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Journal of Applied Oral Science :... 2020Natural products have emerged as a rich source of bioactive compounds for adjunctive treatments of many infectious and inflammatory conditions, including periodontitis....
Natural products have emerged as a rich source of bioactive compounds for adjunctive treatments of many infectious and inflammatory conditions, including periodontitis. Among the monoterpenes with significant biological properties, there is the perillyl alcohol (POH), which can be found in several essential oils and has shown immunomodulatory properties in recent studies, which may be interesting in the treatment of non-neoplastic inflammatory disorders. Objective To determine the antibacterial and immune modulatory activities of the POH. Methodology The minimum inhibitory concentration (MIC) and the minimum bactericidal concentration (MBC) of the POH for two significant Gram-negative periodontal pathogens were determined by macrodilution and subculture, respectively. Cell proliferation and cytotoxicity in RAW 264.7 macrophages were determined by Trypan Blue and mitochondrial enzymatic activity assay. The modulation of reactive oxygen species (ROS) was analyzed by flow cytometry and expression of TNF and arginase-1 by real-time PCR. Results The POH was effective against P. gingivalis (ATCC 33277) and F. nucleatum (ATCC 25586) with MIC= MBC=1600 μM. No cytotoxicity up to 100 µM was observed on macrophages. The cell proliferation was inhibited from 48 hours at 100 μM (p<0.05) and 250 μM (p<0.01). The POH increased ROS production at both 10 μM and 100 μM (p<0.05) in unstimulated cells. The PMA-induced ROS production was not affected by POH, whereas 100 μM significantly reduced lipopolysaccharide-induced (LPS-induced) ROS. The expression of TNF was not affected by POH in unstimulated cells or in cells polarized to M1 phenotype, whereas both concentrations of POH reduced (p<0.05) the expression of arginase-1 in M2-polarized macrophages. Conclusion The POH has antibacterial activity against periodontal pathogens and reduced proliferation of murine macrophages without significant cytotoxicity at concentrations up to 100 μM. In addition, the POH reduced the LPS-induced ROS and the expression of arginase-1 in M2-polarized macrophages.
Topics: Animals; Anti-Bacterial Agents; Arginase; Biological Products; Cell Proliferation; Flow Cytometry; Fusobacterium nucleatum; Gene Expression; Lipopolysaccharides; Macrophages; Mice; Microbial Sensitivity Tests; Monoterpenes; Porphyromonas; RAW 264.7 Cells; Reactive Oxygen Species; Real-Time Polymerase Chain Reaction; Reproducibility of Results; Time Factors; Tumor Necrosis Factor-alpha
PubMed: 32348444
DOI: 10.1590/1678-7757-2019-0519 -
International Journal of Molecular... Apr 2021Terpenes-a diverse group of secondary metabolites-constitute the largest class of natural products abundant in almost every plant species. The properties of concrete... (Review)
Review
Terpenes-a diverse group of secondary metabolites-constitute the largest class of natural products abundant in almost every plant species. The properties of concrete terpenes and essential oils have been intensively studied due to their widespread use in the pharmaceutical, food and cosmetics industries. Despite the popularity of these aromatic compounds, their derivatives, terpenoids, are still not comprehensively characterized despite exhibiting potent bioactive properties. This review aims to assess the anticancer properties of selected monoterpenes including carvone, carvacrol, perillyl alcohol, perillaldehyde, limonene, menthol and their derivatives while also evaluating potential applications as novel anticancer treatments. Special attention is paid to functional groups that improve the bioactivity of monoterpene molecules. This review also covers the therapeutic potential of deep eutectic solvents that contain monoterpene substances. Taken together, the literature supports the use of monoterpene derivatives in the development of new alternatives for disease treatment and prevention.
Topics: Animals; Antineoplastic Agents, Phytogenic; Drug Discovery; Humans; Monoterpenes; Neoplasms; Plants
PubMed: 33946245
DOI: 10.3390/ijms22094763 -
Cancers Dec 2022Many patients with acute myeloid leukemia (AML) are still dying from this disease. In the past, the alkylating agent temozolomide (TMZ) has been investigated for AML and...
