-
Engineering in Life Sciences May 2022()-(+)-perillyl alcohol is widely used in agricultural and anticarcinogenic fields. Microbial production of ()-(+)-perillyl alcohol was investigated in this study. We...
()-(+)-perillyl alcohol is widely used in agricultural and anticarcinogenic fields. Microbial production of ()-(+)-perillyl alcohol was investigated in this study. We optimized biosynthesis of ()-(+)-perillyl alcohol in by using neryl pyrophosphate synthase and NADPH regeneration. Engineering neryl pyrophosphate (NPP)-supplied pathway resulted in a 4-fold improvement of ()-(+)-perillyl alcohol titer. Subsequently, combined engineering of p-cymene monooxygenase () expression and module for NADPH regeneration exhibited a 15.4-fold increase of titer over the initial strain S02. Finally, 453 mg/L ()-(+)-perillyl alcohol was achieved in fed-batch fermentation, which is the highest ()-(+)-perillyl alcohol titer in .
PubMed: 35573132
DOI: 10.1002/elsc.202100135 -
PloS One 2016This study explored the antifungal potential of perillyl alcohol (PA), a natural monoterpene alcohol, against most prevalent human fungal pathogen C. albicans, its...
This study explored the antifungal potential of perillyl alcohol (PA), a natural monoterpene alcohol, against most prevalent human fungal pathogen C. albicans, its clinical isolates and four non-albicans species of Candida. To resolve the potential mechanisms, we used whole genome transcriptome analyses of PA treated Candida cells to examine the affected cellular circuitry of this pathogen. The transcriptome data revealed a link between calcineurin signaling and PA as among the several categories of PA responsive genes the down regulation of calcineurin signaling gene CNB1 was noteworthy which was also confirmed by both molecular docking and susceptibility assays. We observed that PA treated Candida phenocopied compromised calcineurin pathway stress responses and turned sensitive to alkaline pH, ionic, membrane, salinity, endoplasmic reticulum and serum stresses. Indispensability of functional calcineurin was further confirmed as calcineurin mutant was hypersensitive to PA while constitutively expressed calcineurin strain remained resistant. We explored that PA leads to perturbed membrane integrity as depicted through depleted ergosterol levels and disrupted pH homeostasis. Moreover, PA caused cell wall damage which was evident from hypersensitivity against cell wall perturbing agents (congo red, calcoflour white), SEM and enhanced rate of cell sedimentation. Furthermore, PA inhibited potential virulence traits including morphological transition, biofilm formation and displayed diminished capacity to adhere both to the polystyrene surface and buccal epithelial cells. The study also revealed that PA leads to cell cycle arrest and mitochondrial dysfunction in C. albicans. Together, the present study provides enough evidence for further work on PA so that better strategies could be employed to treat Candida infections.
Topics: Antifungal Agents; Biofilms; Calcineurin; Candida albicans; Cell Membrane; DNA Repair; Mitochondria; Monoterpenes; Morphogenesis; Signal Transduction; Transcriptome
PubMed: 27627759
DOI: 10.1371/journal.pone.0162465 -
Molecules (Basel, Switzerland) Jun 2018The present study used isometric tension recording to investigate the vasorelaxant effect of limonene (LM), carveol (CV), and perillyl alcohol (POH) on contractility...
The present study used isometric tension recording to investigate the vasorelaxant effect of limonene (LM), carveol (CV), and perillyl alcohol (POH) on contractility parameters of the rat aorta, focusing in particular on the structure-activity relationship. LM, CV, and POH showed a reversible inhibitory effect on the contraction induced by electromechanical and pharmacomechanical coupling. In the case of LM, but not CV and POH, this effect was influenced by preservation of the endothelium. POH and CV but not LM exhibited greater pharmacological potency on BayK-8644-induced contraction and on electromechanical coupling than on pharmacomechanical coupling. In endothelium-denuded preparations, the order of pharmacological potency on electrochemical coupling was LM < CV < POH. These compounds inhibited also, with grossly similar pharmacological potency, the contraction induced by phorbol ester dibutyrate. The present results suggest that LM, CV and POH induced relaxant effect on vascular smooth muscle by means of different mechanisms likely to include inhibition of PKC and IP3 pathway. For CV and POH, hydroxylated compounds, it was in electromechanical coupling that the greater pharmacological potency was observed, thus suggesting a relative specificity for a mechanism likely to be important in electromechanical coupling, for example, blockade of voltage-dependent calcium channel.
