Epidemiological and experimental studies have found that the consumption of regular coffee has various health benefits. In the present study, we investigated the effect of decaffeinated coffee extracts on the inflammation process and found that aqueous extracts of green and roasted coffee have anti-inflammatory activity. The anti-inflammatory and antioxidant effects of aqueous extract of decaffeinated coffee (AD) and ethanol extract of decaffeinated coffee (ED) were evaluated in animal models using a DPPH radical scavenging test. In the formalin test, the extracts reduced licking activity in both late phases. The inhibitory values of oedema 3 h post-carrageenan indicated an anti-inflammatory effect. In the paw pressure test, the animals treated with extracts exhibited a reduction in the withdrawal threshold. These results provide evidence for the anti-inflammatory and antioxidant properties of decaffeinated coffee extracts that can be attributed to the potential of compounds present in coffee.
Coffee consumption is used for social engagement, leisure, enhancement of work performance and well-being 1. In recent years, there has been increasing interest in both coffee and coffee constituents for their potentially beneficial and adverse health effects 2. The coffee beverage is rich in biologically active substances such as nicotinic acid, trigonelline, quinolinic acid, tannic acid, chlorogenic acids, cafestol, pyrogallic acid and caffeine 3, 4. Of the many bioactive molecules of coffee, clinical studies have focused almost exclusively on caffeine. However, coffee contains several other biologically active substances whose relative concentrations vary depending on the type of coffee as well as the brewing process used. Polyphenols and melanoidins are present at relatively high concentrations and have been found to exhibit properties, such as antioxidant, anti-inflammatory, hepatoprotective and immunomodulator agent, that benefit human health 5, 6, 7, 8, 9. Coffee is a rich source of antioxidants belonging to the hydroxycinnamic acid family (caffeic, chlorogenic, coumaric, ferrulic and sinapic acids) 10, which can markedly change the total polyphenol intake.
The relationship between decaffeinated coffee consumption and health is sometimes used to determine whether the apparent effects of coffee are due to caffeine or other coffee ingredients. A study of the traits of decaffeinated coffee consumers in the US found that decaffeinated coffee consumption could be related to a history of illness in some people but to a healthy lifestyle in others 11. Another study found that concerns associated with regular coffee could be voided almost entirely with a transition from regular to decaffeinated coffee 12. Studies have reported that decaffeinated coffee consumption reduces the risk of type 2 diabetes 13, 14, 15, improve the insulin sensitivity 16 and improve the intestinal barrier integrity 17. Others studies utilizing decaffeinated coffee managed to reduce inflammatory markers 18, 19.
Despite the worldwide consumption of coffee and evidence of its anti-inflammatory properties 12, 20, little is known about the anti-inflammatory and nociceptive activity of its bioactive compounds. Thus, the present study investigated decaffeinated coffee extracts and utilized inflammation assays, nociception animal models and a chemical analysis of the bioactive compounds in decaffeinated coffee.
Analytical grade reference standards of caffeine, chlorogenic acid (CGA), caffeic acid, gallic acid, trigonelline hydrochloride, Folin-Ciocalteu’s reagent, quercetin, carrageenan, morphine, indomethacin, carboxymethyl cellulose (CMC) and 2,2-diphenyl-1-picrylhydrazyl radical (DPPH) were supplied by Sigma Chemical Co. (St. Louis, MO, USA). The high purity chromatography solvents were supplied by Merck (Darmstadt, Germany). Glacial acetic acid was obtained from J.T.Baker®. Water was purified using a Milli-Q system (Millipore, Bedford, MA, USA). Decaffeinated coffee was obtained from a local trader in Alfenas, Minas Gerais, Brazil.
2.2. Preparation of the Extracts and Reference DrugsFor preparation of the aqueous extract (AD) sample, powdered decaffeinated coffee (100 g) was extracted with 1,000 ml of 90°C water followed by filtration. For the ethanol extract (ED) sample, powered roasted decaffeinated coffee beans (100 g) were extracted with 1,000 ml 90% ethanol three times followed by filtration. The solvent was removed under reduced pressure, and the water of the extracts (ED and AD) was removed using a freeze-dryer (Liobras L101, São Paulo, Brazil) to produce a powder for subsequent use in the experiments.