Many patients with acute myeloid leukemia (AML) are still dying from this disease. In the past, the alkylating agent temozolomide (TMZ) has been investigated for AML and found to be partially effective; however, the presence of O6-methylguanine DNA methyltransferase (MGMT; a DNA repair enzyme) in tumor cells confers profound treatment resistance against TMZ. We are developing a novel anticancer compound, called NEO212, where TMZ was covalently conjugated to perillyl alcohol (a naturally occurring monoterpene). NEO212 has revealed robust therapeutic activity in a variety of preclinical cancer models, including AML. In the current study, we investigated its impact on a panel of human AML cell lines and found that it exerted cytotoxic potency even against MGMT-positive cells that were highly resistant to TMZ. Furthermore, NEO212 strongly stimulated the expression of a large number of macrophage-associated marker genes, including CD11b/ITGAM. This latter effect could not be mimicked when cells were treated with TMZ or an equimolar mix of individual agents, TMZ plus perillyl alcohol. The superior cytotoxic impact of NEO212 appeared to involve down-regulation of MGMT protein levels. In a mouse model implanted with TMZ-resistant, MGMT-positive AML cells, two 5-day cycles of 25 mg/kg NEO212 achieved an apparent cure, as mice survived >300 days without any signs of disease. In parallel toxicity studies with rats, a 5-day cycle of 200 mg/kg NEO212 was well tolerated by these animals, whereas animals that were given 200 mg/kg TMZ all died due to severe leukopenia. Together, our results show that NEO212 exerts pleiotropic effects on AML cells that include differentiation, proliferation arrest, and eventual cell death. In vivo, NEO212 was well tolerated even at dosages that far exceed the therapeutic need, indicating a large therapeutic window. These results present NEO212 as an agent that should be considered for development as a therapeutic agent for AML.
PubMed: 36551551
DOI: 10.3390/cancers14246065 -
Frontiers in Bioengineering and... 2022()-(+)-perillyl alcohol is a much valued supplemental compound with a wide range of agricultural and pharmacological characteristics. The aim of this study was to...
()-(+)-perillyl alcohol is a much valued supplemental compound with a wide range of agricultural and pharmacological characteristics. The aim of this study was to improve ()-(+)-perillyl alcohol production using a whole-cell catalytic formula. In this study, we employed plasmids with varying copy numbers to identify an appropriate strain, strain 03. We demonstrated that low levels of alKL provided maximal biocatalyst stability. Upon determination of the optimal conditions, the ()-(+)-perillyl alcohol yield reached 130 mg/L. For cofactor regeneration, we constructed strain 10, expressing FDH from , and achieved ()-(+)-perillyl alcohol production of 230 mg/L. As a result, 1.23 g/L ()-(+)-perillyl alcohol was transformed in a 5 L fermenter. Our proposed method facilitates an alternative approach to the economical biosynthesis of ()-(+)-perillyl alcohol.
PubMed: 35547170
DOI: 10.3389/fbioe.2022.900800 -
ACS Omega Dec 2021In this contribution, the thermodynamic analysis of α- and β-pinene epoxide isomerization over Fe and Cu supported on MCM-41 is presented using computational chemistry...
In this contribution, the thermodynamic analysis of α- and β-pinene epoxide isomerization over Fe and Cu supported on MCM-41 is presented using computational chemistry and group contribution methods (GCMs). Some physical-chemical data ( , , , , ω, , ) and thermodynamic (°, , , Δ , Δ , Δ , Δ , ) properties obtained by different GCMs are reported for several monoterpenes and monoterpenoids, which significantly contribute to the knowledge of the properties of these compounds. Density functional theory (DFT), PBE-D3/6-311G(d,p), was employed for determining the Gibbs free energy and the heat of reaction associated with the transformation of monoterpene epoxides into aldehydes, ketones, and related oxygenated compounds in the presence of different solvents and at several temperatures. The calculations were compared with available data reported and the experimental results of the catalytic reactions. The transformation of α- and β-pinene epoxides into aldehydes appears to be more spontaneous and favorable than their transformations into alcohols in a wide range of temperatures. These results are in agreement with the experiments over Fe/MCM-41 and Cu/MCM-41, where α-pinene epoxide isomerization yields campholenic aldehyde (50-80% selectivity) as the main product. The 1.7Fe/MCM-41 material was more active in all solvents than 1.3Cu/MCM-41 for both α- and β-pinene epoxide isomerization. However, perillyl alcohol (20-70% selectivity) was the most favored for the isomerization reaction, except when ethyl acetate was the solvent. Enthalpy and Gibbs free energy of the studied reactions estimated by both GCMs and DFT calculations did not show large differences for most of the reactions at evaluated temperatures.
