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Organic & Biomolecular Chemistry Jun 2023Terpenes and their derivatives are natural antifungal and antimicrobial agents. In this paper, potential antifungal agents were developed on the basis of farnesol,...
Terpenes and their derivatives are natural antifungal and antimicrobial agents. In this paper, potential antifungal agents were developed on the basis of farnesol, geraniol, myrtenol, perillyl alcohol, cedrol and phytol. The synthesized compounds exist in aqueous solutions as stable associates ( = 142-216 nm, PDI 0.04-0.16, = +0.9-+46 mV). Formation of stable associates of the compounds in solution promotes compaction and dosed release of the drug. The membranotropic activity of the compounds was also investigated to open up their possible application in the treatment of skin diseases. The relationship between membranotropism and lipophilicity coefficient (log ) has been established. The antifungal and antimicrobial activities of the obtained compounds were studied on the clinical isolate of sp., , yeast , Gram-negative () and Gram-positive (, ) bacteria. sp. (0.0781 mg mL) and (0.0049 mg mL) showed the highest sensitivity to the agents.
Topics: Antifungal Agents; Azoles; Saccharomyces cerevisiae; Anti-Infective Agents; Candida albicans; Diterpenes; Microbial Sensitivity Tests; Anti-Bacterial Agents
PubMed: 37249394
DOI: 10.1039/d3ob00528c -
Cancers Feb 2024The Epstein-Barr virus (EBV) is accepted as a primary risk factor for certain nasopharyngeal carcinoma (NPC) subtypes, where the virus persists in a latent stage which...
The Epstein-Barr virus (EBV) is accepted as a primary risk factor for certain nasopharyngeal carcinoma (NPC) subtypes, where the virus persists in a latent stage which is thought to contribute to tumorigenesis. Current treatments are sub-optimal, and recurrence occurs in many cases. An alternative therapeutic concept is aimed at triggering the lytic cycle of EBV selectively in tumor cells as a means to add clinical benefit. While compounds able to stimulate the lytic cascade have been identified, their clinical application so far has been limited. We are developing a novel anticancer molecule, NEO212, that was generated by covalent conjugation of the alkylating agent temozolomide (TMZ) to the naturally occurring monoterpene perillyl alcohol (POH). In the current study, we investigated its potential to trigger the lytic cycle of EBV in NPC cells in vitro and in vivo. We used the established C666.1 cell line and primary patient cells derived from the brain metastasis of a patient with NPC, both of which harbored latent EBV. Upon treatment with NEO212, there was an increase in EBV proteins Zta and Ea-D, key markers of the lytic cycle, along with increased levels of CCAAT/enhancer-binding protein homologous protein (CHOP), a marker of endoplasmic reticulum (ER) stress, followed by the activation of caspases. These effects could also be confirmed in tumor tissue from mice implanted with C666.1 cells. Towards a mechanistic understanding of these events, we used siRNA-mediated knockdown of CHOP and inclusion of anti-oxidant compounds. Both approaches blocked lytic cycle induction by NEO212. Therefore, we established a sequence of events, where NEO212 caused reactive oxygen species (ROS) production, which triggered ER stress and elevated the levels of CHOP, which was required to stimulate the lytic cascade of EBV. Inclusion of the antiviral agent ganciclovir synergistically enhanced the cytotoxic impact of NEO212, pointing to a potential combination treatment for EBV-positive cancers which should be explored further. Overall, our study establishes NEO212 as a novel agent able to stimulate EBV's lytic cycle in NPC tumors, with implications for other virus-associated cancers.
PubMed: 38473298
DOI: 10.3390/cancers16050936 -
Neuro-oncology Oct 2021The antitumor efficacy of human epidermal growth factor receptor 2 (HER2)-targeted therapies, such as humanized monoclonal antibody trastuzumab (Herceptin®, Roche), in...
BACKGROUND
The antitumor efficacy of human epidermal growth factor receptor 2 (HER2)-targeted therapies, such as humanized monoclonal antibody trastuzumab (Herceptin®, Roche), in patients with breast-to-brain cancer metastasis is hindered by the low permeability of the blood-brain barrier (BBB). NEO100 is a high-purity version of the natural monoterpene perillyl alcohol, produced under current good manufacturing practice (cGMP) regulations, that was shown previously to reversibly open the BBB in rodent models. Here we investigated whether NEO100 could enable brain entry of trastuzumab to achieve greater therapeutic activity.
METHODS
An in vitro BBB, consisting of human astrocytes and brain endothelial cells, was used to determine trastuzumab penetration in the presence or absence of NEO100. For in vivo studies, we administered intravenous (IV) trastuzumab or the trastuzumab-drug conjugate ado-trastuzumab emtansine (T-DM1; Kadcyla®, Roche), to mouse models harboring intracranial HER2+ breast cancer, with or without BBB opening via IA NEO100. Brain and tumor tissues were examined for the presence of trastuzumab and infiltration of immune cells. Therapeutic impact was evaluated based on overall survival.
