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Biochemistry Aug 2023The monoterpene limonene is produced by the enzyme limonene synthase in one of the simplest terpene cyclization reactions. The enzyme can use linalyl diphosphate (LPP)...
The monoterpene limonene is produced by the enzyme limonene synthase in one of the simplest terpene cyclization reactions. The enzyme can use linalyl diphosphate (LPP) and neryl diphosphate (NPP) as substrates in addition to the naturally occurring substrate geranyl diphosphate (GPP), but the relationship among the three alternative substrates is not well understood. We explored the (+)-limonene synthase ((+)-LS) reaction using site-directed mutagenesis with the three different substrates (GPP, NPP, and LPP) to tease out details of the mechanism. In total, 23 amino acid positions in the active site of (+)-LS were targeted for mutation. In all cases, substitution with Ala resulted in a significant loss of enzyme activity using GPP or NPP as the substrate, but the mutations fell into two groups depending on the effect of using LPP as a substrate: group 1 mutations resulted in the loss of activity with all three substrates (GPP, NPP, and LPP); group 2 mutations resulted in loss of activity with GPP and NPP, but retained near-WT activity with LPP as a substrate. Importantly, mutations resulting in loss of activity with LPP but retention of activity with GPP and NPP were never observed. These data, in combination with the substrate order of reactivity for the WT enzyme (LPP > NPP > GPP), are consistent with a role for LPP as an intermediate in the (+)-LS reaction using either GPP or NPP as a substrate.
Topics: Terpenes; Intramolecular Lyases; Limonene; Mutation
PubMed: 37531404
DOI: 10.1021/acs.biochem.3c00217 -
Molecules (Basel, Switzerland) May 2024Cancer is ranked among lethal diseases globally, and the increasing number of cancer cases and deaths results from limited access to effective therapeutics. The use of... (Review)
Review
Cancer is ranked among lethal diseases globally, and the increasing number of cancer cases and deaths results from limited access to effective therapeutics. The use of plant-based medicine has been gaining interest from several researchers. Carvacrol and its isomeric compound, thymol, are plant-based extracts that possess several biological activities, such as antimalarial, anticancer, antifungal, and antibacterial. However, their efficacy is compromised by their poor bioavailability. Thus, medicinal scientists have explored the synthesis of hybrid compounds containing their pharmacophores to enhance their therapeutic efficacy and improve their bioavailability. Hence, this review is a comprehensive report on hybrid compounds containing carvacrol and its isomer, thymol, with potent anticancer and antibacterial agents reported between 2020 and 2024. Furthermore, their structural activity relationship (SAR) and recommended future strategies to further enhance their therapeutic effects will be discussed.
Topics: Thymol; Cymenes; Humans; Anti-Bacterial Agents; Antineoplastic Agents; Structure-Activity Relationship; Neoplasms; Animals
PubMed: 38792138
DOI: 10.3390/molecules29102277 -
Journal of Neurotrauma Mar 2024In this study, we investigated the effects of hinokitiol, a small-molecule natural compound, against neuronal ferroptosis after traumatic brain injury (TBI). A...
In this study, we investigated the effects of hinokitiol, a small-molecule natural compound, against neuronal ferroptosis after traumatic brain injury (TBI). A controlled cortical impact (CCI) mouse model and excess glutamate-treated HT-22 cells were used to study the effects of hinokitiol on TBI. Hinokitiol mitigated TBI brain tissue lesions and significantly improved neurological function. Neuron loss and iron deposition were ameliorated after hinokitiol administration. Hinokitiol alleviated excessive glutamate-induced intracellular reactive oxygen species (ROS), lipid peroxidation, and Fe accumulation in HT-22. Mechanistically, hinokitiol upregulated heme oxygenase-1 (HO-1) expression, promoted nuclear factor-erythroid factor 2-related factor 2 (Nrf2) nuclear translocation, and inhibited the activation of microglia and astrocyte after TBI. These results suggest that hinokitiol has neuroprotective effects on rescuing cells from TBI-induced neuronal ferroptosis. In summary, hinokitiol is a potential therapeutic candidate for TBI by activating the Nrf2/Keap1/HO-1 signaling pathway.
