Therapeutic Application of Carvacrol: A Comprehensive Review (Thymol and Oregano Oil potential antimicrobial, anticancer, cancer fighting, anti inflammatory)

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Abstract

Carvacrol is a major natural constituent and is significantly present as an essential oil in aromatic plants and is well known for its numerous biological activities. Therapeutic properties of carvacrol have been demonstrated as anti‐oxidant, anticancer, diabetes prevention, cardioprotective, anti‐obesity, hepatoprotective and reproductive role, antiaging, antimicrobial, and immunomodulatory properties. The carvacrol biosynthesis has been mediated through mevalonate pathway. Carvacrol has the anticancer ability against malignant cells via decreasing the expressions of matrix metalloprotease 2 and 9, inducing apoptosis, enhancing the expression of pro‐apoptotic proteins, disrupting mitochondrial membrane, suppressing extracellular signal‐regulated kinase 1/2 mitogen‐activated protein kinase signal transduction, and also decreasing the phosphoinositide 3‐kinase/protein kinase B. It also decreased the concentrations of alanine aminotransferase, alkaline phosphatase and aspartate aminotransferase, and gamma‐glutamyl transpeptidase as well as also restored liver function, insulin level, and plasma glucose level. Carvacrol also has been found to exert antimicrobial activity against Staphylococcus aureus, Pseudomonas aeruginosa, Coagulase‐negative staphylococcus, Salmonella spp., Enterococcus sp. Shigella, and Escherichia coli. The current review article summarizes the health‐promoting perspectives of carvacrol through various pathways.

Carvacrol is a major natural constituent in applauded for their nutraceutical potential ranging from antioxidant to anticancer

1. Introduction

Carvacrol (2‐Methyl‐5‐[1‐methyl ethyl]‐phenol) is a naturally occurring phenolic monoterpenoid and cymene derivative. Its chemical formula is C6H3CH3 (OH) (C3H7) and is naturally present in thyme (Thymus vulgaris), wild bergamot (bergamia Loise var. Citrus aurantium), Origanum scabrum, black cumin, Origanum microphyllum, Origanum onites, oregano (Origanum vulgare), and pepperwort (Lepidium flavum). Carvacrol oil extracted from thyme is 5%–75%, whereas 50%–70% oil is extracted from the marjoram and hop marjoram (Ares et al., 2020; Churklam et al., 2020; Lee et al., 2020; Sun et al., 2020; Tampau et al., 2020).

Its boiling point is 237–238°C (lit.) and it melts at 1°C (lit.). The density of carvacrol is ranged from 0.976 g/cm3 at 20°C to 0.975 g/cm3 at 25°C. It is not soluble in water but highly soluble in ethanol, carbon tetrachloride, and diethyl ether (Alagawany et al., 2015; Churklam et al., 2020; Lee et al., 2020; Mousavi et al., 2020). Biological activities of carvacrol have been shown in different in vivo and in vitro studies including anti‐oxidant, antiseptic, anticarcinogenic, anti‐inflammatory, antidiabetes role, immunomodulatory, antimicrobial activity, antispasmodic, antibacterial, and growth promoter. As it is a natural cymene derivative, it has potent bacterial inhibiting abilities and due to its flavoring property used in food industry as a preservative (Churklam et al., 2020; Memar et al., 2017; Mousavi et al., 2020; Rezvi & Roy, 2019; Scaffaro et al., 2020; Sun et al., 2020).

Ezz‐Eldin et al. (2020) showed the antiproliferative, anti‐inflammatory, and pain‐relieving properties of carvacrol against bronchial asthma; bronchial asthma in animals was induced by an intranasal dose of ovalbumin. IN serum absolute eosinophil count (AEC) and immunoglobulin E (IgE) and inflammatory biomarkers like IL‐3, IL‐4, IL‐5, IL‐13, TNF‐α, IFN‐γ, and iNOS were determined in bronchoalveolar lavage fluid. The level of oxidative stress biomarkers was also measured. Results determined that carvacrol is a significant anti‐oxidant and antiproliferative agent (Ezz‐Eldin et al., 2020). Plants synthesized carvacrol via the mevalonate pathway. Glucose is first decarboxylated and acetylated to acetyl coenzyme A (acetyl CoA), which could then be turned into mevalonic acid. Aromatization converts mevalonic acid to gamma‐terpinene, which is then converted to p‐cymene. Carvacrol was produced by the hydroxylation of p‐cymene, as shown in Figure 1.