RESULTS
NEO100 greatly increased trastuzumab penetration across an in vitro BBB. In vivo, IA NEO100-mediated BBB opening resulted in brain tumor-selective accumulation of trastuzumab, without detectable presence in normal brain tissue, along with increased presence of immune cell populations. IV delivery of trastuzumab or T-DM1 achieved significantly greater overall survival of tumor-bearing mice when combined with IA NEO100.
CONCLUSION
IA NEO100 facilitates brain tumor entry of trastuzumab and T-DM1 and significantly enhances their therapeutic efficacy, along with increased antibody-dependent immune cell recruitment.
Topics: Animals; Blood-Brain Barrier; Brain; Brain Neoplasms; Breast Neoplasms; Endothelial Cells; Female; Humans; Mice; Monoterpenes; Receptor, ErbB-2; Trastuzumab
PubMed: 33659980
DOI: 10.1093/neuonc/noab041 -
Scientific Reports Oct 2019Skin penetration/permeation enhancers are compounds that improve (trans)dermal drug delivery. We designed hybrid terpene-amino acid enhancers by conjugating natural...
Skin penetration/permeation enhancers are compounds that improve (trans)dermal drug delivery. We designed hybrid terpene-amino acid enhancers by conjugating natural terpenes (citronellol, geraniol, nerol, farnesol, linalool, perillyl alcohol, menthol, borneol, carveol) or cinnamyl alcohol with 6-(dimethylamino)hexanoic acid through a biodegradable ester linker. The compounds were screened for their ability to increase the delivery of theophylline and hydrocortisone through and into human skin ex vivo. The citronellyl, bornyl and cinnamyl esters showed exceptional permeation-enhancing properties (enhancement ratios up to 82) while having low cellular toxicities. The barrier function of enhancer-treated skin (assessed by transepidermal water loss and electrical impedance) recovered within 24 h. Infrared spectroscopy suggested that these esters fluidized the stratum corneum lipids. Furthermore, the citronellyl ester increased the epidermal concentration of topically applied cidofovir, which is a potent antiviral and anticancer drug, by 15-fold. In conclusion, citronellyl 6-(dimethylamino)hexanoate is an outstanding enhancer with an advantageous combination of properties, which may improve the delivery of drugs that have a limited ability to cross biological barriers.
Topics: 3T3 Cells; Administration, Cutaneous; Alcohols; Animals; Chemistry, Pharmaceutical; Cidofovir; Drug Compounding; Epidermis; Esters; Humans; Hydrocortisone; Keratinocytes; Lipid Metabolism; Mice; Monoterpenes; Permeability; Pharmaceutic Aids; Structure-Activity Relationship; Terpenes; Theophylline; Toxicity Tests, Acute; Water Loss, Insensible
PubMed: 31601936
DOI: 10.1038/s41598-019-51226-5 -
ACS Omega Apr 2020In this work, a drug delivery system for perillyl alcohol based on the peptide self-assembly containing 3-(2-benzothiazolyl)-7-(diethylamino)coumarin (C6) as a...
In this work, a drug delivery system for perillyl alcohol based on the peptide self-assembly containing 3-(2-benzothiazolyl)-7-(diethylamino)coumarin (C6) as a fluorescent additive is obtained, and its photophysical characteristics as well as its release dynamics were studied by steady-state and time-resolved fluorescence spectroscopy. Results proved the dynamics of drug release from the peptide nanostructures and showed that the system formed by the self-assembled peptide and C6, along with perillyl alcohol, presents unique photophysical properties that can be exploited to generate singlet oxygen (O) upon irradiation, which is not achieved by the sole components. Through epifluorescence microscopy combined with time-correlated single photon counting fluorescence spectroscopy, the release mechanism was proven to occur upon peptide structure interconversion, which is controlled by environmental changes.
PubMed: 32337442
DOI: 10.1021/acsomega.0c00381 -
Journal of Experimental Botany May 2020Plants produce a large variety of highly functionalized terpenoids. Functional groups such as partially unsaturated rings and carboxyl groups provide handles to use...