Topics: Animals; Mice; Heme Oxygenase-1; NF-E2-Related Factor 2; Ferroptosis; Kelch-Like ECH-Associated Protein 1; Brain Injuries, Traumatic; Brain Injuries; Glutamic Acid; Neurons; Tropolone; Monoterpenes
PubMed: 37962273
DOI: 10.1089/neu.2023.0150 -
Molecules (Basel, Switzerland) Jul 2023infections are highly common amongst the global population. Such infections have been shown to be the cause of gastric ulcers and stomach carcinoma and, unfortunately,...
infections are highly common amongst the global population. Such infections have been shown to be the cause of gastric ulcers and stomach carcinoma and, unfortunately, most cases are asymptomatic. Standard treatment requires antibiotics such as metronidazole or azithromycin to which many strains are now resistant. species have been used as a natural treatment for gastrointestinal diseases throughout history and essential oils (EOs) derived from these plants show promising results as potential antimicrobial agents. In this study, EOs obtained from the leaves and flowers of five cultivars of × and were examined by GC-MS. The investigated mints are representatives of four chemotypes: the menthol chemotype ( × 'Multimentha' and × 'Swiss'), the piperitenone oxide chemotype ( × 'Almira'), the linalool chemotype ( × 'Granada'), and the carvone chemotype ( 'Moroccan'). The chemical composition of EOs from mint flowers and leaves was comparable with the exception of the Swiss cultivar. Menthol was the most abundant component in the leaves while menthone was highest in flowers. The ATCC 43504 reference strain and 10 other clinical strains were examined for their sensitivity to the EOs in addition to their major monoterpenoid components (menthol, menthone, carvone, dihydrocarvone, linalool, 1,8-cineole, and limonene). All tested mint EOs showed inhibitory activity against both the reference ATCC 43504 strain (MIC 15.6-31.3 mg/L) and clinical strains (MIC 31.3-250 mg/L/62.5-500 mg/L). Among the reference monoterpenes, menthol (MIC 7.8/31.3 mg/L) and carvone (MIC 31.3/62.5 mg/L) had the highest anti- activity, which also correlated with a higher activity of EOs containing these compounds ( × 'Swiss' and 'Moroccan'). A synergistic and additive interaction between the most active EOs/compounds and antibiotics possibly points to a new plant-based anti- treatment.
Topics: Humans; Oils, Volatile; Menthol; Mentha; Helicobacter pylori; Helicobacter Infections; Mentha piperita; Anti-Bacterial Agents
PubMed: 37570659
DOI: 10.3390/molecules28155690 -
Acta Pharmacologica Sinica Aug 2023Epilepsy is one common brain disorder, which is not well controlled by current pharmacotherapy. In this study we characterized the therapeutic potential of borneol, a...
Epilepsy is one common brain disorder, which is not well controlled by current pharmacotherapy. In this study we characterized the therapeutic potential of borneol, a plant-derived bicyclic monoterpene compound, in the treatment of epilepsy and elucidated the underlying mechanisms. The anti-seizure potency and properties of borneol were assessed in both acute and chronic mouse epilepsy models. Administration of (+)-borneol (10, 30, 100 mg/kg, i.p.) dose-dependently attenuated acute epileptic seizure in maximal-electroshock seizure (MES) and pentylenetetrazol (PTZ)-induced seizure models without obvious side-effect on motor function. Meanwhile, (+)-borneol administration retarded kindling-induced epileptogenesis and relieved fully kindled seizures. Importantly, (+)-borneol administration also showed therapeutic potential in kainic acid-induced chronic spontaneous seizure model, which was considered as a drug-resistant model. We compared the anti-seizure efficacy of 3 borneol enantiomers in the acute seizure models, and found (+)-borneol being the most satisfying one with long-term anti-seizure effect. In electrophysiological study conducted in mouse brain slices containing the subiculum region, we revealed that borneol enantiomers displayed different anti-seizure mechanisms, (+)-borneol (10 μM) markedly suppressed the high frequency burst firing of subicular neurons and decreased glutamatergic synaptic transmission. In vivo calcium fiber photometry analysis further verified that administration of (+)-borneol (100 mg/kg) inhibited the enhanced glutamatergic synaptic transmission in epilepsy mice. We conclude that (+)-borneol displays broad-spectrum anti-seizure potential in different experimental models via decreasing the glutamatergic synaptic transmission without obvious side-effect, suggesting (+)-borneol as a promising anti-seizure compound for pharmacotherapy in epilepsy.
