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Preclinical development and clinical use of perillyl alcohol for chemoprevention and cancer therapy.American Journal of Cancer Research 2015Perillyl alcohol (POH) is a naturally occurring dietary monoterpene isolated from the essential oils of lavender, peppermint, and other plants. Medical interest in this... (Review)
Review
Perillyl alcohol (POH) is a naturally occurring dietary monoterpene isolated from the essential oils of lavender, peppermint, and other plants. Medical interest in this compound was generated by research findings showing that POH was able to inhibit the growth of tumor cells in cell culture and exert cancer preventive and therapeutic activity in a variety of animal tumor models. Based on this promising preclinical work, POH was formulated in soft gelatine capsules and orally administered to cancer patients several times a day on a continuous basis. However, such clinical trials in humans yielded disappointing results, also because the large number of capsules that had to be swallowed caused hard-to-tolerate intestinal side effects, causing many patients to withdraw from treatment due to unrelenting nausea, fatigue, and vomiting. As a result, efforts to treat cancer patients with oral POH were abandoned and did not enter clinical practice. Intriguingly, clinical trials in Brazil have explored intranasal POH delivery as an alternative to circumvent the toxic limitations of oral administration. In these trials, patients with recurrent malignant gliomas were given comparatively small doses of POH via simple inhalation through the nose. Results from these studies show this type of long-term, daily chemotherapy to be well tolerated and effective. In this review, we will present the vicissitudes of POH's evaluation as an anticancer agent, and its most recent success in therapy of patients with malignant brain tumors.
PubMed: 26175929
DOI: No ID Found -
International Immunopharmacology Feb 2022Psoriasis is a chronic inflammatory and proliferative skin disease characterized by pathological skin lesions which significantly impact the quality of life. Recent...
Psoriasis is a chronic inflammatory and proliferative skin disease characterized by pathological skin lesions which significantly impact the quality of life. Recent studies have been proven that inhibitors of farnesyltransferase enzyme showed significant anti-psoriatic activity. Perillyl alcohol (POH) is one such natural molecule having anti proliferative, anti-inflammatory and anti-oxidant properties by inhibiting farnesyltransferase enzyme which further down regulates NF-κB and STAT3 via Ras/Raf/MAPK pathway. Hence, in the current study we aimed to find the effect of POH on human keratinocytes (HaCat) cells in in-vitro and IMQ induced psoriatic like skin inflammation model in mice. POH significantly decreased the intracellular ROS levels and inhibited the phosphorylation of NF-κB and STAT3 in in-vitro. It was found that POH (200 mg/kg, topical application) has reduced the epidermal hyperplasia, psoriasis area and severity index (PASI) scoring; splenomegaly in imiquimod (IMQ) induced psoriatic mice. Further, POH treatment has decreased the pro-inflammatory serum cytokine levels such as IL-6, IL-12/23, TNF-α and IL-1β and also reduced the expression levels of various inflammatory proteins, COX-2, iNOS, IL-17A, IL-22, NF-кB and STAT3 evidenced by Immunoblotting studies from skin samples. The levels of endogenous antioxidants like glutathione GSH, SOD, Nrf2 were restored to normal levels upon POH treatment. POH downregulated the proteins levels of TLR7, TLR8, CyclinD1 and mRNA expression of Bcl-2 in the skin samples when compared to the IMQ group. POH has ameliorated the hyper-keratosis and acanthosis which was evidenced by histopathology. Collectively, our results suggest that POH has a promising therapeutic application for ameliorating psoriasis-like skin inflammation.
Topics: Animals; Anti-Inflammatory Agents; Cell Proliferation; Cells, Cultured; Humans; Inflammation; Keratinocytes; Male; Mice; Mice, Inbred ICR; Monoterpenes; NF-kappa B; Psoriasis; STAT3 Transcription Factor; Signal Transduction; Skin
PubMed: 34929480
DOI: 10.1016/j.intimp.2021.108436 -
Phytomedicine : International Journal... Mar 2022Rheumatoid arthritis is a chronic and idiopathic autoimmune disorder. Perillyl alcohol (POH) is a monoterpene which can be extracted from widely available essential oils...
Perillyl alcohol attenuates rheumatoid arthritis via regulating TLR4/NF-κB and Keap1/Nrf2 signaling pathways: A comprehensive study onin-vitro and in-vivo experimental models.
BACKGROUND
Rheumatoid arthritis is a chronic and idiopathic autoimmune disorder. Perillyl alcohol (POH) is a monoterpene which can be extracted from widely available essential oils and is known for its strong anti-inflammatory and anti-oxidant properties.