The extracts ED and AD were administered (p.o.) in 30, 100 and 300 mg/kg doses after being suspended in a vehicle (aqueous solution of 0.5% CMC). The control group animals received the same experimental treatment as the test groups, except that the drug treatment was replaced with corresponding volumes of the dosing vehicle. Indomethacin (10 mg/kg, p.o.) and morphine sulphate (1 mg/kg, i.p.) in the vehicle solution were used as reference drugs.
2.3. Compositional Analysis of Extracts by HPLC and Determination of Total Phenolic and Flavonoid ContentThe liquid chromatography (HPLC) profile was obtained using Shimadzu LC-100 equipment with a diode array detector (DAD, monitoring 254 nm), an automatic injector and LC solution software. The HPLC apparatus was equipped with a C18 column (Shimadzu CLC-ODS; 4.6 x 250 mm; 5 µm). The mobile phase consisted of 0.5 mM aqueous acetic acid (A) and acetonitrile (B) with a flow rate of 0.7 ml/min. The following elution profile was used: 0-5 min 95:5 (A:B) (isocratic), 5-13 min 87:13 (linear), 13-27 min 87:13 (isocratic) and 27-30 95:5 (linear). An equilibration period of 10 min was included between runs 21.
The total content of phenolic phytochemicals was measured using the Folin–Ciocalteu method 22. The total phenolic content is expressed in mg of gallic acid equivalents (GAE) per g of extract. Samples were analysed in triplicate. The flavonoid content was measured using a previously developed colorimetric assay 23. The flavonoid content was expressed as mg of quercetin equivalent (QE) per g of extract. Samples were analysed in triplicate.
2.4. Analytical CurvesThe liquid chromatography (HPLC) profile was obtained using Shimadzu LC-100 equipment with a diode array detector (DAD, monitoring 254 nm), an automatic injector and LC solution software. The HPLC apparatus was equipped with a C18 column (Shimadzu CLC-ODS; 4.6 x 250 mm; 5 µm). The mobile phase consisted of 0.5 mM aqueous acetic acid (A) and acetonitrile (B) with a flow rate of 0.7 ml/min. The following elution profile was used: 0-5 min 95:5 (A:B) (isocratic), 5-13 min 87:13 (linear), 13-27 min 87:13 (isocratic) and 27-30 95:5 (linear). An equilibration period of 10 min was included between runs (24). The analytical curves consisted of six data points, and three replicate injections for each concentration level were performed 24.
2.5. DPPH Free Radical-scavenging ActivityThe property to scavenge DPPH free radicals was measured 25. The scavenging property was estimated based on the percentage of DPPH radicals scavenged using the following equation: scavenging effect (%) = [(control absorbance - sample absorbance)/(control absorbance)] x 100. The values are presented as the mean of triplicate analyses. The IC50 value is the effective concentration that could scavenge 50% of the DPPH radicals. Ascorbic acid and BHT standards were used as positive controls.
2.6. Pharmacological ProceduresAdult male Swiss mice (25-35 g) obtained from the Central Animal Facility of the Federal University of Alfenas were housed under controlled light (12:12 h light-dark cycle; lights on at 06:00 am) and temperature conditions (22 ± 1ºC) with access to water and food ad libitum. The animals were allowed to habituate to the housing facilities for at least one week before the experiments. At the end of the experiment, mice were euthanised using an overdose of halothane anaesthetic. All experiments were conducted in accordance with the Declaration of Helsinki on the welfare of experimental animals and with the approval of the Ethics Committee of the Federal University of Alfenas (290/2010).
Acute inflammation was induced by subplantar injection of 1 mg carrageenan (100 μl) in the right hind paw. The vehicle, AD, ED or indomethacin was orally administered 1 h before carrageenan injection, and the effects were evaluated at 1 h intervals from 1 to 4 h after the inflammatory stimulus. Oedema was assessed by measuring the volume of the right hind paw (Plethysmometer 7140, Ugo Basile, Rome, Italy) before and after carrageenan injection 26. The results are presented as change in paw volume (ml) relative to the basal values.
