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Proceedings of the National Academy of... Dec 2021Thymol and carvacrol are phenolic monoterpenes found in thyme, oregano, and several other species of the Lamiaceae. Long valued for their smell and taste, these...
Thymol and carvacrol are phenolic monoterpenes found in thyme, oregano, and several other species of the Lamiaceae. Long valued for their smell and taste, these substances also have antibacterial and anti-spasmolytic properties. They are also suggested to be precursors of thymohydroquinone and thymoquinone, monoterpenes with anti-inflammatory, antioxidant, and antitumor activities. Thymol and carvacrol biosynthesis has been proposed to proceed by the cyclization of geranyl diphosphate to γ-terpinene, followed by a series of oxidations via -cymene. Here, we show that γ-terpinene is oxidized by cytochrome P450 monooxygenases (P450s) of the CYP71D subfamily to produce unstable cyclohexadienol intermediates, which are then dehydrogenated by a short-chain dehydrogenase/reductase (SDR) to the corresponding ketones. The subsequent formation of the aromatic compounds occurs via keto-enol tautomerisms. Combining these enzymes with γ-terpinene in in vitro assays or in vivo in yielded thymol and carvacrol as products. In the absence of the SDRs, only -cymene was formed by rearrangement of the cyclohexadienol intermediates. The nature of these unstable intermediates was inferred from reactions with the γ-terpinene isomer limonene and by analogy to reactions catalyzed by related enzymes. We also identified and characterized two P450s of the CYP76S and CYP736A subfamilies that catalyze the hydroxylation of thymol and carvacrol to thymohydroquinone when heterologously expressed in yeast and Our findings alter previous views of thymol and carvacrol formation, identify the enzymes involved in the biosynthesis of these phenolic monoterpenes and thymohydroquinone in the Lamiaceae, and provide targets for metabolic engineering of high-value terpenes in plants.
Topics: Cymenes; Cytochrome P-450 Enzyme System; Lamiaceae; Metabolic Networks and Pathways; Plant Proteins; Short Chain Dehydrogenase-Reductases; Thymol
PubMed: 34930840
DOI: 10.1073/pnas.2110092118 -
Biomedicine & Pharmacotherapy =... Nov 2022Both thymoquinone (TQ) and thymol (T) have been proved to possess a positive impact on human health. In this research, we aimed to investigate the effect of these...
The protective effect of thymoquinone or/and thymol against monosodium glutamate-induced attention-deficit/hyperactivity disorder (ADHD)-like behavior in rats: Modulation of Nrf2/HO-1, TLR4/NF-κB/NLRP3/caspase-1 and Wnt/β-Catenin signaling pathways in rat model.
Both thymoquinone (TQ) and thymol (T) have been proved to possess a positive impact on human health. In this research, we aimed to investigate the effect of these compounds separately and together on the Attention-deficit/hyperactivity disorder (ADHD)-like behavior induced by monosodium glutamate (MSG) in rats. Forty male, Spargue Dawley rat pups (postnatal day 21), were randomly allocated into five groups: Normal saline (NS), MSG, MSG+TQ, MSG+T, and MSG+TQ+T. MSG (0.4 mg/kg/day), TQ (10 mg/kg/day) and T (30 mg/kg/day) were orally administered for 8 weeks. The behavioral tests proved that rats treated with TQ and/or T showed improved locomotor, attention and cognitive functions compared to the MSG group with more pronounced effect displayed with their combination. All treated groups showed improvement in MSG-induced aberrations in brain levels of GSH, IL-1β, TNF-α, GFAP, glutamate, calcium, dopamine, norepinephrine, Wnt3a, β-Catenin and BDNF. TQ and/or T treatment also enhanced the mRNA expression of Nrf2, HO-1 and Bcl2 while reducing the protein expression of TLR4, NFκB, NLRP3, caspase 1, Bax, AIF and GSK3β as compared to the MSG group. However, the combined therapy showed more significant effects in all measured parameters. All of these findings were further confirmed by the histopathological examinations. Current results concluded that the combined therapy of TQ and T had higher protective effects than their individual supplementations against MSG-induced ADHD-like behavior in rats.