2. Therapeutic Perspectives

2.2. Anticancer activity

Carvacrol has anticancer ability against malignant cells via decreasing the expressions of matrix metalloprotease 2 and 9 (Bayir et al., 2019; Fan et al., 2015; Rezvi & Roy, 2019). Its antiproliferative activities induce apoptosis, which further increases the expression of pro‐apoptotic proteins. In cancer cells lines JAR and JEG3 cells, carvacrol induces calcium ions burden in the mitochondrial matrix via disrupting the mitochondrial membrane, suppresses extracellular signal‐regulated kinase 1/2 mitogen‐activated protein kinase (MAPK) signal transduction, also decreases the phosphoinositide 3‐kinase/protein kinase B, and increases phosphor‐P38 and c‐Jun N‐terminal kinase MAPK expressions (Chraibi et al., 2020; Lim et al., 2019). Carvacrol in normal cells (L92) was also found to induce apoptosis via mitochondrial membrane potential disruption, ROS generation, activation of caspase3, and DNA damage (Jamali et al., 2020). A study conducted by Fan et al. explored that carvacrol works as an anticancer agent in different human colon cell lines such as LoVo and HCT116 via decreasing the matrix metalloprotease 2 and 9, cell‐proliferation, cyclin B1 expression, and In causing In cell In cycle arrest at G2 and M phases. Additionally, it also increased phosphorylation of the extracellular‐regulated protein kinase B and downregulated Bcl‐2 expression (Fan et al., 2015). It also exhibited the dose‐dependent inhibition in tumor growth cells in prostate cancer cells (PC3 cells) (Trindade et al., 2019). In a study, carvacrol‐encapsulated nanoemulsion (CEN) formulated by a combination of polysorbate 80, lecithin, and MCT in lung A549 cells line in a dose‐dependent manner reduced the activation of MAPK, p38, and ERK and decreased the expression of CD31 and VEGF (Carvalho et al., 2020; Khan, Bhardwaj, Shukla, Lee, et al., 2019; Khan, Bhardwaj, Shukla, Min, et al., 2019; Khan, Singh et al., 2019). Carvacrol can inhibit prostate cancer progression by inducing programmed cell death and cell cycle arrest at G0 and M‐phases. In a dose‐ and time‐dependent manner, carvacrol exhibited protective effects against prostate cancer cells via lowering cell viability, increasing the rate of reactive oxygen species, and disrupting the mitochondrial membrane potential. Carvacrol induced cell cycle arrest at G0/G1 that declined increased CDK inhibitor p21 expression and decreased cyclin‐dependent kinase 4 (CDK4), and cyclin D1 expressions. Moreover, carvacrol inhibited Notch signaling in PC‐3 cells via downregulating Jagged‐1 and Notch‐1 (Karam et al., 2019).

Heidarian examined the dose‐dependent effects of carvacrol in human prostate cancer cell lines, which significantly reduced IL‐6 gene expression as compared to the control group in which IL‐6 protein reduced 41.5% and 52.7% at 360 and 420 μM. Carvacrol reduced cellular signaling proteins and gene expression and cellular signaling proteins. Further, it also caused a reduction in the cell survival rate, invasion, and proliferation rate (Bayir et al., 2019; Heidarian & Keloushadi, 2019). A study reported by Pakdemirli et al. in 2020 examined carvacrol effects on both HT‐29 and HCT‐116 via lowering the survival rate and proliferation rate (Pakdemirli et al., 2020). In different in vitro and in vivo studies of MDA‐MB 231 cells, carvacrol‐induced apoptosis lowered the mitochondrial membrane potential resulting in the release of cytochrome c from mitochondria, cleavage of PARP, and caspase activation (Arunasree, 2010). Certain available evidence showed that carvacrol has cell cycle G2 arresting ability against hepatic cancer cells via enhancing cell apoptosis, activation of the caspase‐3, cleavage of PARP, and decreasing gene expression of Bcl‐2. Carvacrol dose‐dependently lowers ERK1/2posphorylation, activates phosphorylation of p38, and alters the phosphorylation of the MAPK (Elshafie et al., 2017; Suntres et al., 2015; Yin et al., 2012). Same findings were discovered by Khan, Bahuguna et al. (2017), Khan, Khan, Ahmad et al. (2017) and Khan, Khan, Farooqui et al. (2017), who investigated that carvacrol in human prostate cancer cell lines induced apoptosis and exhibited cell cycle arrest at G0 and G1phases (Khan, Khan, Farooqui et al., 2017). Similarly, Khan, Bahuguna et al. (2017) found the dose‐ and time‐dependent effects of carvacrol on DU145 cells. Carvacrol induced apoptosis by nuclear condensation, caspase‐3 activation, and Annexin V‐FITC/PI‐positive cells. It disrupts the mitochondrial membrane potential and caused cell cycle arrest at G0 and G1 (Khan, Bahuguna et al., 2017).

Carvacrol was found to have antitumor, antiproliferative, and apoptotic activity against human colon cancer cell lines LoVo and HCT116 when combined with thyme (Fan et al., 2015). Carvacrol decreased cancer cells proliferation and apoptosis via decreasing matrix metalloprotease (MMP‐2, MMP‐9) expressions while downregulating the Bcl‐2 expression and inducing phosphorylation of extracellular regulated protein kinase and protein kinase B(p‐Akt) at the molecular level (Fan et al., 2015).

Figure 4 depicts a model of the anticancer mechanism of carvacrol.

2.4. Anti‐obesity effects

De novo lipogenesis is the process of formation of new adipose cells derived from the ChREBP transcription factor. In this process, white adipocytes are engaged by one large fat droplet. Spalletta et al. (2018) investigated that carvacrol inhibited fat accumulation in humans 30% in Wharton' jelly‐derived mesenchymal stem cells and 40% in murine 3T3‐L1 cells. In addition, it also reduced autophagy and ChREBP expression (Spalletta et al., 2018).