A formalin solution (5% in 0.9% saline; 20 µl/paw) was injected into the hind paw plantar surface (i. pl.), and the animals were individually placed in transparent observation chambers as previously described 27. Oral treatments (p.o.) with vehicle, indomethacin, AD or ED were administered 1 h prior to formalin injection. Morphine was administered (i.p.) 30 min before the test. The time spent licking the injected paw was recorded and expressed as the total licking time in the early (0–5 min) and late (20–30 min) phases after formalin injection.
For the paw pressure test, a hind paw flexion was induced with a handheld force transducer (Electronic anesthesiometer Insight model EFF-302, Brazil) adapted with a 0.5 mm2 polypropylene tip. The investigator was trained to apply the polypropylene tip perpendicularly to the central area of the hind paw with a gradual increase in pressure. The stimulation of the paw was repeated until the animal presented two similar measurements 28. Vehicle, AD or ED was orally administered 1 h before the i.pl. injection of carrageenan (20 µl/paw) or morphine (1 mg/kg, i.v.). The results are expressed as the delta (Δ) withdrawal threshold (in grams), which is calculated by subtracting the zero-time mean measurements from the mean measurements at the indicated times after carrageenan (hypernociceptive agent) injection.
2.7. Statistical AnalysisThe results were expressed as the means ± S.E.M. The data obtained were subjected to one-way analysis of variance (ANOVA) and compared using the Newman-Keuls test, with p < 0.05 for significance. A nonlinear regression was performed on the antioxidant activity data to obtain the IC50 values (concentrations that inhibit the presence of free radicals by 50.0%), and the curves were compared statistically using an F test.
Table 1 shows the results for the phenolic and flavonoid contents, compound quantification by HPLC and scavenging activity. As antioxidant activity is frequently coupled with phenolic content, the total phenolics expressed in gallic acid equivalents (GAE) were determined using the Folin-Ciocalteu C test. The values obtained and the flavonoid content were expressed as mg of quercetin equivalent (QE) per g of extract. The contents of trigonelline, CGA, caffeine and caffeic acid were analysed for HPLC, and each solute concentration was calculated using an analytical curve for the standards. The antioxidant activities of ED were greater than those of the reference antioxidant BHT and AA (3.2 and 3.8-fold, respectively), while AD exhibited less antioxidant activity than can be monitored spectrophotometrically at 517 nm.
The limits of detection (LOD) and quantitation (LOQ) were 0.94 and 2.84 µg/ml for CGA 0.63 and 1.9 µg/ml for caffeine, 0.89 and 2.7 µg/ml for caffeic acid, 2.2 and 6.8 µg/ml for trigonelline hydrochloride, 1.9 and 5.7 µg/ml for total flavonoids and 1.5 and 4.6 µg/ml for total phenolics, respectively. The criteria used to determine the LOD and LOQ were based on the determination of the slope (S) of the analytical curve and the standard deviation of responses (SD) in accordance with the formulas LOD = 3.3 SD/S and LOQ = 10 SD/S. The standard deviation of the response was determined from the standard error estimated by the regression line (Table 2).
The AD and ED extracts (Figure 1) significantly inhibited carrageenan-induced rat paw oedema (F4,34 = 5.95; p = 0.001 and F4,34 = 37.11; p = 0.0001, respectively). Maximal swelling of the carrageenan-injected paws was observed 3 h after carrageenan injection. The inhibitory values of oedema 3 h post-carrageenan injection were 61 and 53% for 100 and 300 mg/kg, respectively, for the AD extract (p < 0.01, Newman-Keuls). Indomethacin produced a percentage inhibition of 70%. The ED extract inhibited oedema by 42, 62 and 53% for 30, 100 and 300 mg/kg (p < 0.01, Newman-Keuls), respectively. This result is notably similar to that observed for the group treated with indomethacin, which inhibited oedema formation by 74%.
In the formalin test, the ED and AD extracts had significant antinociceptive activity compared to the control in both the early (F5,39 =7.29; p < 0.001 and F5,40 = 17.41; p < 0.001, respectively) and late phases (F5,41 = 11.09; p < 0.001 and F5,41 = 10.22; p < 0.001, respectively). The reference drug indomethacin suppressed only the second phase of the formalin test, whereas morphine inhibited both phases of the pain stimulus (p < 0.001; Figure 2).