Plants produce a large variety of highly functionalized terpenoids. Functional groups such as partially unsaturated rings and carboxyl groups provide handles to use these compounds as feedstock for biobased commodity chemicals. For instance, methylperillate, a monoterpenoid found in Salvia dorisiana, may be used for this purpose, as it carries both an unsaturated ring and a methylated carboxyl group. The biosynthetic pathway of methylperillate in plants is still unclear. In this work, we identified glandular trichomes from S. dorisiana as the location of biosynthesis and storage of methylperillate. mRNA from purified trichomes was used to identify four genes that can encode the pathway from geranyl diphosphate towards methylperillate. This pathway includes a (-)-limonene synthase (SdLS), a limonene 7-hydroxylase (SdL7H, CYP71A76), and a perillyl alcohol dehydrogenase (SdPOHDH). We also identified a terpene acid methyltransferase, perillic acid O-methyltransferase (SdPAOMT), with homology to salicylic acid OMTs. Transient expression in Nicotiana benthamiana of these four genes, in combination with a geranyl diphosphate synthase to boost precursor formation, resulted in production of methylperillate. This demonstrates the potential of these enzymes for metabolic engineering of a feedstock for biobased commodity chemicals.
Topics: Biosynthetic Pathways; Salvia; Terpenes; Nicotiana; Trichomes
PubMed: 32090266
DOI: 10.1093/jxb/eraa086 -
Surgical Neurology International 2020Standard of care for glioblastoma (GB), consisting of cytotoxic chemotherapy, steroids, and high-dose radiation, induces changes in the tumor microenvironment through...
BACKGROUND
Standard of care for glioblastoma (GB), consisting of cytotoxic chemotherapy, steroids, and high-dose radiation, induces changes in the tumor microenvironment through its effects on glucose availability, which is a determinant for tumor progression (TP). Low-carbohydrate diet (LCD) reduces the glucose levels needed to drive the Warburg effect.
METHODS
To investigate LCD's effect on GB therapy, we have begun a clinical trial using LCD as an addition to intranasal perillyl alcohol (POH) for recurrent GB (rGB) patients. This study involved 29 individuals and evaluated, over a period of 1 year, the adjuvant effect of LCD associated with POH therapy in terms of toxicity, extent of peritumoral edema, reduced corticosteroid use, seizure frequency, and overall survival. POH group ( = 14) received solely intranasal POH without specific diet regimen, whereas POH/LCD group ( = 15) received intranasal POH in combination with nutritional intervention. Patients' assessment was based on clinical reviews and magnetic resonance data.
RESULTS
In the 1-year follow-up, the POH/LCD group showed a 4.4-fold decrease in the proportion of patients who needed treatment with corticosteroids, as well as a reduction in tumor size and peritumoral edema, as compared to the POH group. While 75% of patients undergoing POH treatment experienced seizures, this fraction was reduced to 56% in the POH/LCD group. A 2.07-fold increase in the proportion of patients with stable disease, along with a 2.8-fold decrease in the proportion of patients with TP, was seen in the POH/LCD group.
CONCLUSION
The results presented in this study show that the LCD associated with intranasal POH therapy may represent a viable option as adjunctive therapy for rGB to improve survival without compromising patients' quality of life. Prospective cohort studies are needed to confirm these findings and validate the efficacy of this novel therapeutic strategy.
PubMed: 33282452
DOI: 10.25259/SNI_445_2020 -
Frontiers in Cellular and Infection... 2024The aim of the work was to analyze the metabolites of the intestinal microbiota from the patients with mild cognitive impairment (MCI) and progressive MCI due to...
PURPOSE
The aim of the work was to analyze the metabolites of the intestinal microbiota from the patients with mild cognitive impairment (MCI) and progressive MCI due to Alzheimer's disease (AD).
METHOD
Two cohorts were established. The first one included 87 subjects with 30 healthy controls (NC), 22 patients with MCI due to AD, and 35 patients with AD. The second cohort included 87 patients with MCI due to AD, who were followed up for 2 years and finally were divided into progressive MCI due to AD group (P-G) and unprogressive MCI due to AD group (U-G) according their cognitive levels. Fecal samples were collected to all patients at the baseline time point. Differential metabolites were subjected to pathway analysis by MetaboAnalyst.
RESULTS
In the first cohort, we found 21 different metabolites among the three groups (AD, MCI, and NC). In the second cohort, we identified 19 differential metabolites between the P-G and U-G groups. By machine learning analysis, we found that seven characteristic metabolites [Erythrodiol, alpha-Curcumene, Synephrine, o-Hydroxylaminobenzoate, 3-Amino-4-hydroxybenzoic acid, 2-Deoxystreptamine, and 9(S] were of characteristic significance for the diagnosis of MCI due to AD, and six metabolites (Indolelactate, Indole-3-acetaldehyde, L-Proline, Perillyl, Mesaconate, and Sphingosine) were the characteristic metabolites of early warning for the progression of MCI due to AD. D-Glucuronic acid was negatively correlated with Apolipoprotein E4 (APOE4). Perillyl alcohol was negatively correlated with all of the five biomarkers [P-tau181, Neurofilament light chain (NF-light), Aβ1-42, Aβ1-40, and glial fibrillary acidic protein (GFAP)], but Indoleacetaldehyde was positively correlated with three biomarkers (P-tau181, Aβ1-42, and GFAP). Three characteristic metabolites (3-Amino-4-hydroxybenzoate, 2-Deoxystreptamine, and p-Synephrine) were positively correlated with Aβ1-42. 2-Deoxystreptamine, 9(S)-HPOT, and Indoleacetaldehyde were positively correlated with GFAP. L-Proline and Indoleacetaldehyde were positively correlated with NF-light.
