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BMC Cancer Apr 2020Polymorphisms in MTHFR gene influence risk and overall survival of patients with brain tumor. Global genomic DNA (gDNA) methylation profile from tumor tissues is... (Clinical Trial)
Clinical Trial
BACKGROUND
Polymorphisms in MTHFR gene influence risk and overall survival of patients with brain tumor. Global genomic DNA (gDNA) methylation profile from tumor tissues is replicated in peripheral leukocytes. This study aimed to draw a correlation between rs1801133 MTHFR variants, gDNA methylation and overall survival of patients with recurrent glioblastoma (rGBM) under perillyl alcohol (POH) treatment.
METHODS
gDNA from whole blood was extracted using a commercially available kit (Axygen) and quantified by spectrophotometry. Global gDNA methylation was determined by ELISA and rs1801133 polymorphism by PCR-RFLP. Statistical analysis of gDNA methylation profile and rs1801133 variants included Mann-Whitney, Kruskal-Wallis, Spearman point-biserial correlation tests (SPSS and Graphpad Prism packages; significant results for effect size higher than 0.4). Prognostic value of gDNA methylation and rs1801133 variants considered survival profiles at 25 weeks of POH treatment, having the date of protocol adhesion as starting count and death as the final event.
RESULTS
Most rGBM patients showed global gDNA hypomethylation (median = 31.7%) and a significant, moderate and negative correlation between TT genotype and gDNA hypomethylation (median = 13.35%; rho = - 0.520; p = 0.003) compared to CC variant (median = 32.10%), which was not observed for CT variant (median = 33.34%; rho = - 0.289; p = 0.06). gDNA hypermethylated phenotype (median = 131.90%) exhibited significant, moderate and negative correlations between TT genotype (median = 112.02%) and gDNA hypermethylation levels when compared to CC (median = 132.45%; rho = - 0,450; p = 0.04) or CT (median = 137.80%; rho = - 0.518; p = 0.023) variants. TT variant of rs1801133 significantly decreased gDNA methylation levels for both patient groups, when compared to CC (d values: hypomethylated = 1.189; hypermethylated = 0.979) or CT (d values: hypomethylated = 0.597; hypermethylated = 1.167) variants. Positive prognostic for rGBM patients may be assigned to gDNA hypermethylation for survivors above 25 weeks of treatment (median = 88 weeks); and TT variant of rs1801133 regardless POH treatment length.
CONCLUSION
rGBM patients under POH-based therapy harboring hypermethylated phenotype and TT variant for rs1801133 had longer survival. Intranasal POH therapy mitigates detrimental effects of gDNA hypomethylation and improved survival of patients with rGBM harboring TT mutant variant for MTHFR rs1801133 polymorphism.
TRIAL REGISTRATION
CONEP -9681- 25,000.009267 / 2004. Registered 12th July, 2004.
Topics: Administration, Intranasal; Adolescent; Adult; Aged; Antineoplastic Agents; Biomarkers, Tumor; Brain Neoplasms; DNA Methylation; Female; Glioblastoma; Humans; Leukocytes; Male; Methylenetetrahydrofolate Reductase (NADPH2); Middle Aged; Monoterpenes; Neoplasm Recurrence, Local; Polymorphism, Single Nucleotide; Young Adult
PubMed: 32264844
DOI: 10.1186/s12885-020-06802-8 -
ACS Sustainable Chemistry & Engineering May 2024Photocurable liquid formulations have been a key research focus for the preparation of mechanically robust and thermally stable networks. However, the development of...
Photocurable liquid formulations have been a key research focus for the preparation of mechanically robust and thermally stable networks. However, the development of renewable resins to replace petroleum-based commodities presents a great challenge in the field. From this perspective, we disclose the design of photoactive resins based on terpenes and itaconic acid, both potentially naturally sourced, to prepare photosets with adjustable thermomechanical properties. Biobased perillyl itaconate (PerIt) was synthesized from renewable perillyl alcohol and itaconic anhydride via a scalable solvent-free method. Photoirradiation of PerIt in the presence of a multiarm thiol and photoinitiator led to the formation of networks over a range of compositions. Addition of nonmodified terpenes (perillyl alcohol, linalool, or limonene) as reactive diluents allowed for more facile preparation of photocured networks. Photosets within a wide range of properties were accessed, and these could be adjusted by varying diluent type and thiol stoichiometry. The resins showed rapid photocuring kinetics and the ability to form either brittle or elastic materials, with Young's modulus and strain at break ranging from 3.6 to 358 MPa and 15 to 367%, respectively, depending on the chemical composition of the resin. Glass transition temperatures () were influenced by thioether content, with temperatures ranging from 5 to 43 °C, and all photosets displayed good thermal resistance with > 190 °C. Selected formulations containing PerIt and limonene demonstrated suitability for additive manufacturing technologies and high-resolution objects were printed via digital light processing (DLP). Overall, this work presents a simple and straightforward route to prepare renewable resins for rapid prototyping applications.