In the paw pressure test, the animals treated with AD exhibited withdrawal threshold reductions of 48, 58 and 53% at 1 h and 48, 46 and 42% at 3 h (for 30, 100 and 300 mg/kg, respectively). For the animals treated with ED, the reductions were 45 and 58% in the first hour (for 100 and 300 mg/kg, respectively) and 43, 37 and 62% in the third hour (30, 100 and 300 mg/kg). The reductions for morphine were 98 and 82% at 1 and 3 hours, respectively (Figure 3).
Although clinical studies on coffee have focused almost exclusively on caffeine, there is increasing evidence that other coffee components are responsible for the effects associated with coffee. Coffee brews are a remarkable source of antioxidants, with contents comparable to those of the bioactive compounds in tea and wine 29, 30. In the present study, we evaluated the anti-inflammatory, antinociceptive and antioxidant properties of decaffeinated coffee extracts.
Studies suggest that the consumption of polyphenol-rich foods reduces the incidence of cancer, coronary heart disease and inflammation 31, 32, 33. Chlorogenic acid (CGA) is one of the most abundant polyphenol compounds in the human diet 34. Decaffeination produced a relative 17% average increase in the levels of total CGA in green coffee, caused mainly by the lixiviation of other compounds during decaffeination and differences in CGA content of regular (caffeinated) and decaffeinated roasted coffees may appear to be relatively small 35. That the antioxidant activities of the extracts in the present study could be monitored spectrophotometrically suggests that the scavenging activity of the extracts was likely due to the high concentration of phenolic compounds obtained through extraction.
The statistical analysis of the data revealed excellent linearity (r > 0.99) for the method from concentrations of 1.00 to 150 µg/ml. The contents of trigonelline, CGA, caffeine and caffeic acid in commercial coffee may be greatly influenced by the coffee species, variety, geographical origin and roasting conditions 36, 37. Decaffeination is performed prior to the roasting process. The most common and least costly caffeine extraction methods in the coffee industry utilise an organic solvent, such as dichloromethane or ethyl acetate, and the use of water/vapour prior to and after extraction 38. This decaffeination process changes the chemical composition of coffee, with the caffeine content typically reduced to 0.02-0.3% by the end of the process. Losses of key flavour components of coffee also tend to occur in the process of decaffeination, especially when solvents that lack specificity, such as water, are used. Among the compounds lost may be CGA and related compounds 35. In the compositional analysis of coffee extracts, we did not verify any caffeine and caffeic acid.
Prior oral treatment with the decaffeinated coffee extracts was effective in reducing the oedematogenic response evoked by carrageenan, and these effects were similar to those exhibited by the group of rats treated with indomethacin. The development of oedema induced by carrageenan is a biphasic event. The early phase (1-2 h) is mediated primarily by histamine, serotonin and bradykinin. The late phase is sustained by the release of prostaglandins and nitric oxide, with a peak at 3 h, and is produced by inducible isoforms of cyclooxygenase (COX-2) and nitric oxide synthase 39. The reduced response may be caused by inhibition of one or more intracellular signalling pathways that mediate the inflammatory response 40.
These results are in agreement with those of reported that aqueous extracts of C. arabica L. display considerable anti-inflammatory action by alleviating paw oedema, formalin-induced pain and reducing LPS-induced leukocyte migration in the peritonitis test 20. The mechanism of effect may be due to the presence of anti-inflammatory substances like flavonoids and antioxidants, which are present in Coffea. Kim et al. 41 reported that kahweol, a coffee-specific diterpene, significantly reduces inducible nitric oxide synthase, carrageenan-induced paw oedema and the level of prostaglandin E2 production in the inflamed paw. Furthermore, our findings corroborate those of other authors 34 that chlorogenic acids began to inhibit carrageenan-induced paw oedema by the second hour of the experimental procedure. Coffee contains antioxidants called polyphenols and flavonoids that scavenge free radicals and protect cells, tissues and organs from damage. Kim et al. 42 demonstrated that certain flavonoids modulate the activities of arachidonic acid-metabolising enzymes, such as phospholipase A2 cyclooxygenase, lipoxygenase and nitric oxide synthase. Accordingly, the inhibition of these enzymes by flavonoids represents an important cellular mechanism underlying anti-inflammatory activity.