Topics: Mice; Animals; Anticonvulsants; Epilepsy; Camphanes; Kindling, Neurologic; Seizures; Disease Models, Animal
PubMed: 36973542
DOI: 10.1038/s41401-023-01075-w -
Fitoterapia Oct 2023Oliveria decumbens Vent., an annual herb resistant to harsh environmental conditions, is an aromatic medicinal plant of the Apiaceae family. O. decumbens has numerous... (Review)
Review
Oliveria decumbens Vent., an annual herb resistant to harsh environmental conditions, is an aromatic medicinal plant of the Apiaceae family. O. decumbens has numerous pharmacological, food and feed, and cosmetic applications. This species is endemic to Iran, Iraq, and Turkey. Published literature, available until 30 November 2022 on the morphology, phytochemistry, and bioactivity of O. decumbens, has been reviewed, and appraised for the potential therapeutic potential of this species, utilizing the databases, Web of Science, Google Scholar, PubMed, and Dictionary of Natural Products. The search term used was O. decumbens. Some manuscripts were issued on the chemical components of O. decumbens essential oil (EO) and various extracts. The EO of O. decumbens was evaluated for its chemical composition and medicinal potential against various diseases. Thymol and carvacrol constituted the primary oxygenated monoterpenes detected in substantial amounts within the EO. Additionally, diverse metabolites of O. decumbens were examined for their bactericidal, antioxidant, larvicidal, and immunomodulatory effects. This review article discusses morphology, phenology, and geographical distribution of O. decumbens and presents a critical appraisal of its phytochemistry and therapeutic potential as documented in the published literature.
Topics: Apiaceae; Molecular Structure; Oils, Volatile; Thymol; Plants, Medicinal; Plant Extracts; Phytochemicals; Ethnopharmacology
PubMed: 37562490
DOI: 10.1016/j.fitote.2023.105647 -
Current Drug Delivery 2024The stratum corneum continues to pose the biggest obstacle to transdermal drug delivery. Chemical penetrant, the first generation of transdermal drug delivery system,... (Review)
Review
The stratum corneum continues to pose the biggest obstacle to transdermal drug delivery. Chemical penetrant, the first generation of transdermal drug delivery system, offers a lot of potential. In order to fully examine the permeation mechanism of 1,8-cineole, a natural monoterpene, this review summarizes the effects of permeation-enhancing medications on drugs that are lipophilic and hydrophilic as well as the toxicity of this substance on the skin and other tissues. For lower lipophilic drugs, 1,8-cineole appears to have a stronger osmotic-enhancing impact. An efficient and secure tactic would be to combine enhancers and dose forms. 1,8-cineole is anticipated to be further developed in the transdermal drug delivery system and even become a candidate drug for brain transport due to its permeability and low toxicity.
Topics: Skin Absorption; Eucalyptol; Drug Delivery Systems; Skin; Administration, Cutaneous; Pharmaceutical Preparations; Permeability
PubMed: 37165499
DOI: 10.2174/1567201820666230509101602 -
Journal of Molecular Medicine (Berlin,... Sep 2023Eucalyptol (EU) is monoterpene oxide that is the main component of the essential oil extracted from aromatic plants such as Eucalyptus globules. EU has therapeutic...
Eucalyptol (EU) is monoterpene oxide that is the main component of the essential oil extracted from aromatic plants such as Eucalyptus globules. EU has therapeutic effects such as antibacterial, anti-inflammatory and antioxidant in chronic diseases including inflammation disorder, respiratory disease, and diabetic disease. However, the effects of EU on osteoblast differentiation and bone diseases such as osteoporosis have not been studied. The present study investigated the effects of EU on osteoblast differentiation and bone formation. EU induces mRNA and protein expression of osteogenic genes in osteoblast cell line MC3T3-E1 and primary calvarial osteoblasts. EU also promoted alkaline phosphatase (ALP) activity and mineralization. Here, the osteoblast differentiation effect of EU is completely reversed by ERK inhibitor. These results demonstrate that osteoblast differentiation effect of EU is mediated by ERK phosphorylation. The efficacy of EU on bone formation was investigated using surgical bone loss-induced animal models. EU dose-dependently promoted bone regeneration in zebrafish caudal fin rays. In the case of ovariectomized mice, EU increased ERK phosphorylation and ameliorated bone loss of femurs. These results indicate that EU ameliorates bone loss by promoting osteoblast differentiation through ERK phosphorylation. We suggest that EU, plant-derived monoterpenoid, may be useful for preventing bone loss. KEY MESSAGES: Eucalyptol (EU) increases osteoblast differentiation in pre-osteoblasts. EU up-regulates the osteogenic genes expression via ERK phosphorylation. EU promotes bone regeneration in partially amputated zebrafish fin rays. Oral administration of EU improves ovariectomy-induced bone loss and increases ERK phosphorylation.