Topics: Animals; Male; Rats; Attention Deficit Disorder with Hyperactivity; bcl-2-Associated X Protein; beta Catenin; Brain-Derived Neurotrophic Factor; Calcium; Caspase 1; Dopamine; Glycogen Synthase Kinase 3 beta; NF-E2-Related Factor 2; NF-kappa B; NLR Family, Pyrin Domain-Containing 3 Protein; Norepinephrine; RNA, Messenger; Saline Solution; Sodium Glutamate; Thymol; Toll-Like Receptor 4; Tumor Necrosis Factor-alpha; Wnt Signaling Pathway
PubMed: 36271575
DOI: 10.1016/j.biopha.2022.113799 -
Molecules (Basel, Switzerland) May 2019One of the most important causative agents of visceral leishmaniasis (VL) is , which is mainly spread by and sandflies in the Old and New World, respectively. Novel...
BACKGROUND
One of the most important causative agents of visceral leishmaniasis (VL) is , which is mainly spread by and sandflies in the Old and New World, respectively. Novel and effective drugs to manage this neglected vector-borne disease are urgently required. In this study, we evaluated the toxicity of carvacrol, thymol and linalool, three common essential oil constituents, on amastigotes and promastigotes of . : in vitro experiments were performed by 24 h MTT assay. Carvacrol, thymol and linalool at concentrations ranging from 1.3 to 10 μg/mL were tested on promastigotes of . For in vivo test, two groups of hamsters () received 100 mg/kg of body weight/day of carvacrol and thymol as intraperitoneal injection on day 7 post-infection, followed by a 48 h later injection. The third group was treated with the glucantime as standard drug (500 mg/kg) and the last group (control) just received normal saline. On the 16th day, the number of parasites and histopathological changes in liver and spleen were investigated.
RESULTS
24 h MTT assay showed promising antileishmanial activity of thymol and carvacrol, with IC values of 7.2 (48 μM) and 9.8 μg/mL (65 μM), respectively. Linalool at all concentrations did not affect promastigote viability. In vivo toxicity data of carvacrol and thymol showed that the former at 100 mg/kg was the safest and most effective treatment with little side effects on the liver.
CONCLUSIONS
Overall, thymol and carvacrol are highly promising candidates for the development of effective and safe drugs in the fight against VL.
Topics: Acyclic Monoterpenes; Animals; Cricetinae; Cymenes; Disease Models, Animal; Inhibitory Concentration 50; Leishmania infantum; Leishmaniasis, Visceral; Liver; Male; Monoterpenes; Parasitic Sensitivity Tests; Thymol; Trypanocidal Agents
PubMed: 31151304
DOI: 10.3390/molecules24112072 -
Toxins Feb 2022is a harmful pathogen causing head blight in cereals such as wheat and barley, and thymol has been proven to inhibit the growth of many pathogens. This study aims to...
is a harmful pathogen causing head blight in cereals such as wheat and barley, and thymol has been proven to inhibit the growth of many pathogens. This study aims to explore the fungistatic effect of thymol on and its mechanism. Different concentrations of thymol were used to treat . The results showed that the EC concentration of thymol against was 40 μg/mL. Compared with the control group, 40 μg/mL of thymol reduced the production of Deoxynivalenol (DON) and 3-Ac-DON by 70.1% and 78.2%, respectively. Our results indicate that thymol can effectively inhibit the growth and toxin production of and cause an extensive transcriptome response. Transcriptome identified 16,727 non-redundant unigenes and 1653 unigenes that COG did not annotate. The correlation coefficients between samples were all >0.941. When FC was 2.0 times, a total of 3230 differential unigenes were identified, of which 1223 were up-regulated, and 2007 were down-regulated. Through the transcriptome, we confirmed that the expression of many genes involved in growth and synthesis of DON and other secondary metabolites were also changed. The gluconeogenesis/glycolysis pathway may be a potential and important way for thymol to affect the growth of hyphae and the production of DON simultaneously.