HYPOTHESIS/PURPOSE
Recent studies have been proven that inhibitors of farnesyltransferase enzyme showed significant anti-arthritic activity. POH is one such natural molecule having anti-inflammatory and anti-oxidant properties by inhibiting farnesyltransferase enzyme which further down regulates NF-κB and Nrf2 via Ras/Raf/MAPK pathway. Also, the effect of POH against rheumatoid arthritis is not known yet. Hence, the present research was intended to assess the anti-arthritic potential of POH in-vitro and in-vivo.
METHODS
The in-vitro effects of POH on RAW 264.7 cells stimulated with LPS 1 µg/ml were investigated to its potential therapeutic effects. CFA 100 µl was intradermally administered to rats for the induction of arthritis. POH 100 mg/kg and 200 mg/kg administered topically from day 1 to day 28. Paw volumes measured, radiography analysis, anti-oxidant status, Gene expression studies, western blot analysis and histological analysis were performed to check the effects of POH.
RESULTS
Our in-vitro findings suggested that POH inhibits inflammation by suppressing reactive oxygen species (ROS), NF-кB and Nrf2 signaling axis. Besides this, POH also rescinded the nitrate levels, pro-inflammatory cytokine levels like IL-1β, IL-6 and TNF-α also PGE2 and COX-2 levels induced by LPS in murine macrophages. Additionally, our in-vivo results revealed that POH conscientiously alleviated CFA induced inflammation by restoring arthritis index, body weight, nitrosative, lipid peroxidation assays. Macroscopically through measuring paw volumes and X-ray, it was evidenced that POH has decreased inflammation and bone erosion. Not only in-vitro but also in-vivo, POH has abridged cytokine levels IL-1β, IL-6, and TNF-α. Histopathological evaluation presented POH treatment alleviated joint inflammation, pannus formation, and bone erosion significantly. Moreover, POH suppressed the protein expression of NF-кB, COX-2, iNOS and improved Nrf2, and SOD2 levels in paw tissues estimated by western blotting.
CONCLUSION
POH was effective in ameliorating LPS stimulation mediated oxidative stress and pro-inflammatory cytokines in RAW 264.7 cells in-vitro and FCA induced arthritis in rats in-vivo through its anti-inflammatory effects via regulating TLR4/NF-κB and Keap1/Nrf2 signaling pathways..
Topics: Animals; Arthritis, Experimental; Arthritis, Rheumatoid; Cytokines; Inflammation; Kelch-Like ECH-Associated Protein 1; Lipopolysaccharides; Mice; Models, Theoretical; Monoterpenes; NF-E2-Related Factor 2; NF-kappa B; Rats; Signal Transduction; Toll-Like Receptor 4
PubMed: 35030388
DOI: 10.1016/j.phymed.2022.153926 -
ACS Chemical Neuroscience Jan 2022NLRP3 activation plays a key role in the initiation and progression of a variety of neurodegenerative diseases. However, understanding the molecular mechanisms involved...
NLRP3 activation plays a key role in the initiation and progression of a variety of neurodegenerative diseases. However, understanding the molecular mechanisms involved in the bidirectional signaling required to activate the NLRP3 inflammasomes is the key to treating several diseases. Hence, the present study aimed to investigate the role of lipopolysaccharide (LPS) and hydrogen peroxide (HO) in activating NLRP3 inflammasome-driven neurodegeneration and elucidated the neuroprotective role of perillyl alcohol (PA) in in vitro and in vivo models of Parkinson's disease (PD). Initial priming of microglial cells with LPS following treatment with HO induced NF-κB translocation to the nucleus with a robust generation of free radicals that act as signal 2 in augmenting NLRP3 inflammasome assembly and its downstream targets. PA treatment suppresses the nuclear translocation of NF-κB, enhances PARKIN translocation into the mitochondria, and maintains cellular redox homeostasis in both mouse and human microglial cells that limit NLRP3 inflammasome activation along with processing of active caspase-1, IL-1β, and IL-18. To further correlate the in vitro study with the in vivo MPTP model, treatment with PA also inhibited the nuclear translocation of NF-κB and downregulated the NLRP3 inflammasome activation. PA administration upregulated various antioxidant enzymes' levels and restored the level of dopamine and other neurotransmitters in the striatum of the mouse brain, subsequently improving the behavioral activities. Therefore, we conclude that NLRP3 inflammasome activation required a signal from damaged mitochondria for its activation. Further pharmacological scavenging of free radicals restricts microglia activation and simultaneously supports neuronal survival via targeting the NLRP3 inflammasome pathway in PD.