PubMed: 34963907
DOI: 10.1021/acsomega.1c03049 -
Pharmaceutics Nov 2020Therapeutic deep eutectic systems (THEDES) have dramatically expanded their popularity in the pharmaceutical field due to their ability to increase active pharmaceutical...
Therapeutic deep eutectic systems (THEDES) have dramatically expanded their popularity in the pharmaceutical field due to their ability to increase active pharmaceutical ingredients (APIs) bioavailability. However, their biological performance has not yet been carefully scrutinized. Herein, THEDES based on the binary mixture of perillyl alcohol (POH) and ibuprofen (IBU) were prepared using different molar ratios. Our comprehensive strategy includes the characterization of their thermal and structural behavior to identify the molar ratios that successfully form deep eutectic systems. The in vitro solubility of the different systems prepared has demonstrated that, unlike other reported examples, the presence of the terpene did not affect the solubility of the anti-inflammatory agent in a physiological simulated media. The biological performance of the systems was studied in terms of their antimicrobial activity against a wide panel of microorganisms. The examined THEDES showed relevant antimicrobial activity against all tested microbial strains, with the exception of . A synergistic effect from the combination of POH and IBU as a eutectic system was verified. Furthermore, the cytotoxic profile of these eutectic systems towards colorectal cancer (CRC) in vitro cell models was also evaluated. The results provide the indication that the cell viability varies in a dose-dependent manner, with a selective THEDES action towards CRC cells. With tunable bioactivities in a ratio-dependent manner, THEDES enhanced the antimicrobial and anticancer properties, representing a possible alternative to conventional therapies. Therefore, this study provides foreseeable indications about the utility of THEDES based on POH and IBU as strong candidates for novel active pharmaceutical systems.
PubMed: 33233659
DOI: 10.3390/pharmaceutics12111121 -
BMC Biotechnology Jan 2021(R)-(+)-perillyl alcohol is a naturally oxygenated monoterpene widely used as the natural flavor additives, insecticides, jet fuels and anti-cancer therapies. It was...
BACKGROUND
(R)-(+)-perillyl alcohol is a naturally oxygenated monoterpene widely used as the natural flavor additives, insecticides, jet fuels and anti-cancer therapies. It was also readily available monoterpene precursors. However, this natural product is present at low concentrations from plant sources which are not economically viable. Therefore, alternative microbial production methods are rapidly emerging as an attractive alternative to make (R)-(+)-perillyl alcohol production more sustainable and environmentally friendly.
RESULTS
We engineered Escherichia coli to possess a heterologous mevalonate (MVA) pathway, including limonene synthase, P-cymene monoxygenase hydroxylase and P-cymene monoxygenase reductase for the production of (R)-(+)-perillyl alcohol. The concentration of (R)-(+)-limonene (the monoterpene precursor to (R)-(+)-perillyl alcohol) reached 45 mg/L from glucose. Enhanced (R)-(+)-perillyl alcohol production was therefore achieved. The strain produced (R)-(+)-perillyl alcohol at a titer of 87 mg/L and a yield of 1.5 mg/g glucose in a 5 L bioreactor fed batch system.
CONCLUSIONS
These datas highlight the efficient production of (R)-(+)-perillyl alcohol through the mevalonate pathway from glucose. This method serves as a platform for the future production of other monoterpenes.
Topics: Bioreactors; Escherichia coli; Limonene; Metabolic Engineering; Mevalonic Acid; Monoterpenes
PubMed: 33419424
DOI: 10.1186/s12896-020-00662-7 -
ACS Bio & Med Chem Au Feb 2022Increased incidences of fungal infections and associated mortality have accelerated the need for effective and alternative therapeutics. Perillyl alcohol (PA) is a...
