors,cytokines, protein kinases and other enzymes, adhesionmolecules, redox status, and growth factors [4]. Two highly
416investigated spices include red pepper spice (RP) and turmeric (TM), but human studies with randomized, doubleblinded, placebo controlled research designs are limited[5–9].The hotness produced by RP is caused by high concentrations of capsaicinoids (0.5–1 %) composed mainly ofcapsaicin and dihydrocapsaicin [10, 11]. Capsaicin has beenwidely studied for its pain-reducing and anti-inflammatoryeffects, influence on weight management, and cardiovascular benefits [10]. The transient potential receptor vanilloid 1(TRPV1), a non-selective cation channel chemically activatedby capsaicin, may be involved in some aspects of inflammation control [10]. Intake of capsaicinoids ranges widelythroughout the world, approaching 200 mg/person per dayin some high-consuming countries, but only 1.5 mg/personper day in the U.S. and Europe [11]. The metabolism ofcapsaicinoids occurs primarily in the liver and metabolite formation is catalyzed by a variety of hepatic enzymes[12].Turmeric is a plant with creeping roots that are boiled,dried, and ground into a deep orange-yellow powder commonly used as a spice in curries and other South Asian andMiddle Eastern cuisine [13]. TM contains over 300 differentcomponents including the active ingredient curcumin (3–5 %) [14]. In vitro and animal research shows that curcuminis a highly pleiotropic molecule capable of interacting withnumerous molecular targets involved in inflammation [3, 4,13, 14]. Curcumin bioavailability is relatively low, however,is rapidly cleared and extensively conjugated in the gastrointestinal tract and liver [13, 15]. Serum curcumin concentrations peak 1–3 h after ingestion of large doses [15]. TM isexceptionally high in total antioxidant content, but theamounts used in the diet may be too small to have a meaningful influence on total antioxidant capacity [16].Spices have been advanced as anti-inflammatory andantioxidant agents in the diet to help counteract the effectsof systemic inflammation and the metabolic syndromecaused by obesity [17], but this hypothesis has not yet beentested in humans using acceptable study design procedures.The study hypothesis was that supplementation with RP orTM would reduce inflammation and oxidative stress, andimprove vascular function in free-living, overweightfemales with underlying chronic inflammation (CRP 2 mg/l).A crossover design under double-blinded, placebo controlled conditions was utilized with culinary levels ofRP (1 g/d) and TM (2.8 g/d) that would be acceptableto U.S. adults. Metabolomics is the measurement ofsmall molecules or metabolites present in biologic samples such as biofluids, tissues, and cellular extracts toelucidate the effect of a particular stimulus on metabolicpathways [18]. The use of metabolomics in nutritionalsciences is gaining momentum, and global metabolomicsprofiling was utilized to help capture potential subtlePlant Foods Hum Nutr (2012) 67:415–421perturbations in metabolites associated with RP andTM supplementation.Materials and MethodsSubjectsOverweight and obese women (n098) (body mass index(BMI) 27 kg/m2 and higher) between the ages of 40 and75 years were recruited via mass advertising and screenedfor elevated C-reactive protein (CRP) ( 2 mg/l). Sixty-foursubjects were selected following screening, and all but threecompleted all aspects of the study. Subjects were apparentlyhealthy with no overt chronic disease (specifically, coronaryheart disease, stroke, cancer (other than skin), diabetesmellitus, rheumatoid arthritis), and not on dietary supplements or medications known to influence inflammation (inparticular, non-steroidal anti-inflammatory drugs). Subjectsagreed to maintain normal dietary and physical activitypatterns during the 10-week study (i.e., two 4-weeksupplementation periods with a 2-week washout period),and make no formal attempts to lose body weight.Written informed consent was obtained from each subject, and the experimental procedures were approved bythe institutional review board for human studies at Appalachian State University.Research DesignSubjects were randomized to RP or TM groups, and underdouble-blinded procedures