In the formalin test, which consists of two distinct phases, the extracts exhibited a significant antinociceptive activity compared to the control during both phases. The first phase, or neurogenic phase (immediately after formalin injection), appears to be a direct effect of formalin on sensory C-fibres. The second phase, or inflammatory phase (starting approximately 20 min after injection), is associated with the development of an inflammatory response and the release of nociceptive mediators 43. It was previously reported that substance P and bradykinin participate in the onset of the early phase responses and that histamine, serotonin, prostaglandin and bradykinin are involved in the late phase responses 44. Centrally acting drugs, such as opioids, inhibit both phases equally, while peripherally acting drugs, such as non-steroidal anti-inflammatory drugs and corticosteroids, inhibit only the late phase 43. The finding of the present study that decaffeinated coffee extracts produce analgesic effects in the early and late phases of the formalin test indicates that the extracts act centrally and peripherally to reduce inflammatory pain.
These results for the formalin test are in agreement with those obtained by Marrassini et al. 45 and Yonathan et al. 46 who similarly concluded that chlorogenic acids contribute to anti-inflammatory and antinociceptive activities. However, the authors 20 reported that aqueous extracts of Coffea produced antinociception only against the inflammatory phase of formalin. Some authors 34 demonstrated that chlorogenic acids inhibit the number of flinches in the late phase of the formalin-induced pain test. Such activities may be derived from the inhibitory action of CGA in the peripheral synthesis/release of inflammatory mediators involved in these responses. Authors 35 proposed that the pharmacological action of CGA is more evident in decaffeinated coffee because of the absence of caffeine.
Because inflammation is correlated with and influenced by various cytokines and chemokines, a reduction in these markers should indicate a decrease in overall inflammation. Coffee is a potentially beneficial substance because it contains compounds such as CGA, caffeine, cafestol, kahweol and trigonelline, which all have antioxidant or anti-inflammatory potential 47. The present findings indicate analgesic effects of the ED and AD extracts at all three hours of the paw pressure test. In general, acute inflammatory pain is characterised by hyper nociception (evaluated here by the Von Frey method) due to the sensitisation of primary sensory nociceptive neurons, also referred to as hyperalgesia or allodynia 48. After the initial tissue injury, several specific primary mediators are synthesised and/or released. Eicosanoids and sympathetic amines are the most important primary mediators ultimately responsible for mechanical hypernociception induced by several stimuli in mice 49.
The decaffeinated coffee extracts had higher concentrations of chlorogenic acid and trigonelline, total phenolics and total flavonoids. AD and ED reduced oedema in treated animals, inhibited both phases of the painful stimulus in the formalin test and produced analgesic effects according to the paw pressure test. As evidenced by previous reports, the mechanism that produces these effects may involve anti-inflammatory and analgesic substances, such as flavonoids and antioxidants, present in Coffea. Thus, the extracts exhibited analgesic activity even in the absence caffeine and other compounds such as polyphenols may be responsible for such activity. More broadly, the results obtained in the animal experiments demonstrated that decaffeinated coffee had beneficial health effects.
AA: Ascorbic acid
AD: Aqueous extract decaffeinated coffee
ANOVA: Analysis of variance
BHT: Butylated hydroxytoluene
CGA: 5-caffeoylquinic acid; chlorogenic acid
CMC: Carboxymethyl cellulose
COX-2: Cyclooxygenase 2
DPPH: 2,2-diphenyl-1-picrylhydrazyl radical
DPPH: 1-diphenyl-2-picrylhydrazyl
IC50: 50% inhibitory concentration
ED: Ethanol extract decaffeinated coffee
FC-test: Folin-Ciocalteu test
GAE: Gallic acid equivalent
HPLC: High performance liquid chromatography
i.p.: Intraperitoneal
i.pl.: Intraplantar
p.o.: Per oral
QE: Quercetin equivalent
UV/Vis: Ultraviolet/ visible.
This work was supported by FAPEMIG, CNPq, CAPES, EMBRAPA CAFÉ and FINEP.
The authors have not competing interests.
