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Pharmaceutics Nov 2020Therapeutic deep eutectic systems (THEDES) have dramatically expanded their popularity in the pharmaceutical field due to their ability to increase active pharmaceutical...
Therapeutic deep eutectic systems (THEDES) have dramatically expanded their popularity in the pharmaceutical field due to their ability to increase active pharmaceutical ingredients (APIs) bioavailability. However, their biological performance has not yet been carefully scrutinized. Herein, THEDES based on the binary mixture of perillyl alcohol (POH) and ibuprofen (IBU) were prepared using different molar ratios. Our comprehensive strategy includes the characterization of their thermal and structural behavior to identify the molar ratios that successfully form deep eutectic systems. The in vitro solubility of the different systems prepared has demonstrated that, unlike other reported examples, the presence of the terpene did not affect the solubility of the anti-inflammatory agent in a physiological simulated media. The biological performance of the systems was studied in terms of their antimicrobial activity against a wide panel of microorganisms. The examined THEDES showed relevant antimicrobial activity against all tested microbial strains, with the exception of . A synergistic effect from the combination of POH and IBU as a eutectic system was verified. Furthermore, the cytotoxic profile of these eutectic systems towards colorectal cancer (CRC) in vitro cell models was also evaluated. The results provide the indication that the cell viability varies in a dose-dependent manner, with a selective THEDES action towards CRC cells. With tunable bioactivities in a ratio-dependent manner, THEDES enhanced the antimicrobial and anticancer properties, representing a possible alternative to conventional therapies. Therefore, this study provides foreseeable indications about the utility of THEDES based on POH and IBU as strong candidates for novel active pharmaceutical systems.
PubMed: 33233659
DOI: 10.3390/pharmaceutics12111121 -
Frontiers in Pharmacology 2018The mevalonate pathway provides sterols for membrane structure and nonsterol intermediates for the post-translational modification and membrane anchorage of... (Review)
Review
The mevalonate pathway provides sterols for membrane structure and nonsterol intermediates for the post-translational modification and membrane anchorage of growth-related proteins, including the Ras, Rac, and Rho GTPase family. Mevalonate-derived products are also essential for the Hedgehog pathway, steroid hormone signaling, and the nuclear localization of Yes-associated protein and transcriptional co-activator with PDZ-binding motif, all of which playing roles in tumorigenesis and cancer stem cell function. The phosphatidylinositol-4,5-bisphosphate 3-kinase-AKT-mammalian target of rapamycin complex 1 pathway, p53 with gain-of-function mutation, and oncoprotein MYC upregulate the mevalonate pathway, whereas adenosine monophosphate-activated protein kinase and tumor suppressor protein RB are the downregulators. The rate-limiting enzyme, 3-hydroxy-3-methylglutaryl coenzyme A reductase (HMGCR), is under a multivalent regulation. Sterol regulatory element binding protein 2 mediates the sterol-controlled transcriptional downregulation of HMGCR. UbiA prenyltransferase domain-containing protein-1 regulates the ubiquitination and proteasome-mediated degradation of HMGCR, which is accelerated by 24, 25-dihydrolanosterol and the diterpene geranylgeraniol. Statins, competitive inhibitors of HMGCR, deplete cells of mevalonate-derived intermediates and consequently inhibit cell proliferation and induce apoptosis. Clinical application of statins is marred by dose-limiting toxicities and mixed outcomes on cancer risk, survival and mortality, partially resulting from the statin-mediated compensatory upregulation of HMGCR and indiscriminate inhibition of HMGCR in normal and tumor cells. Tumor HMGCR is resistant to the sterol-mediated transcriptional control; consequently, HMGCR is upregulated in cancers derived from adrenal gland, blood and lymph, brain, breast, colon, connective tissue, embryo, esophagus, liver, lung, ovary, pancreas, prostate, skin, and stomach. Nevertheless, tumor HMGCR remains sensitive to isoprenoid-mediated degradation. Isoprenoids including monoterpenes (carvacrol, L-carvone, geraniol, perillyl alcohol), sesquiterpenes (cacalol, farnesol, β-ionone), diterpene (geranylgeranyl acetone), "mixed" isoprenoids (tocotrienols), and their derivatives suppress the growth of tumor cells with little impact on non-malignant cells. In cancer cells derived from breast, colon, liver, mesothelium, prostate, pancreas, and skin, statins and isoprenoids, including tocotrienols, geraniol, limonene, β-ionone and perillyl alcohol, synergistically suppress cell proliferation and associated signaling pathways. A blend of dietary lovastatin and δ-tocotrienol, each at no-effect doses, suppress the growth of implanted murine B16 melanomas in C57BL6 mice. Isoprenoids have potential as adjuvant agents to reduce the toxicities of statins in cancer prevention or therapy.