Increased incidences of fungal infections and associated mortality have accelerated the need for effective and alternative therapeutics. Perillyl alcohol (PA) is a terpene produced by the hydroxylation of limonene via the mevalonate pathway. In pursuit of an alternative antifungal agent, we studied the effect of PA on the biofilm community of and on different cellular pathways to decipher its mode of action. PA efficiently inhibited growth and eradicated biofilms by reducing carbohydrate and eDNA content in the extracellular matrix. PA reduced the activity of hydrolytic enzymes in the ECM of biofilm. The chemical profiling study has given insights into the overall mode of action of PA in and the marked involvement of the cell wall and membrane, ergosterol biosynthesis, oxidative stress, and DNA replication. The spectroscopic and RT-PCR studies suggested a strong interaction of PA with chitin, β-glucan, ergosterol, and efflux pump, thus indicating increased membrane fluidity in . Furthermore, the microscopic and flow cytometry analysis emphasized that PA facilitated the change in mitochondrial activity, increased Ca influx via overexpression of voltage-gated Ca channels, and enhanced cytochrome C release from mitochondria. In addition, PA interferes with DNA replication and thus hinders the cell cycle progression at the S-phase. All these studies together established that PA mitigates the biofilms by targeting multiple cellular pathways. Interestingly, PA also potentiated the efficacy of azole drugs, particularly miconazole, against and its clinical isolates. Conclusively, the study demonstrated the use of PA as an effective antifungal agent alone or in combination with FDA-approved conventional drugs for fungal biofilm eradication.
PubMed: 37102177
DOI: 10.1021/acsbiomedchemau.1c00034 -
Chemistry (Weinheim An Der Bergstrasse,... Jun 2020Residual dipolar couplings (RDCs) offer additional information for structure elucidation by NMR spectroscopy. They are measured in anisotropic media, such as lyotropic...
Residual dipolar couplings (RDCs) offer additional information for structure elucidation by NMR spectroscopy. They are measured in anisotropic media, such as lyotropic liquid crystalline phases of polypeptides. Today, some suitable polypeptides are known. Nevertheless, structural influences of these polypeptides on the alignment properties are not really understood. Thus, which influence a chiral side chain has on enantiodiscrimination and whether we can improve the enantiodifferentiation significantly by adding an additional chiral center in the side chain are questions of interest. Therefore, new diastereomeric polypeptide-based alignment media with an additional chiral center in the side chain derived from perillyl alcohol were synthesized and their properties were investigated (secondary structure, liquid crystallinity, etc.). The enantiomers of isopinocampheol and β-pinene were used as model analytes for the study of enantiodiscrimination. Additionally, the usage of H- H-RDCs to improve the alignment tensor quality is demonstrated.
PubMed: 32134524
DOI: 10.1002/chem.201905447 -
Memorias Do Instituto Oswaldo Cruz 2023Cerebral malaria (CM) is a severe immunovasculopathy caused for Plasmodium falciparum infection, which is characterised by the sequestration of parasitised red blood...
BACKGROUND
Cerebral malaria (CM) is a severe immunovasculopathy caused for Plasmodium falciparum infection, which is characterised by the sequestration of parasitised red blood cells (pRBCs) in brain microvessels. Previous studies have shown that some terpenes, such as perillyl alcohol (POH), exhibit a marked efficacy in preventing cerebrovascular inflammation, breakdown of the brain-blood barrier (BBB) and brain leucocyte accumulation in experimental CM models.
OBJECTIVE
To analyse the effects of POH on the endothelium using human brain endothelial cell (HBEC) monolayers co-cultured with pRBCs.
METHODOLOGY
The loss of tight junction proteins (TJPs) and features of endothelial activation, such as ICAM-1 and VCAM-1 expression were evaluated by quantitative immunofluorescence. Microvesicle (MV) release by HBEC upon stimulation by P. falciparum was evaluated by flow cytometry. Finally, the capacity of POH to revert P. falciparum-induced HBEC monolayer permeability was examined by monitoring trans-endothelial electrical resistance (TEER).
FINDINGS
POH significantly prevented pRBCs-induced endothelial adhesion molecule (ICAM-1, VCAM-1) upregulation and MV release by HBEC, improved their trans-endothelial resistance, and restored their distribution of TJPs such as VE-cadherin, Occludin, and JAM-A.
CONCLUSIONS
POH is a potent monoterpene that is efficient in preventing P. falciparum-pRBCs-induced changes in HBEC, namely their activation, increased permeability and alterations of integrity, all parameters of relevance to CM pathogenesis.
Topics: Humans; Plasmodium falciparum; Intercellular Adhesion Molecule-1; Endothelial Cells; Vascular Cell Adhesion Molecule-1; Brain; Malaria, Cerebral; Malaria, Falciparum; Monoterpenes; Blood-Brain Barrier; Endothelium, Vascular; Permeability
PubMed: 37403869
DOI: 10.1590/0074-02760230033