Biomedical Effects of Oregano: Comparison
View Latest Version
Please note this is a comparison between Version 10 by Yamixa Delgado and Version 9 by Yamixa Delgado.

The term oregano refers to a group of several plant genera, including Thymbra, Thymus, Coridothymus, Satureja, and Origanum, containing a high amount of the phytochemicals carvacrol and thymol in their essential oils.

  • phytonutrients
  • phytochemicals
  • oregano
  • Lipinski’s rule of 5
  • Veber’s rules
  • Ghose filter
  • Phytonutrients
  • Phytochemicals
  • Oregano
  • Anticancer
  • Antioxidant
  • Antimicrobial
  • Anti-inflammatory
  • Immunomodulatory

1. Botanical Description

The genus Origanum consists of 43 species. Origanum vulgare (O. vulgare), commonly named “oregano”, is the name of the aromatic plant used as a condiment herb in Mediterranean cuisine [1][2][3]. O. vulgare size is usually 20–80 cm; its 1–4 cm leaves are dark green, with 2-mm bell-shaped calyx purple flowers arranged in erect spikes [4][5][6]. Like other aromatic plants, the oregano plant produces essential oils as secondary metabolites in response to various infectious agents, UV light, and even oxidative stress. Oregano essential oils (OEOs) are usually extracted from the plant leaves and flowering tops. OEOs are famous for their medicinal value and are traditionally used in Turkey to cure diseases such as cough, chronic cold, wounds, gastrointestinal disorders, and skin problems in humans and domestic animals [7].

2. Phytochemicals

The main bioactive compounds present in the OEOs are the aromatic oxygenated monoterpene thymol (5-methyl-2-(1-methylethyl) phenol) and its constitutive isomer carvacrol (5-isopropyl-2-methylphenol, 2-p-cymenol). The ratio of thymol/carvacrol varies according to the oregano plant’s geographical location [8]. Both compounds are lipophilic, volatile, highly soluble in ethanol, and possess low densities [7][9][10][11]. Other bioactive oregano phytochemicals include o-cymene (2-Isopropyltoluene), apigenin (4′,5,7-trihydroxyflavone), and luteolin (7,3′,4′,5-tetrahydroxyflavone) [12][13]. Due to their low general toxicities, the two main chemicals of O. vulgare, thymol and carvacrol, have been approved as food additives by the Food and Drug Administration (FDA) [14].

3. Biomedical Effects

3.1. Anticancer

The antiproliferative/anticancer properties of oregano have been documented in vitro and animal models for cancers. A recent study by Spyridopoulou et al. showed that OEO exerts dose-dependent cytotoxicity against breast cancer (MCF-7), colon cancer cells (HT-29), melanoma (A375), and hepatocellular carcinoma (HepG2) cells, with respective IC50 values of 0.35, 0.35, 8.90, and 10.0 mg/mL. The authors also showed that the treatment of HT-29 cells with 50 mg/mL of OEO correlated with an attenuated migration and an induced apoptosis-related morphological change in HT-29 cells. Furthermore, the oral administration of OEO for 13 days (0.370 g/kg b.w/day) proved to inhibit the growth of CT26 colon tumors in vivo in BALB/c mice [15]. Another study by Coccimiglio reports that an ethanolic leaf extract of O. vulgare promotes the death of A549 human lung carcinoma in a dose-dependent manner (IC50 = 14.0 μg/mL) [16]. The antiproliferative properties of oregano are believed to be mediated by thymol and carvacrol, which possess antioxidant characteristics while being non-mutagenic to cells [16][17][18]. The anticancer properties of thymol were evidenced in in vitro and in vivo models for colorectal cancers [19][20]. One astonishing property of carvacrol is its potential to specifically target cancer cells while being less toxic to normal cells [21]. Furthermore, carvacrol seems to exert a modulatory effect on the toxicity of cisplatin in vitro, a property that could be exploited for reducing the side-effects associated with classical cisplatin-based antitumor treatments [18].

