-
Advances in Experimental Medicine and... 1996Perillyl alcohol is a natural product from cherries and other edible plants. Perillyl alcohol and d-limonene, a closely related dietary monoterpene, have... (Review)
Review
Perillyl alcohol is a natural product from cherries and other edible plants. Perillyl alcohol and d-limonene, a closely related dietary monoterpene, have chemotherapeutic activity against pancreatic, mammary, and prostatic tumors. In addition, perillyl alcohol, limonene, and other dietary monoterpenes have chemopreventive activity. Several mechanisms may account for the antitumorigenic effects of monoterpenes. For example, many monoterpenes inhibit the post-translational isoprenylation of cell growth-regulatory proteins such as Ras. Perillyl alcohol induces apoptosis without affecting the rate of DNA synthesis in both liver and pancreatic tumor cells. In addition, monoterpene-treated, regressing rat mammary tumors exhibit increased expression of transforming growth factor beta concomitant with tumor remodeling/redifferentiation to a more benign phenotype. Monoterpenes are effective, nontoxic dietary antitumor agents which act through a variety of mechanisms of action and hold promise as a novel class of antitumor drugs for human cancer.
Topics: Animals; Anticarcinogenic Agents; Antineoplastic Agents; Breast Neoplasms; Cyclohexenes; Dietary Fats, Unsaturated; Drug Screening Assays, Antitumor; Humans; Limonene; Monoterpenes; Pancreatic Neoplasms; Terpenes
PubMed: 8886131
DOI: 10.1007/978-1-4613-0399-2_10 -
Phytomedicine : International Journal... Nov 2022Ulcerative colitis (UC) is the most prevalent chronic inflammatory immune bowel disease. The modernization of lifestyle accompanied by the stress to cope with the...
Perillyl alcohol attenuates chronic restraint stress aggravated dextran sulfate sodium-induced ulcerative colitis by modulating TLR4/NF-κB and JAK2/STAT3 signaling pathways.
BACKGROUND
Ulcerative colitis (UC) is the most prevalent chronic inflammatory immune bowel disease. The modernization of lifestyle accompanied by the stress to cope with the competition has resulted in a new range of complications where stress became a critical contributing factor for many diseases, including UC. Hence there is an urgent need to develop a dual role in curtailing both systemic and neuroinflammation. Perillyl alcohol (POH) is a natural essential oil found in lavender, peppermint, cherries etc and has been widely studied for its strong anti-inflammatory, antioxidant and anti-stress properties.
HYPOTHESIS/PURPOSE
POH regulates the various inflammatory signaling cascades involved in chronic inflammation by inhibiting farnesyltransferase enzyme. Several studies reported that POH could inhibit the phosphorylation of NF-κB, STAT3 and promote the endogenous antioxidant enzymes like Nrf2 via farnesyltransferase enzyme inhibition. Also, the effects of POH against UC is not known yet. Thus, this study aims to explore the anti-ulcerative properties of POH on stress aggravated ulcerative colitis in C57BL/6 mice.
METHODS
Ulcerative colitis was induced by duel exposure of chronic restraint stress (day 1 to day 28) and 2.5% dextran sulphate sodium (day8 to day14) in mice. POH treatment 100 and 200 mg/kg was administred from day14 ti day28 following oral route of administration. Disease activity index, colonoscopy, western blot analysis and histological analysis, neurotransmitter analysis and Gene expression studies were perofomerd to asses the anti-colitis effects of POH.
RESULTS
The treatment reversed the oxidative stress and inflammatory response by inhibiting TLR4/NF-kB pathway, and IL-6/JAK2/STAT3 pathway in both isolated mice colons and brains. The inhibition of these pathways resulted in a decrease in pro-inflammatory cytokines like IL-6, IL-1β and TNF-α. The treatment improved the physiological and histological changes with decreased ulcerations as examined by colonic endoscopy and Haematoxylin and Eosin staining. The treatment also improved the behavior response as it increased mobility time which was reduced by chronic restrained stress. This was due to increased satiety neurotransmitters like dopamine and serotonin and decreased cortisol in mice brains.
CONCLUSION
These results infer that POH has significant anti-colitis activity on chronic restraint stress aggravated DSS-induced UC in mice.
Topics: Animals; Anti-Inflammatory Agents; Antioxidants; Colitis, Ulcerative; Cytokines; Dextran Sulfate; Dopamine; Eosine Yellowish-(YS); Farnesyltranstransferase; Hydrocortisone; Interleukin-6; Mice; Mice, Inbred C57BL; Monoterpenes; NF-E2-Related Factor 2; NF-kappa B; Oils, Volatile; Serotonin; Signal Transduction; Toll-Like Receptor 4; Tumor Necrosis Factor-alpha
PubMed: 36070663
DOI: 10.1016/j.phymed.2022.154415 -
Current Medicinal Chemistry Jan 2024Perillyl alcohol (POH) is a monoterpenoid found in plant essential oils and has been shown to relax murine vessels, but its effect on human vessels remains poorly...