Carvacrol can control obesity by inhibiting intracellular fat accumulation and adipocyte differentiation as evidenced in high‐fat‐diet‐induced male C57BL/6N mice embryo 3T3‐L1 cells and the mechanism involved in gene expression in thermogenesis, adipogenesis, and inflammation. Carvacrol inhibited visceral adipogenesis through suppression of bone morphogenic protein‐, galanin‐mediated signaling, and fibroblast growth factor‐1. Carvacrol inhibited toll‐like receptor (TLR2 and TLR4)‐mediated signaling and improved pro‐inflammatory cytokines formation in visceral adipose tissues (Cho et al., 2012). Carvacrol in combination with rosiglitazone on diabetic mice C57BL/6J showed a reduction in triglycerides, low‐density lipoproteins cholesterol, total cholesterol, phospholipids, and free fatty acids (Ezhumalai et al., 2015). A study conducted by Umaya and Manpal found that carvacrol has an anti‐obesity role on embryo 3T3‐L1 cells via lowering fat deposition in cells and visceral fats and also improving free fatty acids, liver cholesterol, and HDL‐cholesterol. Carvacrol reduced adipogenesis‐related gene fibroblast growth factor receptor in visceral adipose tissues and galanin receptor 1 and 2 expressions (Suganthi & Manpal, 2013). In a high‐fat‐induced C57BL/6J mice study, carvacrol (20 mg/kg BW) used in combination with thiazolidinediones and rosiglitazone lowered the plasma glucose level, increased hemoglobin level, and increased as well as also alanine aminotransferase, alkaline phosphatase, and aspartate aminotransferase and gamma‐glutamyl transpeptidase (Ezhumalai et al., 2014). In addition, carvacrol (25 and 50 mg/kg) was supplemented to streptozotocin‐induced diabetes rats for 7 days and found that carvacrol significantly reduced the level of glucose, serum total cholesterol, and body weight changes (Amiri & Akbari, 2018).

2.6. Anti‐inflammatory effects

In asthma, airway inflammation can be suppressed by peroxisome proliferator‐activated receptor‐alpha (PPAR‐α) agonists as it reduces the release of inflammatory mediators majorly involved in asthma (Gholijani et al., 2016; Rolim et al., 2019; Sun et al., 2020). Carvacrol protects from intestinal mucositis as it acts as an agonist of transient receptor potential cation channel, subfamily A, member 1(TRPA1). Alvarenga et al. (2016) determined anti‐inflammatory actions via activating the TRPA1 in intestinal mucositis induced by irinotecan hydrochloride (CPT‐11) at 75 mg/kg. It lowered MPO, NF‐ κB, C‐2 receptor, and production of pro‐inflammatory cytokines and lowered the malondialdehyde and nitric oxide level. It also restored villi architecture in the small intestine and side by side improved the blood bacterial count, leukogram, body mass variation, and survival rate. Carvacrol also significantly reduced nitric oxide, lipid peroxides, interleukin‐1 beta, and myeloperoxidase (Alvarenga et al., 2016; Arigesavan & Sudhandiran, 2015). Carvacrol also significantly reduced nitric oxide, lipid peroxides, interleukin‐1 beta, and myeloperoxidase (Arigesavan & Sudhandiran, 2015). Somensi et al. (2019) investigated the molecular pathways of carvacrol action on LPS‐mediated pro‐inflammatory activation of RAW 264.7 macrophages. Preincubation with 100 μM carvacrol prevented ERK1/2 phosphorylation and inhibited NF‐kB (p65) translocation from cytoplasm to nucleus, but it showed no response on p38 and JNK activation (Somensi et al., 2019).

Banik et al. (2019) explored the anti‐inflammatory and antitoxic effects of carvacrol and that it reduced oxidative damage in PC12 cells due to cadmium against caspase‐dependent and apoptosis‐independent pathways. Carvacrol exposure increased glutathione reductase expressions and cellular level of glutathione as well as ameliorated DNA fragmentation magnitude caused by cadmium. Carvacrol improved nuclear factor kappa‐light‐chain‐enhancer of activated B cells (NFКB), downregulation of mammalian target of rapamycin (mTOR), protein kinase B (Akt), and extracellular signal‐regulated kinase‐1 (ERK‐1). Carvacrol also suppressed the cleavage of caspase 3, reduced the apoptosis‐inducing factor (AIF) and cytosolic levels of cytochrome c, and increased the intracellular metallothionein content (Banik et al., 2019). A group of researchers and investigators determined the protective effects of carvacrol against cisplatin resistance in HeLa cells via ERK1/2‐dependent autophagy. Both compounds increased cisplatin‐induced light chain 3 beta expressions enhanced by MEK inhibition (Potočnjak et al., 2018).

Therapeutic effects of carvacrol (75 mg/kg) were studied by Zeytun and Özkorkmaz in 2021 against inflammation of Wistar albino rats and induced positive caspase 3 expression within apoptotic cells of the epithelial layer and connective tissues. Carvacrol increased mitotic activities and degenerative changes. Vascular endothelial growth factor was also seen in the papillary region of epithelium and also dilated vascular endothelial cells (Ezz‐Eldin et al., 2020). Rheumatoid arthritis (RA) is the inflammation of the joints and carvacrol has been proved by different studies that it can reduce inflammation in fibroblast‐like synoviocytes. A study conducted by Li et al. in 2019 showed that carvacrol inhibited LPS‐induced inflammation, cell proliferation, and migration in rheumatoid arthritis‐induced fibroblast‐like synoviocytes. Carvacrol decreased the production of inflammatory cytokines, as well as matrix metalloprotease such as MMP‐1, MMP‐3, and MMP‐13. Moreover, it also inhibited the activation pathways of TLR4/MyD88/NF‐κB, p38, and ERK1/2, respectively (Li et al., 2019). Encapsulated carvacrol in bovine serum albumin (BSA) is used to examine its therapeutic and immunomodulatory effects in adjuvant‐induced arthritis (AIA) in Sprague Dawley rats. Carvacrol‐loaded BSA nanoparticles significantly decreased clinical severity score, erythrocyte sedimentation rate, nitric oxide production, and interleukin (IL)‐17 gene expression (Gholijani et al., 2020).