3.2. Antioxidant

An in vitro study by Gavaric et al. showed that OEO possessed a robust antioxidant activity (IC50 = 0.2 µg/mL). While thymol and carvacrol were the components accounting for the antioxidant properties of oregano, the antioxidant activities of the two compounds were much inferior to the one observed for the whole extract with (IC50 = 70–80 mg/mL for thymol and carvacrol). The authors concluded that thymol, carvacrol, and other extract phytocompounds acted in synergy to promote the scavenging of free radicals [22]. According to a study conducted on the human colon carcinoma intestinal Caco-2 cell line, thymol, carvacrol, and their mixture seem to exhibit double-edged anti- or pro-oxidant effects, depending on the concentration at which they are administered (pro-oxidants at sub-cytotoxic concentrations vs. antioxidants at higher concentrations) [23].

3.3. Antimicrobial

3.3.1. Antiviral

An in vitro study conducted on simian Vero cell line CCL-81 showed that thymol, carvacrol, and p-cymene (all major components of oregano oils) possess antiviral properties against the human herpes simplex virus type 1 with respective IC50 values of 0.002%, 0.037%, and >0.1%. The antiviral properties of the three compounds are believed to be correlated to their ability to interfere with the viral membrane fusion mechanism during the adsorption phase of the virus [24]. Furthermore, an in vitro study by Sánchez and Aznar have reported a dose-dependent titer inhibition of the feline calicivirus and the murine norovirus by thymol, in the 1–2% (v:v) range concentrations [25].

3.3.2. Antibacterial

Thymol and carvacrol have been shown to exert antibacterial activities against Gram-positive and Gram-negative bacteria [26]. In studies using thymol concentrations ranging from 26.5–52.9 mg/cm2 showed potent inhibitory activity against the S. aureus, B. subtilis, E. coli, and Salmonella enteritidis [27]. Studies performed by Du et al. showed the following results: strong antibacterial activity of the OEOs, thymol, and carvacrol against E. coli, C. perfringens, and Salmonella strains. They also performed in vivo studies in 448 male broiler chicks by oral gavage using OEO. They found that OEO alleviated intestinal lesions and decreased E. coli populations [28]. In another study, oregano oil showed great antibacterial activity against the following multidrug-resistant bacteria: three Acinetobacter baumannii, three Pseudomonas aeruginosa, and four methicillin-resistant Staphylococcus aureus with inhibitory concentrations ranging from 0.08–0.64 mg/mL [29]. Another in vitro study showed that the use of OEO and carvacrol could curve Group A streptococci erythromycin-resistant bacterial infections [30].

3.3.3. Antifungal

The in vitro antifungal properties of OEO, thymol, and carvacrol in the 40–350 mg/mL ranges have been reported in several studies against plant pathogenic fungi Colletotrichum acutatum and Botryodiplodia theobromae [31]; Penicillium digitatum and Penicillium italicum [32]; food-relevant fungi Cladosporium spp. and Aspergillus spp. [33]; longan pathogens, Lasiodiplodia spp., Phomopsis spp., Pestalotiopsis spp. and Geotrichum candidum [34]; and against Fusarium verticillioides and Rhizopus stolonifera [35]. Furthermore, an in vivo study conducted in Caenorhabditis elegans suggests that thymol possesses antifungal activity against Candida albicans, the most prevalent cause of fungal infections in humans [36].

3.4. Anti-inflammatory

OEOs possess a strong anti-inflammatory activity, a property that is proposed to be mediated by its main active compounds: thymol and carvacrol. The impact of the OEOs on 14 protein biomarkers was closely related to the inflammatory response. The results show dose-dependent inhibition of the expression of all the proinflammatory and remodeling biomarkers studied: monocyte chemoattractant protein 1 (MCP-1), vascular cell adhesion molecule 1 (VCAM-1), intracellular cell adhesion molecule 1 (ICAM-1), interferon gamma-induced protein 10 (IP-10), interferon-inducible T-cell alpha chemoattractant (I-TAC), monokine induced by gamma interferon, collagen I, collagen III, epidermal growth factor receptor (EGFR), matrix metalloproteinase 1 (MMP-1), plasminogen activator inhibitor 1 (PAI-1), tissue inhibitor of metalloproteinase (TIMP) 1 and 2, and macrophage colony-stimulating factor (M-CSF) [37]. The anti-inflammatory activity of thymol was also reported in vivo in BALB/c mice affected by LPS-induced endometritis [38].