PubMed: 30662405
DOI: 10.3389/fphar.2018.01515 -
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 -
ACS Bio & Med Chem Au Feb 2022Increased incidences of fungal infections and associated mortality have accelerated the need for effective and alternative therapeutics. Perillyl alcohol (PA) is a...
Increased incidences of fungal infections and associated mortality have accelerated the need for effective and alternative therapeutics. Perillyl alcohol (PA) is a terpene produced by the hydroxylation of limonene via the mevalonate pathway. In pursuit of an alternative antifungal agent, we studied the effect of PA on the biofilm community of and on different cellular pathways to decipher its mode of action. PA efficiently inhibited growth and eradicated biofilms by reducing carbohydrate and eDNA content in the extracellular matrix. PA reduced the activity of hydrolytic enzymes in the ECM of biofilm. The chemical profiling study has given insights into the overall mode of action of PA in and the marked involvement of the cell wall and membrane, ergosterol biosynthesis, oxidative stress, and DNA replication. The spectroscopic and RT-PCR studies suggested a strong interaction of PA with chitin, β-glucan, ergosterol, and efflux pump, thus indicating increased membrane fluidity in . Furthermore, the microscopic and flow cytometry analysis emphasized that PA facilitated the change in mitochondrial activity, increased Ca influx via overexpression of voltage-gated Ca channels, and enhanced cytochrome C release from mitochondria. In addition, PA interferes with DNA replication and thus hinders the cell cycle progression at the S-phase. All these studies together established that PA mitigates the biofilms by targeting multiple cellular pathways. Interestingly, PA also potentiated the efficacy of azole drugs, particularly miconazole, against and its clinical isolates. Conclusively, the study demonstrated the use of PA as an effective antifungal agent alone or in combination with FDA-approved conventional drugs for fungal biofilm eradication.
PubMed: 37102177
DOI: 10.1021/acsbiomedchemau.1c00034 -
Chemistry (Weinheim An Der Bergstrasse,... Jun 2020Residual dipolar couplings (RDCs) offer additional information for structure elucidation by NMR spectroscopy. They are measured in anisotropic media, such as lyotropic...
Residual dipolar couplings (RDCs) offer additional information for structure elucidation by NMR spectroscopy. They are measured in anisotropic media, such as lyotropic liquid crystalline phases of polypeptides. Today, some suitable polypeptides are known. Nevertheless, structural influences of these polypeptides on the alignment properties are not really understood. Thus, which influence a chiral side chain has on enantiodiscrimination and whether we can improve the enantiodifferentiation significantly by adding an additional chiral center in the side chain are questions of interest. Therefore, new diastereomeric polypeptide-based alignment media with an additional chiral center in the side chain derived from perillyl alcohol were synthesized and their properties were investigated (secondary structure, liquid crystallinity, etc.). The enantiomers of isopinocampheol and β-pinene were used as model analytes for the study of enantiodiscrimination. Additionally, the usage of H- H-RDCs to improve the alignment tensor quality is demonstrated.
PubMed: 32134524
DOI: 10.1002/chem.201905447 -
International Journal of Molecular... May 2018Tumor infiltration into brain tissue usually remains undetected even by high-resolution imaging. Molecular markers are used to increase diagnostic accuracy, but with...