BACKGROUND
Perillyl alcohol (POH) is a monoterpenoid found in plant essential oils and has been shown to relax murine vessels, but its effect on human vessels remains poorly studied.
OBJECTIVE
The study aimed to characterize the effect of POH on human umbilical arteries (HUA).
METHODS
Rings of HUA were obtained from uncomplicated patients and suspended in an organ bath for isometric recording. The vasorelaxant effect of POH in HUA was evaluated on basal tone and electromechanical or pharmacomechanical contractions, and possible mechanisms of action were also investigated.
RESULTS
POH (1-1000 μM) altered the basal tone of HUA and completely relaxed HUA rings precontracted with KCl (60 mM) or 5-HT (10 μM), obtaining greater potency in the pharmacomechanical pathway (EC50 110.1 μM), suggesting a complex interference in the mobilization of extra- and intracellular Ca2+. POH (1000 μM) inhibited contractions induced by BaCl2 (0.1-30 mM) in a similar way to nifedipine (10 μM), indicating a possible blockade of L-type VOCC. In the presence of potassium channel blockers, tetraethylammonium (1 mM), 4-aminopyridine (1 mM), or glibenclamide (10 μM), an increase in the EC50 value of the POH was observed, suggesting a modulation of the activity of BKCa, KV, and KATP channels.
CONCLUSION
The data from this study suggest that POH modulates Ca2+ and K+ ion channels to induce a relaxant response in HUA.
PubMed: 38204229
DOI: 10.2174/0109298673269428231204064101 -
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 -
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 -
Child's Nervous System : ChNS :... Jul 2021Inhalation of perillyl alcohol (POH) recently emerged as an investigational promising antiglioma strategy. However, little attention has been paid to its therapeutic...
PURPOSE
Inhalation of perillyl alcohol (POH) recently emerged as an investigational promising antiglioma strategy. However, little attention has been paid to its therapeutic potential for other brain tumors, especially in the pediatric setting.
METHODS
The effects of POH were explored in medulloblastoma cell models belonging to the SHH variant with activation of RAS (ONS-76) or with TP53 mutations (DAOY and UW402), by means of proliferation and invasion assays. Interactions with methotrexate, thiotepa, or ionizing radiation were also assessed. Mice bearing subcutaneous tumors were treated with intraperitoneal injections. Alternatively, animals with intracranial tumors were exposed to intranasal POH alone or combined with radiation. Tumor growth was measured by bioluminescence. Analyses of cytotoxicity to the nasal cavity were also performed, and the presence of POH in the brain, lungs, and plasma was surveyed through chromatography/mass spectrometry.
RESULTS
POH decreased cell proliferation and colony formation, with conspicuous death, though the invasive capacity was only affected in the NRAS-mutated cell line. Median-drug effect analysis displayed synergistic combinations with methotrexate. Otherwise, POH showed to be a reasonable radiosensitizer. In vivo, intraperitoneal injection significantly decreased tumor volume. However, its inhalation did not affect orthotopic tumors, neither alone or followed by cranial irradiation. Nasal cavity epithelium showed unimportant alterations, though, no traces of POH or its metabolites were detected in tissue samples.
CONCLUSION
POH presents robust in vitro antimedulloblastoma effects and sensitizes cell lines to other conventional therapeutics, reducing tumor volume when administered intraperitoneally. Nevertheless, further improvement of delivery devices and/or drug formulations are needed to better characterize its effectiveness through inhalation.
Topics: Animals; Antineoplastic Agents; Cerebellar Neoplasms; Child; Hedgehog Proteins; Humans; Medulloblastoma; Mice; Monoterpenes; Tumor Suppressor Protein p53; ras Proteins
PubMed: 33885911
DOI: 10.1007/s00381-021-05115-w -
Naunyn-Schmiedeberg's Archives of... Jun 2021This research aimed to assess the effect of perillyl alcohol (PA) on convulsive behavior in vivo using adult zebrafish (Danio rerio, both sexes). The seizures were... (Comparative Study)
Comparative Study
This research aimed to assess the effect of perillyl alcohol (PA) on convulsive behavior in vivo using adult zebrafish (Danio rerio, both sexes). The seizures were induced with pentylenetetrazole (PTZ) intraperitoneally at 170 mg/kg, and diazepam (DZP) was used as the control anticonvulsant (2 mg/kg, oral); PA was tested at 10, 50, and 100 mg/kg orally. The groups had ten animals per group (total n = 60), observed for 10 minutes after seizure induction. We manually appraised typical seizure phenotypes for quantification and used an animal tracking software (Toxtrac) to assess the motor parameters. Next, we sought to find a mechanism of action for PA anticonvulsant activity in silico using a structure-based activity prediction server and molecular docking. The results show that PTZ induced seizure-like behavior in all untreated animals with hyperlocomotion episodes, seizure itself, posture loss, and immobility. DZP inhibited the seizures in all animals of the positive control group. PA, in turn, inhibited the occurrence of seizures in a dose-dependent manner, with frequencies of 90%, 70%, and 40% (for 10, 50, and 100 mg/kg, respectively). The PA treatments also decreased several seizure endpoints in a dose-dependent manner. Also, the difference of the group treated with highest dose of PA was statistically significant compared with the negative control group for all the endpoints assessed (p < 0.05, Kruskal-Wallis). The in silico analyses suggested that PA can affect the GABAergic system, which might be involved in its anticonvulsant activity, but other mechanisms cannot be ruled out. Overall, our results suggest an anticonvulsant potential in perillyl alcohol.