ingested RP, TM, or placebo(PL) supplements daily for four weeks, with randomizedcrossover to the opposite condition (spice or PL) followinga 2-week washout period. For each 4-week supplementationperiod, body composition, blood pressure, augmentationindex, and blood samples were taken from all subjects preand post-supplementation after an overnight fast between7:00–9:00 am, and always on the same day of the week. Dietrecords, and questionnaire responses to assess potentialadverse effects and adherence to the supplementation regimen were administered pre-study, and after each 4-weeksupplementation period. The food records were analyzedusing a computerized dietary assessment program (FoodProcessor, ESHA Research, Salem, Oregon). The symptomlogs included questions on digestive health (constipation,heartburn, bloating, diarrhea, and nausea), hunger levels(morning, afternoon, and evening), energy levels (morning,afternoon, and evening), sickness (fever, cough, sore throat,stuffy nose, runny nose, and headache), pain (joint, muscle,and back), allergies, stress level, focus/concentration, andoverall well-being. Subjects indicated responses using a 12point Likert scale, with 1 relating to “none at all”, 6
Plant Foods Hum Nutr (2012) 67:415–421“moderate”, and 12 “very high”. Subject compliance wasmonitored by regular email correspondence, and the returnof supplement organizer trays after each supplementationperiod.Red Pepper and Turmeric SupplementsSubjects ingested 2.8 g/d (for four weeks) TM, 1 g/d RP, orPL, with treatments randomized, counterbalanced, anddouble-blinded. The spices and PL (refined, white rice flour)were contained in identical looking blue gelatin capsules(two per day for RP or PL, five per day for TM or PL), andprepared by the McCormick Science Institute (Sparks, MD).The capsules were arranged by day of the week in supplement organizer trays with locking lids. Half of the capsuleswere consumed in the morning, and the other half in theevening, for each day of each 4-week periods of the study.Body CompositionHeight was measured using a stadiometer, and body massand body composition were measured using a Tanita bioelectrical impedance (BIA) scale (Tanita Corporation of America,Inc., Arlington Heights, IL). Subjects were measured whilestanding erect, wearing light clothing, with bare feet on theanalyzer foot pads.Blood Pressure, Augmentation Index, Serum DiagnosticChemistriesBlood pressure was measured by technicians following a15-min seated rest. The SphygmoCor Central Blood Pressure and Pulse Wave Velocity Assessment System (AtCorMedical, Atasca, IL) was used to measure the augmentationindex. The SphygmoCor system derives a calibrated bloodpressure waveform at the ascending aorta from a peripheralpressure waveform, recorded non-invasively at the radialartery using a high-fidelity pressure transducer. Augmentationindex, a measure of systemic arterial stiffness, was calculatedas the ratio of amplitude of the pressure wave above itssystolic shoulder to the total pulse pressure, and thennormalized to a resting heart rate of 75 beats per minute(AIx@75). Blood samples were drawn from an antecubital vein with subjects in the seated position for atleast 15 min after an overnight fast. A serum comprehensive diagnostic chemistry panel was performed byour clinical hematology laboratory.Plasma Cytokine Measurements and C-Reactive ProteinTotal plasma concentrations of seven inflammatory cytokines (interleukin-6 or IL-6, tumor necrosis factor alpha orTNFα, interferon gamma or IFNγ, IL-1β, IL-8, IL-10, IL-41712p70) were determined using an electrochemiluminescence based solid-phase sandwich immunoassay (MesoScale Discovery, Gaithersburg, MD). All samples and provided standards were analyzed in duplicate, and the intraassay CV ranged from 1.7 to 7.5 %, and the inter-assay CV2.4 to 9.6 %, for all cytokines measured. The minimumdetectable concentration of IL-6 was 0.27 pg.ml 1, TNFα0.50 pg.ml 1, IFNγ 0.53 pg.ml 1, IL-1β 0.36 pg.ml 1, IL8 0.09 pg . ml 1 , IL-10 0.21 pg . ml 1 , and IL-12p701.4 pg.ml 1. Pre- and post-supplementation samples for thecytokines were analyzed on the same assay plate todecrease inter-kit assay variability. CRP was measured usingan LX-20 clinical