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[37] | Ortiz, A.L.G., Berti, F., Solano Sánchez, W., Navarini, L., Colomban, S., Crisafulli, P., Forzato, C. “Distribution of p-coumaroylquinic acids in commercial Coffea spp. of different geographical origin and in other wild coffee species”, Food Chemistry, 286, 459-466, 2019. | ||
In article | View Article PubMed | ||
[38] | Pietsch, A. “Decaffeination—Process and Quality”, The Craft and Science of Coffee, 225-243, 2017. | ||
In article | View Article | ||
[39] | Moreira, M.E.C., Dos Santos, M.H., Zolini, G.P.P., Wouters, A.T.B., Carvalho, J.C.T., Schneedorf, J.M. “Anti-Inflammatory and Cicatrizing Activities of a Carbohydrate Fraction Isolated from Sugary Kefir”, Journal of Medicinal Food, 11(2), 356-361, 2008. | ||
In article | View Article PubMed | ||
[40] | Thomazzi, S.M., Silva, C.B., Silveira, D.C.R., Vasconcellos, C.L.C., Lira, A.F., Cambui, E.V.F., Antoniolli, A.R. “Antinociceptive and anti-inflammatory activities of Bowdichia virgilioides (sucupira)”, Journal of Ethnopharmacology, 127(2), 451-456, 2009. | ||
In article | View Article PubMed | ||
[41] | Kim, J.Y., Kim, D.H., Jeong, H.G. “Inhibitory effect of the coffee diterpene kahweol on carrageenan-induced inflammation in rats”, BioFactors, 26, 17-28, 2006. | ||
In article | View Article PubMed | ||
[42] | Kim, H.P., Son, K.H., Chang, H.W., Kang, S.S. “Anti-inflammatory Plant Flavonoids and Cellular Action Mechanisms”, Journal of Pharmacological Sciences, 96(3), 229-245, 2004. | ||
In article | View Article PubMed | ||
[43] | Du, J., Qian, Z.M., Wang, C., Yu, Y., Ke, Y., Zhu, L. “Ligustilide attenuates pain behavior induced by acetic acid or formalin”, Journal of Ethnopharmacology, 112(1), 211-214, 2007. | ||
In article | View Article PubMed | ||
[44] | Abbott, F.V., Franklin, K.B.J., Westbrook, R.F. “The formalin test: scoring properties of the first and second phases of the pain response in rats”, Pain, 60(1), 91-102, 1995. | ||
In article | View Article | ||
[45] | Marrassini, C., Acevedo, C., Miño, J., Ferraro, G., Gorzalczany, S. “Evaluation of antinociceptive, antinflammatory activities and phytochemical analysis of aerial parts of Urtica urens L.”, Phytotherapy Research, 24(12), 1807-1812, 2010. | ||
In article | View Article PubMed | ||
[46] | Yonathan, M., Asres, K., Assefa, A., Bucar, F. “In vivo anti-inflammatory and anti-nociceptive activities of Cheilanthes farinosa”, Journal of Ethnopharmacology, 108(3), 462-470, 2006. | ||
In article | View Article PubMed | ||
[47] | Jeszka-Skowron, M., Zgoła-Grześkowiak, A., Grześkowiak, T. “Analytical methods applied for the characterization and the determination of bioactive compounds in coffee”, European Food Research and Technology, 240(1), 19-31, 2014. | ||
In article | View Article | ||
[48] | Conte, F.P., Ferraris, F.K., Costa, T.E.M.M., Pacheco, P., Seito, L.N., Verri, W.A., Henriques, M.G. “Effect of gedunin on acute articular inflammation and hypernociception in mice”, Molecules, 20(2), 2636-2657, 2015. | ||
In article | View Article PubMed | ||
[49] | Verri, W.A., Cunha, T.M., Parada, C.A., Poole, S., Cunha, F.Q., Ferreira, S.H. “Hypernociceptive role of cytokines and chemokines: Targets for analgesic drug development?”, Pharmacology and Therapeutics, 112(1), 116-138, 2006. | ||
In article | View Article PubMed | ||
Published with license by Science and Education Publishing, Copyright © 2020 Maria Eliza de Castro Moreira, Rosemary Gualberto Fonseca Alvarenga Pereira, Daniele Ferreira Dias, Claudinei Alves da Silva, Thiago Corrêa de Souza, Éderson D’Martin Costa, Bárbara Pereira da Silva, Stella Maris da Silveira Duarte, Alexandre Giusti-Paiva and Marcelo Henrique dos Santos