Carvacrol modulates the neuro‐transmitter pathways, such as serotoninergic, dopaminergic, and γ‐amino butyric acid use in the release and production of inflammatory mediators (Bayir et al., 2019; Lima et al., 2017; Rezvi & Roy, 2019; Sharifi‐Rad et al., 2018).

3.3. Anti-Inflammatory Activity of Essential Oils of Oregano Species

Inflammation is a normal biological response of the body to tissue damage, infections and chemical or physical agents [120]. During inflammation the production of inflammatory mediators is triggered. Examples of these mediators are cytokines, prostaglandins, enzymes, nitric oxide (NO) and reactive oxygen species (ROS), among others [121]. If inflammation is not controlled the pro-inflammatory mediators are overproduced which might induce pathologic processes related to diseases such as arthritis, atherosclerosis and cancer to name a few [122,123]. Consequently, inhibition of the mediators is an imperative goal to treat inflammatory diseases.

There is evidence that mention that EOO have the ability to exert anti-inflammatory activity. For example, Leyva-López et al. [16] demonstrated that terpenes, such as thymol and carvacrol acetate, obtained from the three Mexican oregano species, L. graveolens, L. palmeri and H. patens reduced significantly the levels of ROS and NO produced by RAW 264.7 macrophage cells stimulated with lipopolysaccharide (LPS). Furthermore, EOs of O. majorana (10 μg/mL) reduced the production of tumor necrosis factor-alpha (TNF-α), interleukin-1β (IL-1β) and IL-6 in LPS-activated THP-1 human macrophage cells [124]. Recently, Han and Parker [125] showed that EOs obtained from O. vulgare significantly inhibited the levels of the inflammatory biomarkers monocyte chemoattractan protein-1 (MCP-1), the vascular cell adhesion molecule-1 (VCAM-1) and the intracellular cell adhesion molecule-1 (ICAM-1) on activated-primary human neonatal fibroblasts. These findings suggest that the EOO have anti-inflammatory properties.

The individual components of EOs of oregano have also been studied to better understand their effect on inflammation. For example, Lima et al. [126] demonstrated that carvacrol exerts anti-inflammatory activity on a typical mice inflammation model. When carvacrol was administrated to mice (at 50 and 100 mg/kg), presenting paw edema, the levels of IL-1β and prostaglandin E2 (PGE2) prostaglandins were diminished. The reduction on the mRNA expression of IL-1β and cyclooxygenase-2 (COX-2) might be responsible for the effects mentioned. On the other hand, the levels of the cytokine IL-10 in the swollen paw were improved by carvacrol. So, the anti-inflammatory effect of carvacrol is due to the reduction of pro-inflammatory mediators but also to the increasing of anti-inflammatory cytokines (IL-10) [126]. Carvacrol has also showed the ability to prevent obesity in mice by modulating expression of genes involved in inflammation [127] and to attenuate induced liver injury and ulcer in rats [128,129]. Other EOs components, such as p-cymene [130] and β-caryophyllene [131,132,133,134] have also demonstrated anti-inflammatory properties.

The studies mentioned above indicate that diverse oregano species might be used as anti-inflammatory agents and could be used in formulations for the prevention or the treatment of inflammation-related diseases. Nevertheless, and since the EOO might exert toxic effect on cells, several in vivo and clinical studies are needed before the EOs can be used as an alternative to treat inflammation.

2.8. Neuroprotective role

The neuroprotective role of carvacrol was examined by Guan et al. in 2019 against ischemic stroke, leading to hippocampal neuron damage and impairment in gerbils brain tissue improved. Carvacrol decreased levels of lipid peroxide, reduced cell death, and increased the expression of glutathione peroxidase 4 inhibited by ferroptosis (Guan et al., 2019). In recent findings, Raeini et al. (2019) evaluated that carvacrol has a significant ability to reduce neuronal necrosis and malondialdehyde (MDA) and elevated the levels of superoxide dismutase and catalase activities in the hippocampus of 48 male Wistar rats. Carvacrol improved cognitive functions, spatial learning, and memory capacities (Raeini et al., 2019). Carvacrol deters transient receptor potential melastatin 7 (TRPM7), which involved in the homeostasis of calcium and zinc. A study investigated the neuroprotective effects of carvacrol 50 mg/kg on cerebral ischemia through blockade of zinc influx on 8‐week‐old male Sprague–Dawley rats. Furthermore, carvacrol decreased oxidative damage, microglial activation, number of degenerating neurons, and zinc translocation through downregulating TRPM7 channels (Hong et al., 2018).