Topics: Antifungal Agents; Fusarium; Mycelium; Mycotoxins; Thymol; Transcriptome
PubMed: 35202169
DOI: 10.3390/toxins14020142 -
Nutrients Jul 2022Thymol is a natural antibacterial agent found in the essential oil extracted from thyme, which has been proven to be beneficial in food and medicine. Meanwhile, the...
Thymol is a natural antibacterial agent found in the essential oil extracted from thyme, which has been proven to be beneficial in food and medicine. Meanwhile, the NOD-like receptor family pyrin domain-containing 3 (NLRP3) inflammasome and autophagy have been reported to play key roles in the progression of liver injury. However, the effects of thymol on the NLRP3 inflammasome and autophagy in protecting the liver remain unclear. The present study used a mouse model with liver injury induced by lipopolysaccharides (LPS) to investigate the regulatory mechanisms of thymol. We found that thymol alleviated LPS-induced liver structural damage, as judged by reduced inflammatory cell infiltration and improved structure. In addition, elevated levels of the liver damage indicators (alanine transaminase (ALT), aspartate transaminase (AST), and total bilirubin (TBIL)) dropped after thymol administration. The mRNA and protein expression of inflammatory cytokines (tumor necrosis factor (TNF)-α, interleukin (IL)-6, and IL-22), apoptosis-related genes (caspase3 and caspase9), and the activity of apoptosis-related genes (caspase3 and caspase9) were increased in LPS-treated livers, whereas the changes were alleviated after thymol administration. Thymol inhibited LPS-induced increment in lactate dehydrogenase (LDH) activity in primary hepatocytes of the mouse. In addition, thymol protected mice from liver injury by inhibiting NLRP3 inflammasome activation induced by LPS. Mechanistically, the present study indicates that thymol has liver protective activity resulting from the modulation of the AMP-activated protein kinase-mammalian target of rapamycin (AMPK-mTOR) to regulate the autophagy pathway, hence curbing inflammation.
Topics: AMP-Activated Protein Kinases; Animals; Apoptosis; Autophagy; Hepatitis; Inflammasomes; Inflammation; Lipopolysaccharides; Mice; NLR Family, Pyrin Domain-Containing 3 Protein; TOR Serine-Threonine Kinases; Thymol; Tumor Necrosis Factor-alpha
PubMed: 35889766
DOI: 10.3390/nu14142809 -
Frontiers in Cellular and Infection... 2021The incidence of fungal infections has significantly increased in recent years due to the emergence of antifungal resistance. Biofilm formation is considered to be a...
The incidence of fungal infections has significantly increased in recent years due to the emergence of antifungal resistance. Biofilm formation is considered to be a major contributor to both the infectious diseases and to antimicrobial resistance. Consequently, biofilm-associated infections are often problematic to treat with existing therapeutics. Adhesion of to the host surface or implanted materials followed by hyphal invasion and biofilm formation enhances pathogenicity and virulence. Thus, developing a therapeutic agent that inhibits candidal adherence, biofilm development and morphological switching could improve clinical management of infections. The present investigation studied two emerging and alternatives strategies, namely antibiofilm and combinatorial approach, to attenuate biofilm formation and the expression of virulence factors. Piperine and thymol are major bioactive components of pepper and thyme, respectively. These phytochemicals are known to possess numerous biological activities, including recently reported antibiofilm effects against . The minimum biofilm inhibitory concentration (MBIC) of both phytochemicals was determined to be 32 µg/ml. The phytochemical treatment of biofilms using piperine and thymol revealed synergistic effects at four different combinations of concentrations, i.e. 8 and 8, 8 and 4, 8 and 2 and 4 and 8 µg/ml. These synergistic combinations resulted in the significant reduction in adherence of , hyphal extension and morphological transformation. Moreover, limited exposure of synergistic combinations controlled the hyphal elongation. Results were validated through the gene expression analysis. Results from the present investigation suggest that piperine and thymol can be synergistically employed for the treatment of biofilm-associated infection.