PubMed: 38725455
DOI: 10.1021/acssuschemeng.3c08191 -
Pharmaceutics Feb 2021The low solubility and high volatility of perillyl alcohol (POH) compromise its bioavailability and potential use as chemotherapeutic drug. In this work, we have...
The low solubility and high volatility of perillyl alcohol (POH) compromise its bioavailability and potential use as chemotherapeutic drug. In this work, we have evaluated the anticancer activity of POH complexed with β-cyclodextrin (β-CD) using three complexation approaches. Molecular docking suggests the hydrogen-bond between POH and β-cyclodextrin in molar proportion was 1:1. Thermal analysis and Fourier-transform infrared spectroscopy (FTIR) confirmed that the POH was enclosed in the β-CD cavity. Also, there was a significant reduction of particle size thereof, indicating a modification of the β-cyclodextrin crystals. The complexes were tested against human L929 fibroblasts after 24 h of incubation showing no signs of cytotoxicity. Concerning the histopathological results, the treatment with POH/β-CD at a dose of 50 mg/kg promoted approximately 60% inhibition of tumor growth in a sarcoma S180-induced mice model and the reduction of nuclear immunoexpression of the Ki67 antigen compared to the control group. Obtained data suggest a significant reduction of cycling cells and tumor proliferation. Our results confirm that complexation of POH/β-CD not only solves the problem related to the volatility of the monoterpene but also increases its efficiency as an antitumor agent.
PubMed: 33578857
DOI: 10.3390/pharmaceutics13020245 -
BMC Complementary Medicine and Therapies Jul 2020Pulmonary artery hypertension (PAH) is a vascular disease in the lung characterized by elevated pulmonary arterial pressure (PAP). Many miRNAs play a role in the...
Perillyle alcohol and Quercetin ameliorate monocrotaline-induced pulmonary artery hypertension in rats through PARP1-mediated miR-204 down-regulation and its downstream pathway.
BACKGROUND
Pulmonary artery hypertension (PAH) is a vascular disease in the lung characterized by elevated pulmonary arterial pressure (PAP). Many miRNAs play a role in the pathophysiology of PAH. Perillyle alcohol (PA) and Quercetin (QS) are plant derivatives with antioxidant and anti-proliferative properties. We investigated the effect of PA and QS on PAP, expression of PARP1, miR-204, and their targets, HIF1α and NFATc2, in experimental PAH.
METHODS
Thirty rats were divided into control, MCT, MCT + Veh, MCT + PA and MCT + QS groups. MCT (60 mg/kg) was injected subcutaneously to induce PAH. PA (50 mg/kg daily) and QS (30 mg/kg daily) were administered for 3 weeks after inducing PAH. PAP, lung pathology, expression of miRNA and mRNA, and target proteins were evaluated through right ventricle cannulation, H&E staining, real-time qPCR, and western blotting, respectively.
RESULTS
Inflammation and lung arteriole thickness in the MCT group increased compared to control group. PA and QS ameliorated inflammation and reduced arteriole thickness significantly. miR-204 expression decreased in PAH rats (p < 0.001). PA (p < 0.001) and QS (p < 0.01) significantly increased miR-204 expression. Expression of PARP1, HIF1α, NFATc2, and α-SMA mRNA increased significantly in MCT + veh rats (all p < 0.001), and these were reduced after treatment with PA and QS (both p < 0.01). PA and QS also decreased the expression of PARP1, HIF1α, and NFATc2 proteins that had increased in MCT + Veh group.
CONCLUSION
PA and QS improved PAH possibly by affecting the expression of PARP1 and miR-204 and their downstream targets, HIF1a and NFATc2. PA and QS may be therapeutic goals in the treatment of PAH.
Topics: Animals; Disease Models, Animal; Down-Regulation; Hypertension, Pulmonary; Hypertrophy, Right Ventricular; Hypoxia-Inducible Factor 1, alpha Subunit; Male; MicroRNAs; Monocrotaline; Monoterpenes; NFATC Transcription Factors; Poly (ADP-Ribose) Polymerase-1; Pulmonary Artery; Quercetin; Rats; Rats, Wistar
PubMed: 32660602
DOI: 10.1186/s12906-020-03015-1 -
Neuro-oncology Advances 2020NEO212 is a novel small-molecule anticancer agent that was generated by covalent conjugation of the natural monoterpene perillyl alcohol (POH) to the alkylating agent...