Zotti et al. (2013) documented that the administration of 12.5 mg/kg of carvacrol has an impact on neurochemistry and behavioral outcome in the prefrontal cortex and hippocampus of animal models, which increased serotonin and dopamine levels. Likewise, 450 mg/kg of carvacrol significantly reduced dopamine in the hippocampus of animals. Results suggested that it is a potent brain‐activating molecule that modulates neurotransmitters and neuron activities (Zotti et al., 2013). The peripheral neuro‐degenerative process is considered important for regenerating peripheral nerves genetically or mechanically. Carvacrol regulates transient receptor potential ankyrin 1 (TRPA1), TRP melastatin M7 (TRPM7), TRP canonical 1 (TRPC1), and TRP vanilloid 3 (TRPV3). A study investigated the regulatory effect of carvacrol on TRPM7‐dependent neurodegenerative process carvacrol specificity Schwann cells. Carvacrol significantly suppressed the morphometric indices, such as myelin, stripe, ovoid, and neurofilament indices. Moreover, carvacrol inhibited TRPM7 upregulation in Schwann cells and protected against the peripheral neurodegenerative process (Chun et al., 2019).

Carvacrol also protects from 6‐hydroxydopamine‐induced neurotoxicity as evidenced by various studies on Parkinson's disease; Manouchehrabadi et al. (2019) investigated the neuroprotective effects of carvacrol on Parkinson's disease models in in vitro and in vivo experiments. In in vitro experiment, post‐treatment carvacrol protects the adrenal pheochromocytoma PC12 cells of animals from 6‐hydroxydopamine‐induced neurotoxicity by toxicity induced by a reduction in intracellular reactive oxygen species, increasing cell viability and reduced intra‐cellular lipid In peroxidation In and In annexin In positive In cells In. Additionally, carvacrol protects against neurodegenerative diseases as it improved catalepsy, akinesia, bradykinesia, locomotor activity, and motor coordination. It also reduced the apo‐morphine, decreased the level of malondialdehyde, and increased the level of reduced glutathione content (Manouchehrabadi et al., 2019).

2.9. Hepatoprotective and gastroprotective role

Carvacrol protects from hepatotoxicity caused by D‐galactosamine (D‐GalN). It suppresses the CYP2E1 and upregulates PPAR‐α, mRNA, and protein expressions (Alagawany et al., 2015; Aristatile et al., 2014; Jamali et al., 2020). Carvacrol also reduces restraint stress induced by chronic exposure to oxidative stress leading to tissue damage in the brain, liver, and kidney. A study indicated that carvacrol prevents oxidative damage and restraint stress. Carvacrol was administered systemically for 21 days in animals and the levels of malondialdehyde (MDA) decreased glutathione, SOD, restraint stress, glutathione peroxidase, and glutathione reductase measured in the brain, liver, and kidney of animals. Results showed that in stressed animals' MDA, the level was higher and the levels of GSH and anti‐oxidant enzymes were significantly lower (Samarghandian, Azimi‐Nezhad et al., 2016; Samarghandian, Farkhondeh et al., 2016).

Another study investigated 15 mg/kg of carvacrol's protective effects on age‐associated changes in the action of anti‐oxidant enzymes and levels of lipid per‐oxidation at different ages (2, 10, 20 months) of rats. Results showed more improvement in the actions of anti‐oxidant enzymes of 20 months old rats and carvacrol helped in decreasing lipid peroxidation of 10 and 20 months old rats (Samarghandian, Azimi‐Nezhad et al., 2016). Carvacrol effects on acute pancreatitis (AP) induced by cerulean in animal models analyzed by Bakir et al. in 2016 showed the dose‐dependent manner of carvacrol decreased pancreatitis‐induced malondialdehyde and 8‐hydroxydeoxyguanosine levels as it improved the levels of anti‐oxidant enzymes and decreased the levels of AST, ALT, and LDH (Bakır et al., 2016). Carvacrol also treats cisplatin‐induced acute kidney injury via suppression of ERK and activating PI3K/Akt. Renal oxidative stress increased the expression of 4‐hydroxynonenal, 3‐nitrotyrosine, cytochrome P450 E1 (CYP2E1), heme‐oxygenase‐1 (HO‐1) and expressions of phosphorylated nuclear factor‐kappaB p65 and tumor necrosis factor‐α in animal. The results indicated that acute renal injury suppressed oxidative stress, apoptosis, and inflammation through the modulation of the ERK and PI3K/Akt pathways (Potočnjak & Domitrović, 2016).

A study conducted by Shanmugam et al. in 2019 indicated that carvacrol actions on liver tissues against toxicity was caused by sodium fluoride in rats. Carvacrol supplementation normalized all the anti‐oxidant enzymes and hepatic markers in NaF toxicity rats. Diphenyl‐1‐picrylhydrazyl (DPPH), hydrogen peroxide (H2O2), and hydroxyl radical activities showed potent free‐radical scavenging activities. The study concluded that carvacrol modulated the anti‐oxidant enzymes and hepatic stress markers in NaF rats (Shanmugam et al., 2019). Carvacrol also protects from gastric ulcers and has become a worldwide health problem. A peptic ulcer is one of the gastric problems caused by Helicobacter pylori, smoking, stress, alcohol, and nonsteroidal anti‐inflammatory drugs (NSAID). A study investigated the gastroprotective effects of carvacrol in rodents in which NSAID, ischemia, and reperfusion made gastric lesions. The results demonstrated that carvacrol promoted a marked gastroprotection mediated by endogenous prostaglandins, increase in mucus production, KATP channels opening, NO synthase activation, and anti‐oxidant properties (Oliveira et al., 2012).