CONCLUSION
Specific metabolites of intestinal fora can be used as diagnostic and progressive markers for MCI.
Topics: Humans; Amyloid beta-Peptides; tau Proteins; Synephrine; Alzheimer Disease; Cognitive Dysfunction; Biomarkers; Proline
PubMed: 38404286
DOI: 10.3389/fcimb.2024.1351523 -
Food & Function May 2022Nonalcoholic fatty liver disease (NAFLD) has become the most common cause of chronic liver disease and threatens human health worldwide. As shown in our previous study,... (Randomized Controlled Trial)
Randomized Controlled Trial
Nonalcoholic fatty liver disease (NAFLD) has become the most common cause of chronic liver disease and threatens human health worldwide. As shown in our previous study, co-supplementation with phytosterol ester (PSE) (3.3 g day) and n-3 polyunsaturated fatty acids (PUFAs) (450 mg eicosapentaenoic acid (EPA) + 1500 mg docosahexaenoic acid (DHA) per day) was more effective at ameliorating hepatic steatosis than treatment with PSE or n-3 PUFAs alone. In the present study, we further investigated the changes in the serum metabolic profiles of subjects with NAFLD in response to n-3 PUFAs and PSE. Thirty-one differentially altered serum metabolites were annotated using the nontargeted ultra-performance liquid chromatography-quadrupole/time-of-flight mass spectrometry (UPLC-Q-TOF-MS) analysis technique. Multivariable statistical and clustering analyses showed that co-supplementation of n-3 PUFAs and PSE was more effective at improving metabolic disorders in patients with NAFLD than treatment with n-3 PUFAs or PSE alone. The regulated metabolic pathways included metabolism of retinol, linoleic acid, arachidonic acid, glycerophospholipid, sphingolipid, and steroid hormone biosynthesis. Overall, the co-supplementation of n-3 PUFAs and PSE significantly increased the serum levels of PUFA-containing phosphatidylcholine (PC), lysophosphatidylcholine (LysoPC), perillyl alcohol and retinyl ester in patients with NAFLD after 12 weeks of intervention, and the levels of PC (14:0/20:5, 15:0/20:5), LysoPC (20:5, 22:6) and retinyl ester correlated negatively with the degree of hepatic steatosis. The regulatory effect of co-supplementation of n-3 PUFAs and PSE on metabolomic profiles may explain their potential role in alleviating hepatic steatosis in patients with NAFLD.
Topics: Docosahexaenoic Acids; Eicosapentaenoic Acid; Fatty Acids, Omega-3; Humans; Non-alcoholic Fatty Liver Disease; Phytosterols; Retinyl Esters
PubMed: 35438091
DOI: 10.1039/d1fo03921k -
Cells Mar 2023Despite important advances in the pre-clinical animal studies investigating the neuroinhibitory microenvironment at the injury site, traumatic injury to the spinal cord...
Despite important advances in the pre-clinical animal studies investigating the neuroinhibitory microenvironment at the injury site, traumatic injury to the spinal cord remains a major problem with no concrete response. Here, we examined whether (1) intranasal (IN) administration of miR133b/Ago2 can reach the injury site and achieve a therapeutic effect and (2) NEO100-based formulation of miR133b/Ago2 can improve effectiveness. 24 h after a cervical contusion, C57BL6 female mice received IN delivery of miR133b/Ago2 or miR133b/Ago2/NEO100 for 3 days, one dose per day. The pharmacokinetics of miR133b in the spinal cord lesion was determined by RT-qPCR. The role of IN delivery of miR133b on motor function was assessed by the grip strength meter (GSM) and hanging tasks. The activity of miR133b at the lesion site was established by immunostaining of fibronectin 1 (FN1), a miR133b target. We found that IN delivery of miR133b/Ago2 (1) reaches the lesion scar and co-administration of miR133b with NEO100 facilitated the cellular uptake; (2) enhanced the motor function and addition of NEO100 potentiated this effect and (3) targeted FN1 expression at the lesion scar. Our results suggest a high efficacy of IN delivery of miR133b/Ago2 to the injured spinal cord that translates to improved healing with NEO100 further potentiating this effect.
Topics: Animals; Female; Mice; Administration, Intranasal; Argonaute Proteins; Cicatrix; Contusions; MicroRNAs; Spinal Cord Injuries
PubMed: 36980272
DOI: 10.3390/cells12060931