BACKGROUND
NEO212 is a novel small-molecule anticancer agent that was generated by covalent conjugation of the natural monoterpene perillyl alcohol (POH) to the alkylating agent temozolomide (TMZ). It is undergoing preclinical development as a therapeutic for brain-localized malignancies. The aim of this study was to characterize metabolism and pharmacokinetic (PK) properties of NEO212 in preclinical models.
METHODS
We used mass spectrometry (MS) and modified high-performance liquid chromatography to identify and quantitate NEO212 and its metabolites in cultured glioblastoma cells, in mouse plasma, brain, and excreta after oral gavage.
RESULTS
Our methods allowed identification and quantitation of NEO212, POH, TMZ, as well as primary metabolites 5-aminoimidazole-4-carboxamide (AIC) and perillic acid (PA). Intracellular concentrations of TMZ were greater after treatment of U251TR cells with NEO212 than after treatment with TMZ. The half-life of NEO212 in mouse plasma was 94 min. In mice harboring syngeneic GL261 brain tumors, the amount of NEO212 was greater in the tumor-bearing hemisphere than in the contralateral normal hemisphere. The brain:plasma ratio of NEO212 was greater than that of TMZ. Excretion of unaltered NEO212 was through feces, whereas its AIC metabolite was excreted via urine.
CONCLUSIONS
NEO212 preferentially concentrates in brain tumor tissue over normal brain tissue, and compared to TMZ has a higher brain:plasma ratio, altogether revealing favorable features to encourage its further development as a brain-targeted therapeutic. Its breakdown into well-characterized, long-lived metabolites, in particular AIC and PA, will provide useful equivalents for PK studies during further drug development and clinical trials with NEO212.
PubMed: 33392507
DOI: 10.1093/noajnl/vdaa160 -
Neuro-oncology Advances 2021Better treatments for glioblastoma (GBM) patients, in particular in the recurrent setting, are urgently needed. Clinical trials performed in Brazil indicated that...
BACKGROUND
Better treatments for glioblastoma (GBM) patients, in particular in the recurrent setting, are urgently needed. Clinical trials performed in Brazil indicated that intranasal delivery of perillyl alcohol (POH) might be effective in this patient group. NEO100, a highly purified version of POH, was current good manufacturing practice (cGMP) manufactured to evaluate the safety and efficacy of this novel approach in a Phase I/IIa clinical trial in the United States.
METHODS
A total of 12 patients with recurrent GBM were enrolled into Phase I of this trial. NEO100 was administered by intranasal delivery using a nebulizer and nasal mask. Dosing was 4 times a day, every day. Four cohorts of 3 patients received the following dosages: 96 mg/dose (384 mg/day), 144 mg/dose (576 mg/day), 192 mg/dose (768 mg/day), and 288 mg/dose (1152 mg/day). Completion of 28 days of treatment was recorded as 1 cycle. Adverse events were documented, and radiographic response Response Assessment in Neuro-Oncology (RANO) criteria was evaluated every 2 months. Progression-free and overall survival were determined after 6 and 12 months, respectively (progression-free survival-6 [PFS-6], overall survival-12 [OS-12]).
RESULTS
Intranasal NEO100 was well tolerated at all dose levels and no severe adverse events were reported. PFS-6 was 33%, OS-12 was 55%, and median OS was 15 months. Four patients (33%), all of them with isocitrate dehydrogenase 1 (IDH1)-mutant tumors, survived >24 months.
CONCLUSION
Intranasal glioma therapy with NEO100 was well tolerated. It correlated with improved survival when compared to historical controls, pointing to the possibility that this novel intranasal approach could become useful for the treatment of recurrent GBM.
PubMed: 33604574
DOI: 10.1093/noajnl/vdab005 -
Molecules (Basel, Switzerland) Jun 2020The interaction between a drug molecule and its carrier's components is an important factor which influences the drug release profile. For this purpose, molecular...
