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Biomedicines Oct 2023Perillyl alcohol (PA), a naturally existing monocyclic terpene related to limonene, is characterized by its poor aqueous solubility and very limited bioavailability. Its...
Perillyl alcohol (PA), a naturally existing monocyclic terpene related to limonene, is characterized by its poor aqueous solubility and very limited bioavailability. Its potential anti-cancer activity against malignant glioma has been reported. The aim was to develop PA-loaded lipid-based nanocarriers (LNCs), and to investigate their anti-cancer activity against two different brain cell lines. Non-medicated and PA-loaded LNCs were prepared and characterized. The mechanism of cytotoxic activity of PA was conducted using a molecular docking technique. The cell viabilities against A172 and ANGM-CSS cells were evaluated. The results revealed that the average particle size of the prepared LNCs ranged from 248.67 ± 12.42 to 1124.21 ± 12.77 nm, the polydispersity index was 0.418 ± 0.043-0.509 ± 0.064, while the zeta potential ranged from -36.91 ± 1.31 to -15.20 ± 0.96 mV. The molecular docking studies demonstrated that the drug had binding activity to human farnesyltransferase. Following exposure of the two glioblastoma cell lines to the PA-loaded nanoformulations, MTS assays were carried out, and the data showed a far lower half-maximal inhibitory concentration in both cell lines when compared to pure drug and non-medicated nanocarriers. These results indicate the potential in vitro antiproliferative activity of PA-loaded LNCs. Therefore, the prepared PA-loaded nanocarriers could be used to enhance drug delivery across the blood-brain barrier (BBB) in order to treat brain cancer, especially when formulated in a suitable dosage form. The size, surface charge, and lipid composition of the LNCs make them promising for drug delivery across the BBB. Detailed pharmacokinetic and pharmacodynamic assessments, including the evaluation of BBB penetration, are necessary to better understand the compound's distribution and effects within the brain.
PubMed: 37893144
DOI: 10.3390/biomedicines11102771 -
Journal of Applied Microbiology Oct 2023The use of phytochemicals to improve the effectiveness of antibiotics is a promising strategy for the development of novel antimicrobials. In this study, the antibiofilm...
AIMS
The use of phytochemicals to improve the effectiveness of antibiotics is a promising strategy for the development of novel antimicrobials. In this study, the antibiofilm activity of perillyl alcohol and hydrocinnamic acid, both phytochemicals present in several plants, and two antibiotics from different classes (amoxicillin and chloramphenicol) was tested, alone and in combination, against Escherichia coli.
METHODS AND RESULTS
Each molecule was tested at the minimum inhibitory concentration (MIC), 5 × MIC, and 10 × MIC, and characterized concerning biomass removal, metabolic inactivation, and cellular culturability. The highest percentages of metabolic inactivation (88.5% for 10 × MIC) and biomass reduction (61.7% for 10 × MIC) were obtained with amoxicillin. Interestingly, for 5 × MIC and 10 × MIC, phytochemicals provided a total reduction of colony-forming units (CFUs). Dual and triple combinations of phytochemicals and antibiotics (at MIC and 5 × MIC) demonstrated high efficacy in metabolic inactivation, moderate efficacy in terms of biomass reduction, and total reduction of cellular culturability for 5 × MIC.
CONCLUSIONS
The results demonstrated the antibiofilm potential of phytochemicals, highlighting the advantage of phytochemical/antibiotic combinations for biofilm control.
Topics: Anti-Bacterial Agents; Escherichia coli; Biofilms; Amoxicillin; Phytochemicals; Microbial Sensitivity Tests
PubMed: 37827567
DOI: 10.1093/jambio/lxad234 -
Pharmaceuticals (Basel, Switzerland) Jul 2023Perillyl alcohol (POH), a bioactive monoterpenoid derived from limonene, shows promise as an antitumor agent for brain tumor treatment. However, its limited oral...