Topics: Animals; Anticonvulsants; Behavior, Animal; Diazepam; Disease Models, Animal; Dose-Response Relationship, Drug; Female; Male; Molecular Docking Simulation; Monoterpenes; Patient Acuity; Pentylenetetrazole; Seizures; Zebrafish
PubMed: 33515278
DOI: 10.1007/s00210-021-02050-0 -
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 -
Antiviral Therapy 2020Infection by herpes simplex type-1 virus (HSV-1) causes several pathological processes, including cutaneous, oral and genital infections, fatal encephalitis and...
BACKGROUND
Infection by herpes simplex type-1 virus (HSV-1) causes several pathological processes, including cutaneous, oral and genital infections, fatal encephalitis and cognitive dysfunction due to grey matter loss. Acyclovir is the reference compound used as HSV-1 antiviral therapy. However, with the emergence of HSV-resistant strains to current antiviral drugs, development of new antiviral agents with distinct modes of action is urgently needed.
METHODS
In this study, we examined the mechanism of action of monoterpenes perillyl alcohol (POH) and perillic acid (PA) upon in vitro replication of HSV-1 KOS wild-type and the syn-mutant 17+ strain on Vero cells by plaque assay.
RESULTS
The cytotoxicity of POH and PA was measured by MTT assay and indicated that both compounds had high anti-HSV-1 activities in a concentration range that was not toxic for Vero cells. In addition, PCR analysis showed that POH and PA did not inhibit viral genome replication, but rather the release of infective virion particles from Vero cells.
CONCLUSIONS
Such findings suggest that POH and PA exert action upon late stages of HSV-1 maturation, therefore, indicating a promising perspective to its application in clinical investigation as effective anti-HSV-1 therapy preventing intermittent reactivation and progressive grey matter loss.
Topics: Animals; Antiviral Agents; Blotting, Western; Chlorocebus aethiops; Cyclohexenes; Herpesvirus 1, Human; Monoterpenes; Real-Time Polymerase Chain Reaction; Vero Cells; Viral Plaque Assay; Virus Shedding
PubMed: 31099756
DOI: 10.3851/IMP3315 -
Cancer Research Sep 2005The cell death induced by the monoterpene anticancer agent perillyl alcohol correlates to the increased expression of certain proapoptotic genes known to influence cell...
The cell death induced by the monoterpene anticancer agent perillyl alcohol correlates to the increased expression of certain proapoptotic genes known to influence cell survival. Whereas sequence-specific DNA-binding factors dictate the expression patterns of genes through transcriptional regulation, those transcriptional factors influencing constitutive cell survival with perillyl alcohol treatment are not well studied. Here, we investigated whether the monoterpenes can regulate the activity of nuclear factor-kappaB (NF-kappaB), a calcium-dependent transcription factor necessary for survival in the WEHI-231 B-lymphoma cells. Unique among the monoterpenes, perillyl alcohol short-term treatment induced a persistent decrease of calcium levels, whereas other various monoterpenes caused transient reductions in calcium levels. Perillyl alcohol treatment also rapidly elicited reductions of NF-kappaB DNA-binding activity and target gene induction, which was associated with an increase in apoptosis in these B-lymphoma cells. This apoptosis was directly due to NF-kappaB because its prior activation abolished the cell killing effects of perillyl alcohol treatment. Our findings suggest that perillyl alcohol can inhibit NF-kappaB function to modulate gene expression patterns and cell survival of certain B-lymphoma cells. The effects of perillyl alcohol were not limited to these B-lymphoma cells but were also observed in MDA-MB 468 cells, an estrogen receptor-negative breast cancer cell line. These results identify a calcium-dependent NF-kappaB pathway as a molecular target of perillyl alcohol activity in different cancer cell types.
Topics: Antineoplastic Agents; Apoptosis; Breast Neoplasms; Calcium; Calcium Channel Blockers; Calcium Channels, L-Type; Cell Line, Tumor; Humans; Lymphoma, B-Cell; Monoterpenes; NF-kappa B
PubMed: 16166337
DOI: 10.1158/0008-5472.CAN-04-4072