This work is licensed under a Creative Commons Attribution 4.0 International License. To view a copy of this license, visit
https://creativecommons.org/licenses/by/4.0/
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In article | View Article | ||
[37] | Ortiz, A.L.G., Berti, F., Solano Sánchez, W., Navarini, L., Colomban, S., Crisafulli, P., Forzato, C. “Distribution of p-coumaroylquinic acids in commercial Coffea spp. of different geographical origin and in other wild coffee species”, Food Chemistry, 286, 459-466, 2019. | ||
In article | View Article PubMed | ||
[38] | Pietsch, A. “Decaffeination—Process and Quality”, The Craft and Science of Coffee, 225-243, 2017. | ||
In article | View Article | ||
[39] | Moreira, M.E.C., Dos Santos, M.H., Zolini, G.P.P., Wouters, A.T.B., Carvalho, J.C.T., Schneedorf, J.M. “Anti-Inflammatory and Cicatrizing Activities of a Carbohydrate Fraction Isolated from Sugary Kefir”, Journal of Medicinal Food, 11(2), 356-361, 2008. | ||
In article | View Article PubMed | ||
[40] | Thomazzi, S.M., Silva, C.B., Silveira, D.C.R., Vasconcellos, C.L.C., Lira, A.F., Cambui, E.V.F., Antoniolli, A.R. “Antinociceptive and anti-inflammatory activities of Bowdichia virgilioides (sucupira)”, Journal of Ethnopharmacology, 127(2), 451-456, 2009. | ||
In article | View Article PubMed | ||
[41] | Kim, J.Y., Kim, D.H., Jeong, H.G. “Inhibitory effect of the coffee diterpene kahweol on carrageenan-induced inflammation in rats”, BioFactors, 26, 17-28, 2006. | ||
In article | View Article PubMed | ||
[42] | Kim, H.P., Son, K.H., Chang, H.W., Kang, S.S. “Anti-inflammatory Plant Flavonoids and Cellular Action Mechanisms”, Journal of Pharmacological Sciences, 96(3), 229-245, 2004. | ||
In article | View Article PubMed | ||
[43] | Du, J., Qian, Z.M., Wang, C., Yu, Y., Ke, Y., Zhu, L. “Ligustilide attenuates pain behavior induced by acetic acid or formalin”, Journal of Ethnopharmacology, 112(1), 211-214, 2007. | ||
In article | View Article PubMed | ||
[44] | Abbott, F.V., Franklin, K.B.J., Westbrook, R.F. “The formalin test: scoring properties of the first and second phases of the pain response in rats”, Pain, 60(1), 91-102, 1995. | ||
In article | View Article | ||
[45] | Marrassini, C., Acevedo, C., Miño, J., Ferraro, G., Gorzalczany, S. “Evaluation of antinociceptive, antinflammatory activities and phytochemical analysis of aerial parts of Urtica urens L.”, Phytotherapy Research, 24(12), 1807-1812, 2010. | ||
In article | View Article PubMed | ||
[46] | Yonathan, M., Asres, K., Assefa, A., Bucar, F. “In vivo anti-inflammatory and anti-nociceptive activities of Cheilanthes farinosa”, Journal of Ethnopharmacology, 108(3), 462-470, 2006. | ||
In article | View Article PubMed | ||
[47] | Jeszka-Skowron, M., Zgoła-Grześkowiak, A., Grześkowiak, T. “Analytical methods applied for the characterization and the determination of bioactive compounds in coffee”, European Food Research and Technology, 240(1), 19-31, 2014. | ||
In article | View Article | ||
[48] | Conte, F.P., Ferraris, F.K., Costa, T.E.M.M., Pacheco, P., Seito, L.N., Verri, W.A., Henriques, M.G. “Effect of gedunin on acute articular inflammation and hypernociception in mice”, Molecules, 20(2), 2636-2657, 2015. | ||
In article | View Article PubMed | ||
[49] | Verri, W.A., Cunha, T.M., Parada, C.A., Poole, S., Cunha, F.Q., Ferreira, S.H. “Hypernociceptive role of cytokines and chemokines: Targets for analgesic drug development?”, Pharmacology and Therapeutics, 112(1), 116-138, 2006. | ||
In article | View Article PubMed | ||