3.5. Immunomodulatory

Recent investigations cited in previous sections have demonstrated that oregano has potent antioxidant, antimicrobial, and anti-inflammatory properties, leading to an improved immune response. Oregano’s immunomodulatory activity can be attributed to thymol by its ability to modify the secretion of cytokines, probably through the regulation of NF-κB, but also through the MAPK signaling pathway, or through their ability to affect the cellular expression of iNOS and the secretion of prostaglandins [39]. De Santis et al. studied the immunomodulatory effects of several 50% (v/v) hydroalcoholic O. vulgare extracts on human-derived dendritic cells type-1 and type-2 macrophages infected with M. bovis Bacille Calmette–Guérin. The authors showed that the hydroalcoholic extract stimulated the anti-mycobacterial innate immunity and limited the inflammatory response in all the tested cell types [40]. On the contrary, Gholijani et al. showed that intraperitoneal injections of 80 mg/kg of thymol or carvacrol in BALB/c mice trigger an immunosuppressive response, a property that could be exploited for treating autoimmune diseases [41].

3.6. Predicted gastrointestinal absorption (GIA) 

The physicochemical properties for the main five most bioactive phytochemicals in oregano (carvacrol, thymol, o-cymene, apigenin, and luteolin) were calculated based on the combination of Lipinski’s, Ghose’s, and Veber’s rules (L-Ro5, GF, VR). The range of pharmacokinetics data for the molecules are summarized as follow: molecular weight (160-500 Da); hydrogen bond donors ≤5; hydrogen bond acceptors ≤10; molar refractivity (40-130); lipophilicity (LogP) (-0.4–5.6); rotatable bonds ≤ 10: polar surface area <140; the total number of atoms (20-70); lipophilicity considering ionizable groups at pH 7.4 (LogD) [42],[43],[44],[45]. 40 % of the oregano’s bioactive phytochemicals (apigenin and luteolin) comply with all of the “drug-likeness” rules. The remaining 60% (carvacrol, thymol, and o-cymene) violate the GF of MW = 160 – 480 Da rule. Accordingly, oregano, carvacrol, thymol, and o-cymene are predicted to have the lowest GIA.

4. Contraindications

As detailed in this entry, O. vulgare offers a wide range of medicinal benefits. In addition, Schönknecht et al. concluded that including primrose and thymol in combination with conventional therapy could alleviate cough and dyspnea in upper respiratory tract infections [46]. However, in a study of several decades ago, thymol and carvacrol have been shown to induce dose-dependent structural chromosomal aberrations in Rattus norvegicus, when consumed at doses over 40 mg/kg, despite being non-toxic at low to moderate doses [47]. Although all the studies mentioned here cited oregano, more robust studies are needed to have a profound evaluation of its efficacy.
This entry is adapted from 10.3390/app11188477