Topics: Alkaloids; Antifungal Agents; Benzodioxoles; Biofilms; Candida albicans; Hyphae; Morphogenesis; Piperidines; Polyunsaturated Alkamides; Thymol
PubMed: 35127553
DOI: 10.3389/fcimb.2021.780545 -
Microbiology Spectrum Aug 2022Colistin-resistant (Col-R) bacteria are increasing sharply, which poses a serious threat to public health. Thymol is a phenolic compound used for its wide-spectrum...
Colistin-resistant (Col-R) bacteria are increasing sharply, which poses a serious threat to public health. Thymol is a phenolic compound used for its wide-spectrum antimicrobial activity, while the combination of nontraditional drugs to restore colistin activity is an attractive strategy to treat infections caused by these pathogens. This study showed that thymol could play a synergistic role with colistin against Gram-negative bacteria (GNB), including nonfermenting bacteria and Enterobacteriaceae. According to antimicrobial resistance profiles, most of the colistin-resistant strains we collected showed multidrug-resistant (MDR) phenotypes. The checkerboard method and time-kill curve confirmed the synergistic effect of thymol combined with colistin against Col-R GNB. The synergistic antibiofilm activity of thymol combined with colistin was assessed via crystal violet staining and scanning electron microscopy (SEM) assays. Results showed that compared with a single drug, the combination partially destroyed bacterial cells and inhibit the formation of bacterial biofilms. Mechanismly, the thymol/colistin combination synergistically potentiated the antibacterial activity by accelerating the damage and permeability of the bacterial outer membrane. Preliminary data indicated that the thymol/colistin combination could decrease the number of bacteria ≥2 log CFU/mL after 24 h of therapy in a mouse thigh infection model. Our results fully prove that thymol and colistin combination possesses a promising treatment option against colistin-resistant GNB infections. Colistin is being considered "the last ditch" treatment in many infections caused by multidrug-resistant GNB clinical isolates, but colistin-resistant (Col-R) strains with different drug resistance mechanisms have appeared worldwide. Hence, it is of great significance to rejuvenate sensitization of clinical Col-R Gram-negative bacteria to colistin. In this study, the thymol/colistin combination showed notable antibacterial activity and . These findings suggest that the thymol/colistin combination may have promise as a treatment approach for treating the infections caused by Col-R pathogens.
Topics: Animals; Anti-Bacterial Agents; Colistin; Drug Resistance, Multiple, Bacterial; Gram-Negative Bacteria; Mice; Microbial Sensitivity Tests; Thymol
PubMed: 35700133
DOI: 10.1128/spectrum.00184-22 -
Scientific Reports Apr 2021The present study involved in vivo evaluation of the growth promoting effects of thymol and thymol nanoemulsion and their protection against Salmonella Typhimurium...
The present study involved in vivo evaluation of the growth promoting effects of thymol and thymol nanoemulsion and their protection against Salmonella Typhimurium infection in broilers. One-day old 2400 chicks were randomly divided into eight groups; negative and positive control groups fed basal diet without additives and thymol and thymol nanoemulsion groups (0.25, 0.5 and 1% each). At d 23, all chicks except negative control were challenged with S. Typhimurium. Over the total growing period, birds fed 1% thymol nanoemulsion showed better growth performance even after S. Typhimurium challenge, which came parallel with upregulation of digestive enzyme genes (AMY2A, PNLIP and CCK). Additionally, higher levels of thymol nanoemulsion upregulated the expression of MUC-2, FABP2, IL-10, IgA and tight junction proteins genes and downregulated IL-2 and IL-6 genes expression. Moreover, 1% thymol nanoemulsion, and to lesser extent 0.5% thymol nanoemulsion and 1% thymol, corrected the histological alterations of cecum and liver postinfection. Finally, supplementation of 1% thymol, 0.5 and 1% thymol nanoemulsion led to increased Lactobacilli counts and decreased S. Typhimurium populations and downregulated invA gene expression postinfection. This first report of supplying thymol nanoemulsion in broiler diets proved that 1% nano-thymol is a potential growth promoting and antibacterial agent.