Topics: Female; Mice; Animals; Osteogenesis; Zebrafish; Eucalyptol; Phosphorylation; Cell Differentiation; Osteoblasts
PubMed: 37470800
DOI: 10.1007/s00109-023-02348-x -
Critical Reviews in Food Science and... 2024Extensive use of α-pinene in cosmetics, and medicine, especially for its antioxidant/antibacterial, and anti-cancer properties, and also as a flavoring agent, has made... (Review)
Review
Extensive use of α-pinene in cosmetics, and medicine, especially for its antioxidant/antibacterial, and anti-cancer properties, and also as a flavoring agent, has made it a versatile product. α-Pinene (one of the two pinene isomers) is the most abundant terpene in nature. When extracting α-pinene from plants and, to a lesser extent, fruits, given that its purity is essential, purification methods should also be used as described in this study. Also, an attempt has been made to describe the extraction techniques of α-pinene, carried out by conventional and novel methods. Some disadvantages of conventional methods (such as hydrodistillation or solvent extraction) are being time consuming, low capacity per batch and being labor intensive and the requirement of trained operators. Most novel methods, such as supercritical fluid extraction and microwave-assisted extraction, can reduce the extraction time, cost, and energy compared to conventional methods, and, in fact, the extraction and preservation efficiency of α-pinene in these methods is higher than conventional methods. Although the above-mentioned extraction methods are effective, they still require rather long extraction times. In fact, advanced methods such as green and solvent-free ultrasonic-microwave-assisted extraction are much more efficient than microwave-assisted extraction and ultrasound-assisted extraction because the extraction efficiency and separation of α-pinene in these methods are higher; furthermore, no solvent consumption and maximum extraction efficiency are some crucial advantages of these techniques. However, the application of some novel methods, such as ultrasound-assisted extraction, in industry scale is still problematic because of their intricate design data.
Topics: Bicyclic Monoterpenes; Plant Extracts; Microwaves; Chromatography, Supercritical Fluid; Fruit; Monoterpenes
PubMed: 36384372
DOI: 10.1080/10408398.2022.2140331 -
Journal of Natural Products Mar 2024Oleocanthal is a secoiridoid found in olive oil, which lately gained great scientific interest due to its important pharmacological spectrum and biological properties....
Oleocanthal is a secoiridoid found in olive oil, which lately gained great scientific interest due to its important pharmacological spectrum and biological properties. However, limited data exist on the metabolic fate of oleocanthal , a commonly underestimated aspect in natural products research. Especially, its pharmacokinetic (PK) characteristics have never been described so far. Thus, in the current study, a mouse-based protocol was designed, and oleocanthal was administered intraperitoneally in a standard dose of 5 mg/kg. In order to determine the PK parameters of oleocanthal or its metabolites, plasma samples were collected at 10 time points. Extraction and analysis protocols were developed and applied for the recovery and detection of oleocanthal in plasma, as well as the identification of its metabolites, using LC-HRMS/MS. Oleocanthal was not detected, proving the short lifetime of the compound and 13 metabolites were identified. Among them, oleocanthalic acid and tyrosol sulfate were proposed as oleocanthal's biomarkers, . This is the first report associating oleocanthalic acid with oleocanthal administration , while its PK parameters, Tmax (T0) and Cmax (926 μg/mL), were also determined. The current study enlightens bioavailability and metabolism aspects of oleocanthal and suggests the association of specific metabolites with the biological effects attributed to oleocanthal administration. More studies are needed to give better insights into the metabolism and the mechanism of action of secoiridoids as well as to respond to identification challenges related to secoiridoid setups.
Topics: Animals; Mice; Phenols; Cyclopentane Monoterpenes; Olive Oil; Iridoids; Aldehydes
PubMed: 37910854
DOI: 10.1021/acs.jnatprod.3c00422