References

  1. Baser, K.H.C. Biological and Pharmacological Activities of Carvacrol and Carvacrol Bearing Essential Oils. Curr. Pharm. Des. 2008, 14, 3106–3119.
  2. Leyva-López, N.; Gutiérrez-Grijalva, E.P.; Vazquez-Olivo, G.; Heredia, J.B. Essential oils of oregano: Biological activity be-yond their antimicrobial properties. Molecules 2017, 22, 989.
  3. Nostro, A.; Papalia, T. Antimicrobial Activity of Carvacrol: Current Progress and Future Prospectives. Recent Pat. Anti-Infect. Drug Discov. 2012, 7, 28–35.
  4. Grbović, F.; Stanković, M.S.; Ćurčić, M.; Đorđević, N.; Šeklić, D.; Topuzović, M.; Marković, S. In vitro cytotoxic activity of origanum vulgare l. On hct-116 and mda-mb-231 cell lines. Plants 2013, 2, 371–378.
  5. Grevsen, K.; Fretté, X.; Christensen, L.P. Content and composition of volatile terpenes, flavonoids and phenolic acids in greek oregano (origanum vulgare l. Ssp hirtum) at different development stages during cultivation in cool temperate climate. Eur. J. Horticult. Sci. 2009, 74, 193–203.
  6. Oregano | Diseases and Pests, Description, Uses, Propagation. 2021. Available online: https://plantvillage.psu.edu/topics/oregano/infos/diseases_and_pests_description_uses_propagation (accessed on 20 May 2021).
  7. Gutiérrez-Grijalva, E.P.; Picos-Salas, M.A.; Leyva-López, N.; Criollo-Mendoza, M.S.; Vazquez-Olivo, G.; Heredia, J.B. Fla-vonoids and phenolic acids from oregano: Occurrence, biological activity and health benefits. Plants 2017, 7, 2.
  8. Elpiniki, S.; Alexandra, D.S.; Nicholaos, G.D. Ecology, cultivation and utilization of the aromatic greek oregano (origanum vulgare l.): A review. Not. Bot. Horti Agrobot. Cluj-Napoca 2019, 47, 545–552.
  9. Guarda, A.; Rubilar, J.F.; Miltz, J.; Galotto, M.J. The antimicrobial activity of microencapsulated thymol and carvacrol. Int. J. Food Microbiol. 2011, 146, 144–150.
  10. Sharifi-Rad, M.; Varoni, E.M.; Iriti, M.; Martorell, M.; Setzer, W.N.; Maria, D.M.C.; Salehi, B.; Soltani-Nejad, A.; Rajabi, S.; Tajbakhsh, M.; et al. Carvacrol and human health: A comprehensive review. Phytother. Res. 2018, 32, 1675–1687.
  11. Zhu, P.; Chen, Y.; Fang, J.; Wang, Z.; Xie, C.; Hou, B.; Chen, W.; Xu, F. Solubility and solution thermodynamics of thymol in six pure organic solvents. J. Chem. Thermodyn. 2016, 92, 198–206.
  12. Ruiz Reyes, E.; Moreira Castro, J. Secondary metabolites in medicinal plants to heal for gastrointestinal problems. A review of Ecuadorian ancestral medicine. Rev. Bases Cienc. 2017, 2, 1–16.
  13. Pozzatti, P.; Scheid, L.A.; Spader, T.B.; Atayde, M.L.; Santurio, J.M.; Alves, S.H. In vitro activity of essential oils extracted from plants used as spices against fluconazole-resistant and fluconazole-susceptible Candida spp. Can. J. Microbiol. 2008, 54, 950–956.
  14. Food and Drug Administration Code of Federal Regulations. 2021. Available online: https://www.accessdata.fda.gov/scripts/cdrh/cfdocs/cfcfr/CFRSearch.cfm?fr=172.515&SearchTerm=thymol (accessed on 28 March 2021).
  15. Spyridopoulou, K.; Fitsiou, E.; Bouloukosta, E.; Tiptiri-Kourpeti, A.; Vamvakias, M.; Oreopoulou, A.; Papavassilopoulou, E.; Pappa, A.; Chlichlia, K. Extraction, Chemical Composition, and Anticancer Potential of Origanum onites L. Essential Oil. Molecules 2019, 24, 2612.
  16. Coccimiglio, J.; Alipour, M.; Jiang, Z.-H.; Gottardo, C.; Suntres, Z. Antioxidant, Antibacterial, and Cytotoxic Activities of the Ethanolic Origanum vulgare Extract and Its Major Constituents. Oxidative Med. Cell. Longev. 2016, 2016, 1–8.
  17. Llana-Ruiz-Cabello, M.; Gutiérrez-Praena, D.; Pichardo, S.; Moreno, F.J.; Bermúdez, J.M.; Aucejo, S.; Cameán, A.M. Cyto-toxicity and morphological effects induced by carvacrol and thymol on the human cell line caco-2. Food. Chem. Toxicol. 2014, 64, 281–290.