Topics: Animals; Dopaminergic Neurons; Hydrogen Peroxide; Inflammasomes; Mice; Monoterpenes; NLR Family, Pyrin Domain-Containing 3 Protein; Parkinson Disease
PubMed: 34904823
DOI: 10.1021/acschemneuro.1c00550 -
Biotechnology Advances Nov 2020Limonene and its derivatives have great market potential with diverse applications in food, pharmaceuticals, cosmetics, etc. Commercial production of limonene and its... (Review)
Review
Limonene and its derivatives have great market potential with diverse applications in food, pharmaceuticals, cosmetics, etc. Commercial production of limonene and its derivatives through extraction from plants suffers from the unstable market supply, while chemical synthesis of these compounds is hindered by high energy consumption and pollutant emission. Microbial biosynthesis provides a promising alternative approach for the sustainable supply of limonene and its derivatives. However, low efficiency and specificity of the biosynthetic enzymes and pathways in heterologous hosts make it still challenging for the commercialization of microbial limonene production. On the other hand, the limonene toxicity heavily reduces cellular fitness, which poses a serious challenge for improving limonene titer. Here, we critically review the recent progresses in engineering microbes for limonene biosynthesis and derivation with the emphasis on enzyme characterization and pathway optimization. In particular, we introduce the current trends in microbial limonene decoration for the biosynthesis of bio-active molecules such as α-terpineol and perillyl alcohol. We also discuss the feasible strategies for relieving limonene toxicity and enhancing the robustness of microbial cell factories.
Topics: Cyclohexenes; Limonene; Metabolic Engineering
PubMed: 32882371
DOI: 10.1016/j.biotechadv.2020.107628 -
Biotechnology Letters Mar 2018To investigate the biocatalytic potential of Colletotrichum acutatum and Colletotrichum nymphaeae for monoterpene biotransformation.
OBJECTIVE
To investigate the biocatalytic potential of Colletotrichum acutatum and Colletotrichum nymphaeae for monoterpene biotransformation.
RESULTS
C. acutatum and C. nymphaeae used limonene, α-pinene, β-pinene, farnesene, citronellol, linalool, geraniol, perillyl alcohol, and carveol as sole carbon and energy sources. Both species biotransformed limonene and linalool, accumulating limonene-1,2-diol and linalool oxides, respectively. α-Pinene was only biotransformed by C. nymphaeae producing campholenic aldehyde, pinanone and verbenone. The biotransformation of limonene by C. nymphaeae yielded 3.34-4.01 g limonene-1,2-diol l, depending on the substrate (R-(+)-limonene, S-(-)-limonene or citrus terpene (an agro-industrial by-product). This is among the highest concentrations already reported for this product.
CONCLUSIONS
This is the first report on the biotransformation of these terpenes by Colletotrichum spp. and the biotransformation of limonene to limonene-1,2-diol possibly involves enzymes similar to those found in Grosmannia clavigera.
Topics: Acyclic Monoterpenes; Biotransformation; Carbon; Colletotrichum; Computational Biology; Cyclohexenes; Limonene; Monoterpenes; Plant Oils; Terpenes
PubMed: 29288353
DOI: 10.1007/s10529-017-2503-2 -
Biomedical Chromatography : BMC Apr 2021Perillyl alcohol (POH) is a monocyclic terpene that has strong antitumor activity. Brain tumors are particularly difficult to treat with therapeutic agents, and clinical...
Intranasal administration of perillyl alcohol-loaded nanoemulsion and pharmacokinetic study of its metabolite perillic acid in plasma and brain of rats using ultra-performance liquid chromatography/tandem mass spectrometry.
Perillyl alcohol (POH) is a monocyclic terpene that has strong antitumor activity. Brain tumors are particularly difficult to treat with therapeutic agents, and clinical trials have shown their low tolerance through oral administration. We proposed the entrapment of POH into an oil-in-water chitosan nanoemulsion aiming its intranasal administration for brain targeting. An ultra-performance liquid chromatography/tandem mass spectrometry (UPLC-MS/MS) method was developed and validated for the quantitation of total metabolite perillic acid (PA) in plasma and brain of rats. The rat samples containing the metabolite were treated by liquid-liquid extraction with acetonitrile. The mobile phase was 0.1% formic acid in water (solvent A) and 0.1% formic acid in methanol (solvent B), at a flow rate of 0.3 mL min in gradient elution. The chromatography was run for 10 min, and analytical curves were built in acetonitrile, plasma, and brain. The PA was detected in positive ion mode with multiple reaction monitoring. The method has shown high selectivity, sensitivity, and throughput. The low quantification limits of 162, 178, and 121 ng mL for acetonitrile, brain, and plasma, respectively, indicate a good detectability of the method. The repeatability and precision observed were within the limits recommended in the literature. The accuracy of the method was verified through high recovery rates (106-118%). The validated method was successfully applied to the pharmacokinetic study of the metabolite PA after the intranasal administration of free or POH-loaded nanoemulsion in rats. The results showed that chitosan nanoemulsion improved the plasma and brain bioavailability of POH, representing a promising alternative to free POH treatment.