Carvacrol has significant protective effects in reducing the side effects of chemotherapeutics such as irinotecan hydrochloride anticancer drugs that cause induction of intestinal mucositis. Irinotecan hydrochloride triggers inflammation and leads to cell damaging via the transient receptor potential cation channel, subfamily A, and member 1 receptor. Carvacrol reduced inflammatory biomarkers, such as nuclear factor κB and cyclooxygenase‐2, and levels of nitric oxides, malondialdehyde, and glutathione create oxidative stress. It also acts as an agonist of the transient receptor potential cation channel. Carvacrol also restored the tissue architecture of the villi and crypts in the small intestine and side by side improved the blood bacterial count, leukogram, body mass variation, and survival rate (Alvarenga et al., 2016). Arigesavan and Sudhandiran (2015) showed the anti‐inflammatory effects of carvacrol in the colon of Fischer 344 rats against inflammation induced by 1, 2‐dimethyl hydrazine plus dextran sodium sulfate. F344 rats were given three subcutaneous injections of DMH (40 mg/kg body wt) in the first week to F344 rats and free access to drinking water containing 1% DSS for the next 1 week was also given for 7–14 days as three cycles. 50 mg/kg body weight (o.p) carvacrol was administrated before and after tumor induction. Carvacrol‐treated groups suppress the inflammation in DMH/DSS‐induced animals, increased anti‐oxidant status; developed an endogenous anti‐oxidant system was observed and restorative histological lesions. Carvacrol also increased significantly the level of anti‐oxidant enzymes such as glutathione levels, superoxide dismutase, catalase, reduced nitric oxide, lipid peroxides, interleukin‐1 beta, and myeloperoxidase as compared to DMH/DSS induced rats (Arigesavan & Sudhandiran, 2015).

4. Immunomodulatory Role

Carvacrol action can modulate immune responses via different inflammatory parameters such as proliferation of T‐cells, isolated polymorph nuclear neutrophils IL‐2 and TNF‐α cytokines production, and ROS generating from whole blood phagocytes. Ezz‐Eldin et al. (2020) investigated the immunomodulatory effect of carvacrol against bronchial asthma induced by an intranasal dose of ovalbumin. It significantly caused a reduction in absolute eosinophil count, absolute eosinophil count, immunoglobulin E, inflammatory biomarkers (TNF‐α, L‐4, IL‐5, IL‐13, and interferon‐gamma), and enhancement in anti‐oxidant enzymes further that prevent from the inflammatory symptoms in asthma (Ezz‐Eldin et al., 2020). Combination of carvacrol with essential oils (Foeniculum vulgare, Saturea cuneifolia, and Origanum munitiflorum) can inhibit ROS production, T‐cells proliferation, and pro‐inflammatory cytokines (Khazdair et al., 2018; Orhan et al., 2016). Encapsulated carvacrol (250–650 μg/g) in necrotic enteritis animal disease caused by C. perfringens in chicken intestine prevented the immune‐mediated responses (Liu et al., 2016). Thymol and carvacrol in human mesenchymal stromal cells protect from oxidative stress‐related damage and cytotoxicity and preserve cell morphology (Bouhtit et al., 2019).

Tolerogenic dendritic cells (DCs) are a condition that leads to the induction of dampened pathogenic T cell responses and FoxP3+ regulatory T cells. Spiering et al. (2012) investigated the immunomodulatory properties of carvacrol by suppressing autoimmune arthritis in a mouse model. Amirghofran et al. (2016) also investigated carvacrol and thymol actions on DCs maturation and T cell activation. Both compounds also inhibited the mitogenic and allogeneic T‐cells responses and release of cytokines (Amirghofran et al., 2016). Carvacrol was also found to lower the vascular cell adhesion molecule 1 (VCAM‐1), monocyte chemo‐attractant protein (MCP‐1), intracellular cell adhesion molecule 1 (ICAM‐1), interferon gamma‐induced protein 10, interferon‐inducible T‐cell alpha chemo‐attractant(I‐TAC), etc., as well as also decrease the remodeling biomarkers such as collagen I, III, epidermal growth factor receptor(EGFR), matrix metalloproteinase 1, and plasminogen activator inhibitor 1 (Han & Parker, 2017).

By investigating thymol and carvacrol (25 μg/ml) effects against Jurkat leukemia cells in in vitro models, Gholijani et al. in 2015 concluded that both compounds reduced IL‐2 and IFN‐γ production via downregulating AP‐1 and NFAT‐2 transcription factors (Gholijani et al., 2015). A study reported by Gandhi et al. found that carvacrol also regulates cytokine production, inhibits ROS accumulations, and inactivates eosinophils migration lungs. EO suppressed cytokine production, pro‐inflammatory and anti‐inflammatory mediators formation, and accumulation (Gandhi et al., 2020).