Tumor infiltration into brain tissue usually remains undetected even by high-resolution imaging. Molecular markers are used to increase diagnostic accuracy, but with limited continuous monitoring application. We evaluated the potential of circulating cell-free DNA (cfDNA) as a molecular indicator of the response to therapy by the intranasal administration (ITN) of perillyl alcohol (POH) in brain tumors. The cohort included 130 healthy subjects arranged as control-paired groups and patients at terminal stages with glioblastoma (GBM, = 122) or brain metastasis (BM, = 55) from stage IV adenocarcinomas. Serum cfDNA was isolated and quantified by fluorimetry. Compared with the controls (40 ng/mL), patients with brain tumors before ITN-POH treatment had increased ( < 0.0001) cfDNA median levels: GBM (286 ng/mL) and BM (588 ng/mL). ITN-POH treatment was significantly correlated (rho = -0.225; = 0.024) with survival of >6 months at a concentration of 599 ± 221 ng/mL and of.
Topics: Adult; Aged; Aged, 80 and over; Brain Neoplasms; Cell-Free Nucleic Acids; Female; Glioblastoma; Humans; Magnetic Resonance Imaging; Male; Middle Aged; Monoterpenes; Prognosis; Retrospective Studies
PubMed: 29848970
DOI: 10.3390/ijms19061610 -
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 -
BMC Cancer Aug 2021D-limonene and its derivatives have demonstrated potential chemopreventive and anticancer activity in preclinical and clinical studies. The aim of this scoping review... (Meta-Analysis)
Meta-Analysis Review
BACKGROUND
D-limonene and its derivatives have demonstrated potential chemopreventive and anticancer activity in preclinical and clinical studies. The aim of this scoping review was to assess and critically appraise current literature on the effect of these bioactive citrus peel compounds on breast cancer in human trials and to identify knowledge gaps for exploration in future studies.
METHODS
This study followed a scoping review framework. Peer-reviewed journal articles were included if they reported the effect of d-limonene or its derivatives on breast cancer in human subjects. Articles were retrieved from academic databases - PubMed, EMBASE, CINAHL, Web of Science, and Cochrane reviews - and iteratively through review of bibliographies of relevant manuscripts. Titles and abstracts were appraised against the aforementioned inclusion criteria in a first round of screening. Through consensus meetings and full article review by authors, a final set of studies were selected. Results were reported according to the PRISMA extension for scoping reviews.
RESULTS
Our search strategy yielded 367 records. Following screening and adjudication, five articles reporting on phase 1(n = 2), phase 2 (n = 2) and both trial phases (n = 1) were included as the final dataset for this review. Trials evaluating the effect of d-limonene (n = 2) showed it was well tolerated in subjects. One study (n = 43 participants) showed d-limonene concentrated in breast tissue (mean 41.3 μg/g tissue) and reduction in tumor cyclin D1 expression, which is associated with tumor proliferation arrest. This study did not show meaningful change in serum biomarkers associated with breast cancer, except for a statistically significant increase in insulin-like growth factor-1 (IGF-I) levels. While elevation of IGF-I is associated with increased cancer risk, the clinical implication of this study remains uncertain given its short duration. Trials with perillyl alcohol (n = 3) showed low tolerance and no effect on breast cancer.
CONCLUSION
This review demonstrated a dearth of clinical studies exploring the effect of d-limonene and its derivatives on breast cancer. Limited literature suggests d-limonene is safe and tolerable in human subjects compared to its derivative, perillyl alcohol. Our review demonstrates the need for additional well-powered placebo-controlled trials that assess d-limonene's efficacy on breast cancer compared to other therapies.
Topics: Adult; Aged; Aged, 80 and over; Antineoplastic Agents, Phytogenic; Breast Neoplasms; Combined Modality Therapy; Drug Monitoring; Female; Humans; Limonene; Maximum Tolerated Dose; Middle Aged; Molecular Structure; Treatment Outcome
PubMed: 34362338
DOI: 10.1186/s12885-021-08639-1 -
Neuro-oncology Jan 2021Intracarotid injection of mannitol has been applied for decades to support brain entry of therapeutics that otherwise do not effectively cross the blood-brain barrier...