Topics: 3-Pyridinecarboxylic acid, 1,4-dihydro-2,6-dimethyl-5-nitro-4-(2-(trifluoromethyl)phenyl)-, Methyl ester; Animals; Aorta, Thoracic; Cyclohexane Monoterpenes; Cyclohexenes; Isometric Contraction; Limonene; Molecular Structure; Monoterpenes; Muscle, Smooth, Vascular; Phenylephrine; Phorbol 12,13-Dibutyrate; Rats; Structure-Activity Relationship; Terpenes; Vasodilator Agents
PubMed: 29899230
DOI: 10.3390/molecules23061430 -
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 -
Journal of Neurosurgery. Case Lessons Aug 2022Intranasal delivery of NEO100, a pharmaceutical-grade version of the natural monoterpene perillyl alcohol (POH), is undergoing clinical phase IIa testing as a treatment...
BACKGROUND
Intranasal delivery of NEO100, a pharmaceutical-grade version of the natural monoterpene perillyl alcohol (POH), is undergoing clinical phase IIa testing as a treatment for glioblastoma (GBM). However, so far there is no evidence that intranasal delivery of NEO100 indeed results in POH reaching intracranial malignancies in a patient.
OBSERVATIONS
After surgical removal of her recurrent GBM tumor, a patient received daily intranasal NEO100 therapy for more than 3 years before a second recurrence emerged. At that time, a final dose of NEO100 was given shortly before the tumor tissue was surgically removed, and the tissue was processed for high-performance liquid chromatography analysis of POH and its primary metabolite, perillic acid (PA). Both molecules could readily be detected in the tumor tissue.
LESSONS
This is the first demonstration of POH and PA in brain tumor tissue from any patient. It reveals that intranasal administration of NEO100 is a valid approach to achieve delivery of this agent to a brain tumor. In view of the noninvasive and safe nature of this method, along with tentative indications of activity, our findings add confidence to the notion that intranasal administration of NEO100 holds potential as a new treatment option for brain-localized malignancies.
PubMed: 36088606
DOI: 10.3171/CASE22215 -
Archivum Immunologiae Et Therapiae... Feb 2014Perillyl alcohol (POH) presents antitumoral activity but clinical application is hampered by adverse effects following oral administration. This work aimed to verify the...
Perillyl alcohol (POH) presents antitumoral activity but clinical application is hampered by adverse effects following oral administration. This work aimed to verify the cytotoxic effect of intranasal POH administration in the histology of lung, liver, brain; the cellularity and function of peripheral and bronchoalveolar-associated immune system. C57 adult mice received 1-min inhalation with POH, vehicle 70 % ethanol or saline buffer, once (84 μg/day) or twice (164 μg/day) during five consecutive days, and were killed 72 h after treatment. Spleen, cervical and mesenteric lymph nodes were removed for (3)H-thymidine proliferation assay, leukocyte cellularity and flow cytometry analysis. Peripheral blood and bronchoalveolar lavage cells were collected to assess cellularity and immunoglobulin (IgA, IgM) levels. Intranasal POH did not alter body weight or liver, brain and lung morphology, but increased splenocyte and cervical lymph node cell proliferation, and IgM production without altering peripheral lymphocyte subsets. Treatment also increased the percentage of alveolar macrophages (83 %) and IgA-producing lymphocytes (15 %), a pattern characteristic of activated bronchoalveolar innate immune system. Intranasal administration of POH activated peripheral immune system and innate immunity of bronchus-associated lymphoid tissue, thus suggesting a possible role for POH as a chemotherapeutic drug also in pathological processes affecting the lung.
Topics: Administration, Intranasal; Animals; Antineoplastic Agents; B-Lymphocytes; Bronchi; Bronchoalveolar Lavage Fluid; Cells, Cultured; Female; Immune System; Immunity, Innate; Immunoglobulin A; Immunoglobulin M; Lung Diseases; Lung Neoplasms; Lymphocyte Activation; Macrophages, Alveolar; Male; Mice; Mice, Inbred C57BL; Monoterpenes
PubMed: 24257817
DOI: 10.1007/s00005-013-0262-x -
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 -
Journal of Experimental & Clinical... Oct 2018Temozolomide-perillyl alcohol conjugate (TMZ-POH), a novel Temozolomide (TMZ) analog developed based on the conjugation of TMZ and perillyl alcohol (POH), displayed...