analyzer (Beckman Coulter Electronics,Brea, CA).Oxidative StressPlasma F2-isoprostanes were determined using gas chromatography mass spectrometry (GC-MS). Free F2-isoprostaneswere extracted with deuterated [2H4] prostaglandin F2αadded as an “internal” standard, and then added to a C18Sep Pak column, followed by silica solid phase extractions.F2-isoprostanes were converted to pentafluorobenzyl esters,subjected to thin layer chromatography, and converted totrimethylsilyl ether derivatives. Samples were analyzed by anegative ion chemical ionization GC-MS using an Agilent6890 N gas chromatography interfaced to an Agilent 5975Binert MSD mass spectrometer (Agilent Technologies, Inc.,Santa Clara, CA). Oxidized LDL was measured using standard protocols for a competitive ELISA kit (CV09.7 %)(Mercodia Oxidized LDL Competitive Enzyme-Linked Immunosorbent Assay, Mercodia Inc., Sweden).Metabolomics ProceduresSamples were prepared for metabolomics profiling by spiking 300 μl of serum with 1.05 ml aliquot of two internalstandards (0.2 mg/ml of p-chlorophenylalanine and heptadeconic acid in a 3:1 methanol/chloroform solution), derivitized with methoxyamine, and analyzed on an Agilent7890A GC system coupled to an Agilent 5975C EI/CI MassSelective Detector (Foster City, CA). The raw data filesgenerated by GC-MS were converted to NetCDF formatand processed using ChromaTOF software (v4.24, LecoCo., CA, USA). Metabolite annotation was performed bycomparing unknown signal patterns from the study samplesto those of reference standards from an internal librarycontaining approximately 600 human metabolites (SigmaAldrich, St. Louis, MO) and the NIST and Leco/Fiehnmetabolomics libraries. The average CV for heptadecanoicacid was less than 5 %. The mean CV of the internalstandard across the entire sample analysis (158 injections)was 15.3 %.
418Statistical ProceduresData are reported as mean SE. Data for each supplementationgroup (RP and TM) were analyzed using a 2 (condition) x 2(time) repeated measures ANOVA between subjects model, withpre- to post-supplementation changes calculated and comparedusing a Student’s t-test. Diet record and symptom log data wereanalyzed in a similar fashion using a 2 2 repeated measuresANOVA. For the metabolomics data, all initial mathematicalcalculations including peak signal compensations, normalizationto internal standards, and univariate analyses (nonparametricMann–Whitney-Wilcoxon test) were performed using customscripts in MATLAB R2010a (MathWorks, Inc., Natick, MA).Multivariate statistical analyses including principal componentanalysis (PCA) and partial least square - discriminant analysis(PLS-DA) were performed using SIMCA-P 12.0.1 (Umetrics,Umeå, Sweden). PLS-DA was used to visualize the differencebetween global metabolic profiles for the three groups, with Q2Yused for the predictive accuracy of the model (values of 0.4 orgreater indicate a reliable model).ResultsThirty-one (age 57.7 1.6 y) and 30 (age 55.7 1.4 y) femalesubjects completed all requirements for the RP and TMstudies, respectively. Three subjects were unable to complywith the supplementation regimen and dropped out of thestudy. Figure 1 depicts a scatterplot relationship betweenBMI and pre-study CRP for all 61 subjects (r00.25, P00.048). BMI was 34.7 0.9 and 34.5 0.8 kg/m2, and CRP7.64 0.82 and 8.05 1.33 mg/l, for the RP and TM groups,respectively.Supplementation with 1 g/d RP or 2.8 g/d TM over a 4week period had no influence relative to PL on body weight,percent body fat, systolic blood pressure, augmentation index,serum glucose (Table 1), inflammation and oxidative stressbiomarkers (Table 2), and all components of the diagnosticchemistry panel (data not shown). Data from the symptomlogs indicated no difference pre- to post-supplementationFig. 