BACKGROUND
Intracarotid injection of mannitol has been applied for decades to support brain entry of therapeutics that otherwise do not effectively cross the blood-brain barrier (BBB). However, the elaborate and high-risk nature of this procedure has kept its use restricted to well-equipped medical centers. We are developing a more straightforward approach to safely open the BBB, based on the intra-arterial (IA) injection of NEO100, a highly purified version of the natural monoterpene perillyl alcohol.
METHODS
In vitro barrier permeability with NEO100 was evaluated by transepithelial/transendothelial electrical resistance and antibody diffusion assays. Its mechanism of action was studied by western blot, microarray analysis, and electron microscopy. In mouse models, we performed ultrasound-guided intracardiac administration of NEO100, followed by intravenous application of Evan's blue, methotrexate, checkpoint-inhibitory antibodies, or chimeric antigen receptor (CAR) T cells.
RESULTS
NEO100 opened the BBB in a reversible and nontoxic fashion in vitro and in vivo. It enabled greatly increased brain entry of all tested therapeutics and was well tolerated by animals. Mechanistic studies revealed effects of NEO100 on different BBB transport pathways, along with translocation of tight junction proteins from the membrane to the cytoplasm in brain endothelial cells.
CONCLUSION
We envision that this procedure can be translated to patients in the form of transfemoral arterial catheterization and cannulation to the cerebral arteries, which represents a low-risk procedure commonly used in a variety of clinical settings. Combined with NEO100, it is expected to provide a safe, widely available approach to enhance brain entry of any therapeutic.
Topics: Animals; Blood-Brain Barrier; Brain; Endothelial Cells; Humans; Mice; Monoterpenes; Tight Junctions
PubMed: 32877532
DOI: 10.1093/neuonc/noaa206 -
BMC Biology Nov 2022The SARS-CoV-2/COVID-19 pandemic has inflicted medical and socioeconomic havoc, and despite the current availability of vaccines and broad implementation of vaccination...
BACKGROUND
The SARS-CoV-2/COVID-19 pandemic has inflicted medical and socioeconomic havoc, and despite the current availability of vaccines and broad implementation of vaccination programs, more easily accessible and cost-effective acute treatment options preventing morbidity and mortality are urgently needed. Herbal teas have historically and recurrently been applied as self-medication for prophylaxis, therapy, and symptom alleviation in diverse diseases, including those caused by respiratory viruses, and have provided sources of natural products as basis for the development of therapeutic agents. To identify affordable, ubiquitously available, and effective treatments, we tested herbs consumed worldwide as herbal teas regarding their antiviral activity against SARS-CoV-2.
RESULTS
Aqueous infusions prepared by boiling leaves of the Lamiaceae perilla and sage elicit potent and sustained antiviral activity against SARS-CoV-2 when applied after infection as well as prior to infection of cells. The herbal infusions exerted in vitro antiviral effects comparable to interferon-β and remdesivir but outperformed convalescent sera and interferon-α2 upon short-term treatment early after infection. Based on protein fractionation analyses, we identified caffeic acid, perilla aldehyde, and perillyl alcohol as antiviral compounds. Global mass spectrometry (MS) analyses performed comparatively in two different cell culture infection models revealed changes of the proteome upon treatment with herbal infusions and provided insights into the mode of action. As inferred by the MS data, induction of heme oxygenase 1 (HMOX-1) was confirmed as effector mechanism by the antiviral activity of the HMOX-1-inducing compounds sulforaphane and fraxetin.
CONCLUSIONS
In conclusion, herbal teas based on perilla and sage exhibit antiviral activity against SARS-CoV-2 including variants of concern such as Alpha, Beta, Delta, and Omicron, and we identified HMOX-1 as potential therapeutic target. Given that perilla and sage have been suggested as treatment options for various diseases, our dataset may constitute a valuable resource also for future research beyond virology.
Topics: Humans; SARS-CoV-2; Antiviral Agents; Teas, Herbal; Pandemics; COVID-19 Serotherapy; COVID-19 Drug Treatment
PubMed: 36447206
DOI: 10.1186/s12915-022-01468-z