The interaction between a drug molecule and its carrier's components is an important factor which influences the drug release profile. For this purpose, molecular dynamics (MD) may be the in silico tool which can help to understand the mechanism of drug loading/release. The aim of this work is to explain the effect of interactions between different types of terpenes, namely perillyl alcohol, forskolin, ursolic acid, and the nanoemulsion droplet core, on the release by means of experimental and theoretical studies. The basic nanoemulsion was composed of caprylic/capric triglyceride as the oil phase, polysorbate 80 as the emulsifier, and water. The in vitro release tests from a terpene-loaded nanoemulsion were carried out to determine the release profiles. The behavior of terpenoids in the nanoemulsion was also theoretically investigated using the molecular dynamics method. The forskolin-loaded nanoemulsion showed the highest percentage of drug release (almost 80% /) in contrast to ursolic acid and perillyl alcohol-loaded nanoemulsions (about 53% / and 19% /, respectively). The results confirmed that the kinetic model of release was terpene-type dependent. The zero-order model was the best to describe the ursolic acid release profile, while the forskolin and the perillyl alcohol followed a first-order and Higuchi model, respectively. Molecular dynamics simulations, especially energetical analysis, confirmed that the driving force of terpenes diffusion from nanoemulsion interior was their interaction energy with a surfactant.
Topics: Emulsifying Agents; Emulsions; Kinetics; Models, Chemical; Nanostructures; Polysorbates; Terpenes
PubMed: 32545817
DOI: 10.3390/molecules25122747 -
Food Chemistry Jun 2024Degradation of trans-cinnamaldehyde and limonene in cucumber was evaluated under laboratory and greenhouse conditions. Two commercial biopesticides, one based on...
Degradation of trans-cinnamaldehyde and limonene in cucumber was evaluated under laboratory and greenhouse conditions. Two commercial biopesticides, one based on cinnamon extract and other from orange oil, were utilized. Compound degradation was monitored using gas chromatography (GC) and ultra-high-performance liquid chromatography (UHPLC) coupled to a quadrupole-high-resolution mass analyzer (Q-Orbitrap). In both studies, trans-cinnamaldehyde followed a second-order degradation kinetics, whereas limonene followed a first-order kinetics. The half-life values (DT or t) for trans-cinnamaldehyde ranged from 2.02 to 2.49 h, while for limonene this value ranged from 0.49 to 6.17 h. Non-targeted analysis (suspect and unknown modes) allowed for the detection of trans-cinnamaldehyde and limonene metabolites. Benzyl alcohol, cinnamyl alcohol, cinnamic acid, p-tolylacetic acid and 4-hydoxycinnamic acid were tentatively identified as trans-cinnamaldehyde metabolites. While three limonene metabolites, carvone, limonene-1,2-epoxide, and perillyl alcohol, were tentatively identified. Greenhouse studies have not revealed any metabolites of these compounds because the parent compounds degrade more quickly.
Topics: Limonene; Cucumis sativus; Chromatography, High Pressure Liquid; Biological Control Agents; Allergens; Chromatography, Gas; Acrolein
PubMed: 38241992
DOI: 10.1016/j.foodchem.2024.138443 -
ChemistryOpen Apr 2021A series of tetraimidazolium salts with different anions was prepared and applied in the isomerization of β-pinene oxide. After examining the activity of different...
A series of tetraimidazolium salts with different anions was prepared and applied in the isomerization of β-pinene oxide. After examining the activity of different catalysts, a remarkable enhancement of the selectivity of perillyl alcohol (47 %) was obtained over [PEimi][HNO ] under mild reaction conditions and using DMSO as the solvent. Furthermore, noncovalent interactions between solvent molecules and the catalyst were found by FT-IR spectroscopy and confirmed by computational chemistry. The homogeneous catalyst showed excellent stability and was reused up to six times without significant loss.
PubMed: 33908700
DOI: 10.1002/open.202000318 -
AMB Express Apr 2022Optimized recombinant whole cells of E. coli bearing CYP153A6 were employed for catalyzing the hydroxylation of different monoterpene derivatives. In most cases, high...
Optimized recombinant whole cells of E. coli bearing CYP153A6 were employed for catalyzing the hydroxylation of different monoterpene derivatives. In most cases, high selectivity was observed with exclusive hydroxylation of the allylic methyl group bound to the aliphatic ring. In the case of (R)- and (S)-carvone, hydroxylation occurred also on the other allylic methyl group, although to a lesser extent. Biotransformations carried out in fed-batch mode on (S)-limonene and α-terpineol showed that recombinant whole cells retained activity for at least 24 h, allowing for the recovery of 3.25 mg mL of (S)-perillyl alcohol and 5.45 mg mL of 7-hydroxy-α-terpineol, respectively.
PubMed: 35478304
DOI: 10.1186/s13568-022-01389-8