1 Scatterplot relationship between BMI and pre-study CRP for all61 subjects (r00.25, P00.048)Plant Foods Hum Nutr (2012) 67:415–421relative to PL except for significant increases in heartburnand bloating symptoms in the RP group (data not shown).Three day food records revealed no pre- to post-4 week differences for energy, macronutrient, and micronutrient intake forRP and TM relative to PL (data not shown).Score plots from the PLS-DA models visualized theglobal metabolic differences between RP and PL conditions(Fig. 2a) and TM and PL conditions (Fig. 2b) using ratios(pre- to post-supplementation). The Q2Y scores of the twoPLS-DA models were below 0.4 (0.245 for RP, and 0.212for TM), indicating that the global metabolic profile differences between 4-week supplementation periods with RP andTM compared to PL were non-significant.Table 3 summarizes significant fold change comparisonsbetween spice and PL conditions for individual metabolites.Fold changes were relatively small and disparate, with noconsistent change pattern established for metabolite clustersor pathways. The small fold change (1.3) for the four metabolites related to RP supplementation had no apparent connectionwith each other. An equally dissimilar list of 10 metabolites forTM (fold change range of 1.6 to 1.4) included a decrease foran essential fatty acid (linolenic acid) and a decrease for amedium chain fatty acid (nonanoic acid), an increase in anessential amino acid (lysine), a decrease in a carboxylic ester(1,2-benzenedicarboxylic acid, diisooctyle ester), and changesin three amine-related metabolites (n-butylamine, trimethylamine, and 4-hydroxy-proline).DiscussionFour weeks supplementation with 1 g/d RP ( 10 mg capsaicin/d)or 2.8 g/d TM ( 112 mg curcumin) had no influence on inflammation, oxidative stress biomarkers, or arterial stiffness relative toplacebo in overweight/obese females with underlying systemicinflammation. This interpretation was strengthened utilizing astrong research design and the tool of metabolomics thatshowed no trial differences in global metabolic scores.Spices possess many unique functional food propertiesthat make them attractive for use as supplements or inclusion in healthful food products. TM and RP have highantioxidant content [16], and cell culture data support stronganti-inflammatory activity through a variety of pathways[1, 3]. Few randomized, placebo control studies in nondiseased humans, however, have been conducted with individual spices. Culinary-level doses of RP and TM werechosen, with supplements used for a relatively short timeperiod by systemically inflamed but otherwise healthyfemales, and measured no apparent benefits on body weight,serum glucose, arterial stiffness, inflammation, and oxidative. Ahuja et al. [5, 6] reported no alterations in arterialstiffness, disease risk factors, and total antioxidant status in36 subjects consuming 30 g/d of a chilli blend supplement
Plant Foods Hum Nutr (2012) 67:415–421Table 1 Influence of RP(n031) and TM (n030)supplementation on bodyweight, systolic bloodpressure, augmentationindex, and serum glucoseVariable419Red pepperWeight (kg)Pre-study92.0 2.7Post-4 weeks92.3 2.7Body fat (%)Pre-study46.9 0.5Post-4 weeks46.2 0.7Systolic BP (mmHg)Pre-study133 3.5Post-4 weeks132 3.2ALX75Pre-study29.1 1.6Post-4 weeks27.5 2.0Glucose (mmol/l)Pre-study5.45 0.17Post-4 weeks5.54 0.18(55 % cayenne chilli) using a 4-week, randomized, crossover design. No differences in weight change betweengroups of overweight men and women consuming 6 mg/dcapsinoids or placebo for 12 weeks was measured bySnitker et al. [7], but a small but significant capsinoidadvantage in abdominal fat loss was reported. Fasting plasma glucose and lipids were unaltered in 11 healthy, youngTable 2 Influence of RP(n031) and TM (n030)supplementation oninflammation and oxidativestress measuresVariableRed pepperSerum CRP (mg/l)Pre-study7.64 0.82Post-4 weeks8.13 1.00Plasma IL-6 (pg/ml)Pre-study2.96 0.85Post-4 weeks4.14 1.06Plasma IL-8 (pg/ml)Pre-study4.81 0.40PlaceboTurmericPlaceboInteraction P-values92.1 2.792.5 2.791.5 2.091.6 2.091.2 2.191.8 2.00.8310.25547.3 0.646.5 0.647.4 0.646.9 1.347.1 0.646.7 0.60.8540.890133 3.5133 3.3123 2.4126 2.6124 2.2126 2.10.6160.71629.0 2.030.9 1.733.2 1.433.6 1.332.8 1.731.2 1.10.2750.2815.56 0.175.76 0.215.82 0.380.2065.54 0.185.91 0.395.82 0.320.615adult subjects supplemented with 2.8 g/d TM for four weeks[8].The lack of support in human studies for alterations indisease risk factors, inflammation, and oxidative stress whenconsuming RP or TM may be related to several factorsincluding dosing paradigms, and absorption, distribution, metab
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