Topics: Administration, Intranasal; Animals; Brain Chemistry; Chromatography, High Pressure Liquid; Cyclohexenes; Emulsions; Limit of Detection; Linear Models; Monoterpenes; Nanostructures; Rats; Reproducibility of Results; Tandem Mass Spectrometry
PubMed: 33238042
DOI: 10.1002/bmc.5037 -
Journal of Cardiovascular Pharmacology Jun 2021Pulmonary arterial hypertension (PAH) is a pulmonary vascular disease causing right ventricular (RV) hypertrophy, failure, and death. Some miRNAs are involved in the... (Comparative Study)
Comparative Study
Quercetin, Perillyl Alcohol, and Berberine Ameliorate Right Ventricular Disorders in Experimental Pulmonary Arterial Hypertension: Effects on miR-204, miR-27a, Fibrotic, Apoptotic, and Inflammatory Factors.
Pulmonary arterial hypertension (PAH) is a pulmonary vascular disease causing right ventricular (RV) hypertrophy, failure, and death. Some miRNAs are involved in the pathophysiology of PAH. As the current treatments cannot prevent the progression of the disease, we investigated whether 3 plant derivatives, namely perillyl alcohol (PA), quercetin (QS), and berberine (BBR), can improve RV function and affect the expression of miR-204, miR-27a, and biochemical factors in monocrotaline-induced PAH (MCT-PAH). Thirty-six rats were divided into control (CTL), MCT, MCT+Veh (vehicle), MCT+PA, MCT+QS, and MCT + BBR groups (n = 6 each). After inducing PAH using MCT (60 mg/kg), PA (50 mg/kg), QS (30 mg/kg), and BBR (30 mg/kg) were administrated daily for 3 weeks. miR-204 expression, total antioxidant capacity, and antiapoptotic protein Bcl-2 significantly declined in the RV of PAH rats, and PA, QS, and BBR treatment significantly compensated for these decreases. Proapoptotic protein Bax and p21 cell cycle inhibitor increased in the RV. All 3 herbal derivatives compensated for Bax increase, and BBR caused a decrease in p21. TNFα, IL-6, and malondialdehyde increased in the RV, and PA, QS, and BBR significantly counterbalanced these increases. miR-27a expression was not affected by MCT and plant derivatives. Overall, PA, QS, and BBR improved ventricular disorders in rats with PAH by decreasing inflammation, apoptosis, and fibrosis and increasing the antioxidant-to-oxidant ratio. Therefore, these herbal derivatives may be considered as target therapeutic goals for this disease either alone or in combination with current medications.
Topics: Animals; Antioxidants; Apoptosis; Berberine; Disease Models, Animal; Fibrosis; Hypertrophy, Right Ventricular; Male; MicroRNAs; Monocrotaline; Monoterpenes; Pulmonary Arterial Hypertension; Quercetin; Rats; Rats, Wistar; Ventricular Function, Right
PubMed: 34016844
DOI: 10.1097/FJC.0000000000001015 -
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 -
Pharmacological Research Jul 2020Gliomas remain a group of malignant brain tumors with dismal prognosis and limited treatment options with molecular mechanisms being constantly investigated. The past... (Review)
Review
Gliomas remain a group of malignant brain tumors with dismal prognosis and limited treatment options with molecular mechanisms being constantly investigated. The past decade, extracellular stress and intracellular DNA damage have been shown to disturb proteostasis leading to Endoplasmic Reticulum (ER) stress that is implicated in the regulation of gene expression and the pathogenesis of several tumor types, including gliomas. Upon ER stress induction, neoplastic cells activate the adaptive mechanism of unfolded protein response (UPR), an integrated signaling system that either restores ER homeostasis or induces cell apoptosis. Recently, the manipulation of the UPR has emerged as a new therapeutic target in glioma treatment. General UPR activators or selective GRP78, ATF6 and PERK inducers have been detected to modulate cell proliferation and induce apoptosis of glioma cells. At the same time, target-specific UPR inhibitors and small molecule proteostasis disruptors, work in reverse to increase misfolded proteins and cause a dysregulation in protein maturation and sorting, thus preventing the growth of neoplastic cells. Herein, we discuss the pathogenic implication of ER stress in gliomas onset and progression, providing an update on the current UPR modifying agents that can be potentially used in glioma treatment.
Topics: Animals; Antineoplastic Agents; Apoptosis; Brain Neoplasms; Cell Proliferation; Drug Resistance, Neoplasm; Endoplasmic Reticulum; Endoplasmic Reticulum Chaperone BiP; Endoplasmic Reticulum Stress; Glioma; Humans; Proteostasis; Signal Transduction; Unfolded Protein Response
PubMed: 32305494
DOI: 10.1016/j.phrs.2020.104823