BACKGROUND
Temozolomide-perillyl alcohol conjugate (TMZ-POH), a novel Temozolomide (TMZ) analog developed based on the conjugation of TMZ and perillyl alcohol (POH), displayed strong anticancer potency in multiple cancer types. In this study, we aimed to clarify the relationship between TMZ-POH and autophagy, and explore the underlying mechanisms involved in.
METHODS
The proteins involved in autophagy, mitochondrial fission, lysosomal function and membrane traffic were detected by western blots; Autophagosome, mitochondria and lysosome were visualized by transmission electron microscope (TEM) and immunostaining; Apoptosis analysis and fluorescence probe detection were applied by flow cytometry.
RESULTS
TMZ-POH blocked mitophagy flux although the number of autophagosomes which colocalized with mitochondria in the cells was increased via inducing lysosomal dysfunction as evidence from impaired lysosomal acidification, maturation and hampered autophagosome- lysosome fusion, which largely depended on its downregulation on the small GTPase RAB7A via mevalonate pathway. More importantly, our data demonstrated TMZ-POH sensitized cancer cell to irradiation induced apoptosis.
CONCLUSIONS
Temozolomide-perillyl alcohol conjugate impairs mitophagy flux by inducing lysosomal dysfunction in Non-Small Cell Lung Cancer (NSCLC) cells and sensitizes them to irradiation, thereby proposing TMZ-POH as a potential radiosensitizer.
Topics: Antineoplastic Agents, Alkylating; Carcinoma, Non-Small-Cell Lung; Cell Line, Tumor; Humans; Lung Neoplasms; Lysosomes; Mitophagy; Monoterpenes; Radiation-Sensitizing Agents; Temozolomide
PubMed: 30326943
DOI: 10.1186/s13046-018-0905-1 -
Anti-cancer Drugs Jan 2010Breast cancer is the second leading cause of cancer deaths among women in the United States. Several treatment options exist, with different side effects. To alleviate...
Breast cancer is the second leading cause of cancer deaths among women in the United States. Several treatment options exist, with different side effects. To alleviate the side effects, several research groups have studied chemotherapeutic effects of plant compounds on cancer cells. These could be used as an alternative treatment option either alone or in combination with other chemotherapeutic drugs. The aim of this study was to evaluate the activity of a combination of perillyl alcohol (POH), methyl jasmonate (MJ) with cisplatin to define the most effective schedule and to investigate the mechanism of action in breast cancer cells. POH and MJ treatment (20% decrease in cell viability concentration) enhanced the cytotoxicity for subsequent exposure to cisplatin in MDA-MB-435 and MDA-MB-231 cells. Combination treatment of POH and MJ blocked cells at the G0/G1 phase of the cell cycle and the addition of cisplatin forced the cells to progress through the cell cycle and induced apoptosis. Apoptotic mechanistic studies indicated that POH and MJ treatment activated tumor necrosis factor receptor 1 and this was further increased by the addition of cisplatin. It was also found that mitochondrial membrane potential decreased with POH and MJ treatment; this effect was further enhanced by cisplatin treatment. These findings contributed to a better understanding of molecular mechanism of apoptosis in combination treatment of POH, MJ, and cisplatin. Results also showed that the combination treatment of three drugs is more effective than single drug alone or two drugs together.
Topics: Acetates; Antineoplastic Agents; Apoptosis; Breast Neoplasms; Cell Culture Techniques; Cell Cycle; Cell Line, Tumor; Cell Proliferation; Cell Survival; Cisplatin; Cyclopentanes; Drug Synergism; Female; Flow Cytometry; Humans; Membrane Potential, Mitochondrial; Monoterpenes; Oxylipins; Receptors, Tumor Necrosis Factor, Type I; Tumor Necrosis Factor-alpha; Tumor Stem Cell Assay
PubMed: 19820395
DOI: 10.1097/CAD.0b013e32832a68ad -
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