  18. Potočnjak, I.; Gobin, I.; Domitrović, R. Carvacrol induces cytotoxicity in human cervical cancer cells but causes cisplatin re-sistance: Involvement of mek-erk activation. Phytother. Res. 2018, 32, 1090–1097.
  19. Zeng, Q.; Che, Y.; Zhang, Y.; Chen, M.; Guo, Q.; Zhang, W.J.D.D. Thymol isolated from thymus vulgaris l. Inhibits colorectal cancer cell growth and metastasis by suppressing the wnt/β-catenin pathway. Drug Des. Dev. Ther. 2020, 14, 2535.
  20. Khan, I.; Bahuguna, A.; Kumar, P.; Bajpai, V.K.; Kang, S.C. In vitro and in vivo antitumor potential of carvacrol nanoemulsion against human lung adenocarcinoma a549 cells via mitochondrial mediated apoptosis. Sci. Rep. 2018, 8, 144.
  21. Günes-Bayir, A.; Kocyigit, A.; Güler, E.M.; Bilgin, M.G.; Ergün, İ.S.; Dadak, A. Effects of carvacrol on human fibroblast (ws-1) and gastric adenocarcinoma (ags) cells in vitro and on wistar rats in vivo. Mol. Cell. Biochem. 2018, 448, 237–249.
  22. Gavaric, N.; Mozina, S.S.; Kladar, N.; Bozin, B. Chemical profile, antioxidant and antibacterial activity of thyme and oregano essential oils, thymol and carvacrol and their possible synergism. J. Essent. Oil Bear Plants 2015, 18, 1013–1021.
  23. Llana-Ruiz-Cabello, M.; Gutiérrez-Praena, D.; Puerto, M.; Pichardo, S.; Jos, Á.; Cameán, A.M. In vitro pro-oxidant/antioxidant role of carvacrol, thymol and their mixture in the intestinal Caco-2 cell line. Toxicol. Vitr. 2015, 29, 647–656.
  24. Sharifi-Rad, J.; Salehi, B.; Schnitzler, P.; Ayatollahi, S.A.; Kobarfard, F.; Fathi, M.; Eisazadeh, M.; Sharifi-Rad, M. Susceptibil-ity of herpes simplex virus type 1 to monoterpenes thymol, carvacrol, p-cymene and essential oils of sinapis arvensis l., lallemantia royleana benth. and pulicaria vulgaris gaertn. Cell Mol. Biol. 2017, 63, 42–47.
  25. Sánchez, G.; Aznar, R. Evaluation of Natural Compounds of Plant Origin for Inactivation of Enteric Viruses. Food Environ. Virol. 2015, 7, 183–187.
  26. Zarrini, G.; Delgosha, Z.B.; Moghaddam, K.M.; Shahverdi, A.R. Post-antibacterial effect of thymol. Pharm. Biol. 2010, 48, 633–636.
  27. Gniewosz, M.; Synowiec, A. Antibacterial activity of pullulan films containing thymol. Flavour Fragr. J. 2011, 26, 389–395.
  28. Du, E.; Gan, L.; Li, Z.; Wang, W.; Liu, D.; Guo, Y. In vitro antibacterial activity of thymol and carvacrol and their effects on broiler chickens challenged with Clostridium perfringens. J. Anim. Sci. Biotechnol. 2015, 6, 1–12.
  29. Lu, M.; Dai, T.; Murray, C.K.; Wu, M.X. Bactericidal Property of Oregano Oil against Multidrug-Resistant Clinical Isolates. Front. Microbiol. 2018, 9, 2329.
  30. Magi, G.; Marini, E.; Facinelli, B. Antimicrobial activity of essential oils and carvacrol, and synergy of carvacrol and erythro-mycin, against clinical, erythromycin-resistant group a streptococci. Front. Microbiol. 2015, 6, 165.
  31. Numpaque, M.A.; Oviedo, L.A.; Gil, J.H.; García, C.M.; Durango, D.L. Thymol and carvacrol: Biotransformation and antifungal activity against the plant pathogenic fungi colletotrichum acutatum and botryodiplodia theobromae. Trop. Plant. Pathol. 2011, 36, 3–13.
  32. Pérez-Alfonso, C.O.; Martínez-Romero, D.; Zapata, P.J.; Serrano, M.; Valero, D.; Castillo, S. The effects of essential oils car-vacrol and thymol on growth of penicillium digitatum and p. Italicum involved in lemon decay. Int. J. Food Microbiol. 2012, 158, 101–106.
  33. Abbaszadeh, S.; Sharifzadeh, A.; Shokri, H.; Khosravi, A.R.; Abbaszadeh, A. Antifungal efficacy of thymol, carvacrol, eugenol and menthol as alternative agents to control the growth of food-relevant fungi. J. Mycol. Med. 2014, 24, e51–e56.