Carvacrol also protects in case of multiple sclerosis (MS) development by modulating pro‐ and anti‐inflammatory properties (TGF‐β, IL‐4, and IL‐10). Mahmoodi et al. (2019) studied carvacrol 5 and 10 mg/kg dose effect on auto‐immune encephalomyelitis and exhibited immune‐modulating actions on pro‐ and anti‐inflammatory cytokines. Carvacrol also improved pathological problems and improved clinical symptoms in patients (Gholijani & Amirghofran, 2016; Mahmoodi et al., 2019). Similarly, carvacrol (73 mg/kg) in combination with pomegranate (225 mg/kg/day) was studied against methotrexate (MTX)‐induced intestinal damage in 32 male Sprague–Dawley rats, using immunohistochemical and histopathological techniques (Türkcü et al., 2015). Carvacrol effects on cytokines genes expression in splenocytes of asthmatic mice were studied by Kianmehr et al. (2016) in rats in which asthma is induced by ovalbumin (OVA) and it was concluded that carvacrol significantly modulated the immune response by decreasing IL‐4, IL‐17, and TGF‐β gene expressions and increased IFN‐γ and FOXP3 (Kianmehr et al., 2016).

Khazdair and Boskabady (2019a, 2019b) investigated carvacrol effects on serum levels of interferon‐gamma (IFNγ), interleukins (IL‐2, IL‐4, IL‐6, IL‐8, and IL‐10), and pulmonary function tests in 22 patients exposed to sulfur mustard (SM) 27–30 years in a double‐blind manner for 2 months divided into placebo and carvacrol 1.2 mg/kg/day. It was concluded that carvacrol reduced inflammatory cytokines, while increased anti‐inflammatory cytokines and improved PFT tests in SM‐induced lung injury (Khazdair & Boskabady, 2019a, 2019b). Another study evaluated the immunomodulatory and ulcer protective action of carvacrol (25, 50 & 100 mg/kg) on an animal model in which gastric lesions were made by acetic acid. Results showed carvacrol gastric healing actions and also proved that it interferes with secretion and production of inflammatory mediators in case of ulcer (Hussein et al., 2019; Silva et al., 2012; Table 1).

4. Reproductive Role

Oxidative stress decreases the number of germ cells and damages testicular tubules, as reactive oxygen species (ROS) is very important for the sperm condensation, sperm‐oocyte fusion, and hyper‐activation required for normal fertilization, but excessive lipid peroxidation and ROS could damage sperm dysfunction and cause DNA damage and loss of motility. Oxidative stress leads to the damage of spermatozoa due to the lack of cytoplasmic defensive barriers and spermatozoon plasma membranes containing polyunsaturated fatty acids (PUFA) get injured as well as destroy lipid structure in spermatozoa membranes and cause loss of motility and damage to membrane integrity. A study described by Shoorei et al. in 2019 investigated the role of carvacrol in 32 male adult Wistar rats in which diabetes was induced by streptozotocin (50 mg/kg) supplement. Findings suggested that carvacrol 75 mg/kg reduced the rate of germ cell apoptosis, reduced the activity of SOD and GPx enzymes, diminished the elevated levels of MDA, and improved morphology of the testis as well as decreased Bax and increased Bcl‐2 at the levels of gene and protein expression (Shoorei et al., 2019). A study conducted by Güvenç et al. (2019) found that carvacrol in combination with thymol has a significant impact on the quality of sperms improved by decreasing level of oxidative stress, MDA levels in testicles, liver, and kidney tissues, enhancing the GSH‐Px and catalase activities along with enhancement in spermatozoa concentration and motility (Güvenç et al., 2019). Moreover, carvacrol also improves the mean motility, movement characteristics, sperm capacitation, and fertilizing ability and prevents testicular damage (Cengİz et al., 2017). Carvacrol (25 and 50 mg/kg) prevented ketamine‐induced oxidative stress and damage in testicular tissues by lowering the level of MDA‐induced schizophrenia and increasing the anti‐oxidant enzymes (Araghi et al., 2017). Similarly, carvacrol prevents cyclophosphamide‐induced testis toxicity and damage in male rats due to its anti‐oxidative role (Cengiz et al., 2017). In adult male Sprague–Dawley rats, cisplatin induces reproductive toxicity by damaging the dermatological parameters (live sperm rate, motility, and abnormal sperm rate), increasing the oxidative stress, and inducing testicular degeneration whereas daily orally administrated carvacrol at the rate of 75 mg/kg prevented from these changes (Aksu et al., 2016).

5. Conclusion

The purpose of this comprehensive review was to highlight and explain the biosynthesis mechanism of carvacrol and the significant protective effects of carvacrol as an anti‐oxidant, anticancer potential, anti‐inflammatory, antimicrobial, hepatoprotective effects, and neuro‐protective and anti‐obesity effects. Scientists and researchers have studied the potential of carvacrol and thymol for cancer prevention, diabetes prevention, wound healing, and immuno‐modulatory in vivo and in vitro assays. Carvacrol exhibits a high potential for the development of new therapeutic alternatives to cure human maladies. However, the extensive studies still required to elucidate the potential therapeutic effect of carvacrol on molecular level by involving long‐term human efficacy trial with special reference to its lethal dose, toxicity, and RDA.

Acknowledgments

The authors acknowledge HEC for its support.