Topics: Animal Feed; Animals; Cecum; Chickens; Emulsions; Gastrointestinal Tract; Intestinal Mucosa; Nanotechnology; Salmonella typhimurium; Thymol; Virulence Factors
PubMed: 33833292
DOI: 10.1038/s41598-021-86990-w -
Scientific Reports Sep 2022The seeds of Trachyspermum ammi were gathered at the ripening stage from different regions of Iran and grouped into 14 populations (P1-P14) accordingly. The essential...
The seeds of Trachyspermum ammi were gathered at the ripening stage from different regions of Iran and grouped into 14 populations (P1-P14) accordingly. The essential oil (EO) extraction yielded in the 3.16-5% range. EOs were analyzed by gas chromatography-flame ionization detection (GC-FID) and gas chromatography-mass spectrometry (GC-MS) and 11 constituents were identified. Thymol (59.92-96.4%), p-cymene (0.55-21.15%), γ-terpinene (0.23-17.78%), and carvacrol (0.41-2.77%) were the major constituents. The highest contents of thymol and carvacrol were found in the Ghayen population (P2). Also, P2 and P8 (Estahban) had the highest value of total phenol (TPC) 43.2 mg gallic acid equivalent (GAE)/g DW, and total flavonoids (TFC) 8.03 mg quercetin equivalent (QE)/g DW, respectively. P1 (Kalat) had the highest total coumarin (TCC) value (0.26 mg coumarin equivalent CE/g DW). Based on EO constituents, principal component analysis (PCA) and cluster analysis classified populations into two chemotypes of thymol/p-cymene/γ-terpinene and thymol/carvacrol. The highest positive correlation coefficient was between α-terpinene and limonene (0.96), while the highest negative correlation was between thymol and p-cymene (-0.984). The antioxidant activities of extracts and EOs were evaluated by phosphomolybdenum (total antioxidant capacity; TAC), diphenylpicrylhydrazyl (DPPH IC), and ferric ion reducing antioxidant power (FRAP) assays. Also, the antimicrobial activity of EOs was studied against Escherichia coli and Staphylococcus aureus. P8 with high thymol, EO content (%v/w), TFC, and antibacterial and antioxidant activities is recommended but further studies are needed to confirm the chemotype introduction.
Topics: Ammi; Anti-Bacterial Agents; Antioxidants; Coumarins; Cyclohexane Monoterpenes; Cymenes; Gallic Acid; Gas Chromatography-Mass Spectrometry; Iran; Limonene; Oils, Volatile; Phenols; Plant Extracts; Quercetin; Seeds; Thymol
PubMed: 36123425
DOI: 10.1038/s41598-022-19594-7 -
Acta Pharmaceutica (Zagreb, Croatia) Sep 2020The aim of this study was to investigate the stability of three major antioxidants of Nigella sativa: thymoquinone (TQ), carvacrol (CR) and thymol (THY), under different...
The aim of this study was to investigate the stability of three major antioxidants of Nigella sativa: thymoquinone (TQ), carvacrol (CR) and thymol (THY), under different stress conditions using HPLC and LC-MS/MS. Forced degradation for each compound was performed under different conditions, including oxidation, hydrolysis, photolysis and thermal decomposition. The results showed that both CR and THY were stable under the studied conditions, whereas TQ was not affected by acidic, basic and oxidative forced conditions but the effect of light and heat was significant. The degradation products of TQ were further investigated and characterized by LC-MS/MS. HPLC-UV method has been fully validated in terms of linearity and range, the limit of detection and quantitation, precision, selectivity, accuracy and robustness. The method was successfully applied to quantitative analysis of the principal antioxidants of Nigella sativa TQ, CR and THY in different phytopharmaceuticals.
Topics: Antioxidants; Benzoquinones; Chromatography, High Pressure Liquid; Chromatography, Liquid; Cymenes; Drug Stability; Nigella sativa; Reproducibility of Results; Spectrometry, Mass, Electrospray Ionization; Tandem Mass Spectrometry; Thymol
PubMed: 32074066
DOI: 10.2478/acph-2020-0028