  34. Suwanamornlert, P.; Sangchote, S.; Chinsirikul, W.; Sane, A.; Chonhenchob, V. Antifungal activity of plant-derived compounds and their synergism against major postharvest pathogens of longan fruit in vitro. Int. J. Food Microbiol. 2018, 271, 8–14.
  35. Ochoa-Velasco, C.E.; Navarro-Cruz, A.R.; Vera-López, O.; Palou, E.; Avila-Sosa, R. Growth modeling to control (in vitro) Fusarium verticillioides and Rhizopus stolonifer with thymol and carvacrol. Revista Argentina de Microbiología 2018, 50, 70–74.
  36. Shu, C.; Sun, L.; Zhang, W. Thymol has antifungal activity against candida albicans during infection and maintains the innate immune response required for function of the p38 mapk signaling pathway in caenorhabditis elegans. Immunol. Res. 2016, 64, 1013–1024.
  37. Han, X.; Parker, T.L. Anti-inflammatory, tissue remodeling, immunomodulatory, and anticancer activities of oregano (origanum vulgare) essential oil in a human skin disease model. Biochim. Open. 2017, 4, 73–77.
  38. Wu, H.; Jiang, K.; Yin, N.; Ma, X.; Zhao, G.; Qiu, C.; Deng, G. Thymol mitigates lipopolysaccharide-induced endometritis by regulating the tlr4- and ros-mediated nf-κb signaling pathways. Oncotarget 2017, 8, 20042–20055.
  39. Liang, D.; Li, F.; Fu, Y.; Cao, Y.; Song, X.; Wang, T.; Wang, W.; Guo, M.; Zhou, E.; Li, D.; et al. Thymol inhibits LPS-stimulated inflammatory response via down-regulation of NF-kB and MAPK signaling pathways in mouse mammary epithelial cells. Inflammation 2014, 37, 214–222.
  40. de Santis, F.; Poerio, N.; Gismondi, A.; Nanni, V.; di Marco, G.; Nisini, R.; Thaller, M.C.; Canini, A.; Fraziano, M. Hydroal-coholic extract from origanum vulgare induces a combined anti-mycobacterial and anti-inflammatory response in innate immune cells. PLoS ONE 2019, 14, e0213150.
  41. Gholijani, N.; Amirghofran, Z. Effects of thymol and carvacrol on T-helper cell subset cytokines and their main transcription factors in ovalbumin-immunized mice. J. Immunotoxicol. 2016, 13, 729–737.
  42. Jablonsky, Michal; Haz, Ales; Burcova, Zuzana; Kreps, Frantisek; Jablonsky, Jozef; Pharmacokinetic properties of biomass-extracted substances isolated by green solvents. BioResources 2019, 14, 6294–6303.
  43. Christopher P. Tinworth; Robert J. Young; Facts, Patterns, and Principles in Drug Discovery: Appraising the Rule of 5 with Measured Physicochemical Data. Journal of Medicinal Chemistry 2020, 63, 10091-10108, 10.1021/acs.jmedchem.9b01596.
  44. Michael P. Pollastri; Overview on the Rule of Five. Current Protocols in Pharmacology 2010, 49, 9.12.1-9.12.8, 10.1002/0471141755.ph0912s49.
  45. Leslie Z. Benet; Chelsea M. Hosey; Oleg Ursu; Tudor Oprea; BDDCS, the Rule of 5 and drugability. Advanced Drug Delivery Reviews 2016, 101, 89-98, 10.1016/j.addr.2016.05.007.
  46. Karina Schönknecht; Hanna Krauss; Jerzy Jambor; Andrzej Fal; [Treatment of cough in respiratory tract infections - the effect of combining the natural active compounds with thymol].. Wiadomości Lekarskie 2017, 69, 791-798.
  47. Margret M. Ris; Richard A. Deitrich; Jean-Pierre Von Wartburg; Inhibition of aldehyde reductase isoenzymes in human and rat brain. Biochemical Pharmacology 1975, 24, 1865-1869, 10.1016/0006-2952(75)90405-0.
  48. Karina Schönknecht; Hanna Krauss; Jerzy Jambor; Andrzej Fal; [Treatment of cough in respiratory tract infections - the effect of combining the natural active compounds with thymol].. Wiadomości Lekarskie 2017, 69, 791-798.
  49. Margret M. Ris; Richard A. Deitrich; Jean-Pierre Von Wartburg; Inhibition of aldehyde reductase isoenzymes in human and rat brain. Biochemical Pharmacology 1975, 24, 1865-1869, 10.1016/0006-2952(75)90405-0.
More
© Text is available under the terms and conditions of the Creative Commons Attribution (CC BY) license (http://creativecommons.org/licenses/by/4.0/)
Video Production Service
Feedback