Notes

Imran, M. , Aslam, M. , Alsagaby, S. A. , Saeed, F. , Ahmad, I. , Afzaal, M. , Arshad, M. U. , Abdelgawad, M. A. , El‐Ghorab, A. H. , Khames, A. , Shariati, M. A. , Ahmad, A. , Hussain, M. , Imran, A. , & Islam, S. (2022). Therapeutic application of carvacrol: A comprehensive review. Food Science & Nutrition, 10, 3544–3561. 10.1002/fsn3.2994 [PMC free article] [PubMed] [CrossRef] [Google Scholar]

Author Contributions

Ali Imran, Email: moc.liamg@tf.narmiila.

Saiful Islam, Email: db.ca.ud@sfnilufias.

Conflicts of Interest

The authors declare no conflicts of interest.

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3.6. Antiprolifertive and Citotoxic Activity of Essential Oils of Oregano

Essential oil constituents could exert antiproliferative effect. Different mechanisms such antioxidant, antimutagenic, antiproliferative, among others are responsible for their chemopreventive properties [155] The antiproliferative effects of EOs have been demonstrated in diverse cancer cell models through several pathways [156].

Marrelli et al. [117] studied the antiproliferative activity of EOs of Origanum species. At 100 µg/mL concentration, EOs derived from O. dictamnus showed the most interesting biological activity with an inhibition on colon carcinoma cell line (LoVo) of 58.39% after 24 h. Additionally, the IC50 value for this essential oil was 84.76 µg/mL after 24 h and 72.26 µg/mL after 48 h of treatment. In the same study, it was reported that the EOs from O. dictamnus and O. libanoticum had an antiproliferative activity of 49.83% and 48.50% in the hepatocarcinoma cell line (HepG2) at 100 µg/mL concentration. Begnini et al. [157] showed that EOs from O. vulgare inhibit cell proliferation in human breast adenocarcinoma (MCF-7), and human colon adenocarcinoma (HT-29) cells at 50 mg/mL (60.8% and 48.9%, respectively).However, an increase in the EOO concentration did not increase the cell growth inhibition. The authors implied that the effect could be attributed to the main components (terpinen-4-ol, thymol, γ-terpinene and carvacrol). Besides, EOs of O. hirtum significantly reduced the proliferation of human lung adenocarcinoma epithelial (A549) cell line, after 24 h incubation, compared with untreated control cells [76]. Furthermore, it was suggested that the EOO modifies the onset of mitosis, possibly prior to the G2 phase and prophase.

Many evidences have shown that EOO had antitumor effect. EOO have shown antitumor activity both in in vivo and in vitro assays. An in vivo study reported that low doses of EOO in a three-month period exerted preventive action by decreasing the sizes of tumors by 1.5 times in diseased animals. It was suggested that the EOO could possible affect the development and progression of the tumor process via the activation of regulator cell molecules [158]. The in vitro antitumor activity of EOs of O. onites, was analyzed against rat adipose tissue endothelial cells and c-H-ras transformed rat embryonic fibroblasts (5RP7) cells. EOO at 125, 250 and 500 µg/mL resulted in significant inhibition of cell viability. In addition, EOO induced apoptosis of 5RP7 cells and blocked in vitro tube formation which accounts for its angiogenic activity [159].

Besides, EOO have shown activity against genotoxic agents, which are capable of altering DNA and thereby causing cancer or mutation [160]. The effects of AFB1 (5 µM), a cancer promotor, on human peripheral lymphocytes, were decreased after treatment with EOs of O. rotundifolium (1.5 µL and 2.0 µL). This activity could be attributed in part to the EO composition and its antioxidant capacity [161]. Similarly, the combined treatment of prallethrin and EOs from O. majorana in bone marrow cells of rats, resulted in the reduction of the chromosomal aberration (54.54%), thus, EOO demonstrated to have genotoxic effect. The effects could be attributed to the scavenge ability of EOO and its contribution in hindering lipid peroxidation [162].

Furthermore, in human breast (MCF-7) and prostate (LNCaP) cancer cell lines, EOs of O. majorana and O. vulgare showed an inhibitory effect on cancer cell viability in a range of 79–88% at 0.5 mg/mL (24 h). Origanum majorana was more cytotoxic than O. vulgare against MCF-7 and LNCaP cells with IC50s of 70.0 and 85.3 µg/mL [163]. Similarly, cytotoxicity of EOs was tested using human keratinocyte (HaCaT) and lung cancer (A549) cell lines. Cell viability decreased in a concentration-dependent manner on both cell lines. Essential oils of O. hirtum exhibited cytotoxicity both on HaCaT and A549 cells with IC50 values ranging from 146.8 to 148.8 μg/mL and from 147.1 to 177.1 μg/mL respectively, after 24, 48 and 72 h [80]. In another study, EOs of O. compactum have shown to be non-toxic towards MCF-7 cells (IC50 > 100 mg/L) [111].

Essential oils from oregano have been proposed as dietary inhibitors of mutagenesis and carcinogenesis [162]. Nonetheless, investigations about anticarcinogenic effect of EOO are scarce. Likewise, there are considerably fewer works dedicated to the biological activity of EOs using cell cultures and using in vivo models [158]. Furthermore, the molecular targets at the genome level and the involved genetic pathways of the mechanisms of EOO are remaining poorly explored [164].

A brief compilation of the biological activities, mentioned above, of EOs from different species of oregano is shown in Table 2.

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Therapeutic Application of Carvacrol: A Comprehensive Review