Perillyl alcohol (POH), a bioactive monoterpenoid derived from limonene, shows promise as an antitumor agent for brain tumor treatment. However, its limited oral bioavailability and inadequate brain distribution hinder its efficacy. To address these challenges, this study developed nanostructured lipid carriers (NLCs) loaded with POH to improve its brain biodistribution. The NLCs prepared using hot homogenization exhibited an average diameter of 287 nm and a spherical morphology with a polydispersity index of 0.143. High encapsulation efficiency of 99.68% was achieved. X-ray diffraction analyses confirmed the semicrystalline state of POH-loaded NLCs. In vitro release studies demonstrated a biphasic release profile. Stability studies in simulated gastric and intestinal fluids confirmed their ability to withstand pH variations and digestive enzymes. In vivo pharmacokinetic studies in rats revealed significantly enhanced oral bioavailability of POH when encapsulated in the NLCs. Biodistribution studies showed increased POH concentration in brain tissue with NLCs compared with free POH, which was distributed more in non-target tissues such as the liver, lungs, kidneys, and spleen. These findings underscore the potential of NLCs as effective delivery systems for enhancing oral bioavailability and brain biodistribution of POH, providing a potential therapeutic strategy for brain tumor treatment.
PubMed: 37630970
DOI: 10.3390/ph16081055 -
Autophagy Dec 2023Glioblastoma (GBM) is the most aggressive primary brain tumor, exhibiting a high rate of recurrence and poor prognosis. Surgery and chemoradiation with temozolomide...
Glioblastoma (GBM) is the most aggressive primary brain tumor, exhibiting a high rate of recurrence and poor prognosis. Surgery and chemoradiation with temozolomide (TMZ) represent the standard of care, but, in most cases, the tumor develops resistance to further treatment and the patients succumb to disease. Therefore, there is a great need for the development of well-tolerated, effective drugs that specifically target chemoresistant gliomas. NEO214 was generated by covalently conjugating rolipram, a PDE4 (phosphodiesterase 4) inhibitor, to perillyl alcohol, a naturally occurring monoterpene related to limonene. Our previous studies in preclinical models showed that NEO214 harbors anticancer activity, is able to cross the blood-brain barrier (BBB), and is remarkably well tolerated. In the present study, we investigated its mechanism of action and discovered inhibition of macroautophagy/autophagy as a key component of its anticancer effect in glioblastoma cells. We show that NEO214 prevents autophagy-lysosome fusion, thereby blocking autophagic flux and triggering glioma cell death. This process involves activation of MTOR (mechanistic target of rapamycin kinase) activity, which leads to cytoplasmic accumulation of TFEB (transcription factor EB), a critical regulator of genes involved in the autophagy-lysosomal pathway, and consequently reduced expression of autophagy-lysosome genes. When combined with chloroquine and TMZ, the anticancer impact of NEO214 is further potentiated and unfolds against TMZ-resistant cells as well. Taken together, our findings characterize NEO214 as a novel autophagy inhibitor that could become useful for overcoming chemoresistance in glioblastoma. ATG: autophagy related; BAFA1: bafilomycin A; BBB: blood brain barrier; CQ: chloroquine; GBM: glioblastoma; LAMP1: lysosomal associated membrane protein 1; MAP1LC3/LC3: microtubule associated protein 1 light chain 3; MGMT: O-6-methylguanine-DNA methyltransferase; MTOR: mechanistic target of rapamycin kinase; MTORC: MTOR complex; POH: perillyl alcohol; SQSTM1/p62: sequestosome 1; TFEB: transcription factor EB; TMZ: temozolomide.
Topics: Humans; Glioblastoma; Temozolomide; Autophagy; Rolipram; Cell Death; Monoterpenes; Glioma; TOR Serine-Threonine Kinases; Sirolimus; Chloroquine; Lysosomes
PubMed: 37545052
DOI: 10.1080/15548627.2023.2242696 -
Pharmacological Reports : PR Oct 2023Melanoma is a highly aggressive and life-threatening form of skin cancer that accounts for a significant proportion of cancer-related deaths worldwide. Although... (Review)
Review
Melanoma is a highly aggressive and life-threatening form of skin cancer that accounts for a significant proportion of cancer-related deaths worldwide. Although conventional cancer therapies, such as surgical excision, chemotherapy, and radiation, have been used to treat malignant melanoma, their efficacy is often limited due to the development of resistance and adverse side effects. Therefore, there is a growing interest in developing alternative treatment options for melanoma that are more effective and less toxic. Terpenes, a diverse group of naturally occurring compounds of plant origin, have emerged as potential anticancer agents due to their ability to inhibit tumor growth and induce apoptosis in cancer cells. In this review, the current understanding of the anticancer effects of terpenes (including, thymoquinone, β-elemene, carvacrol, limonene, α-pinene, β-caryophyllene, perillyl alcohol, taxol, betulinic acid, α-bisabolol, ursolic acid, linalool, lupeol, and artesunate) was summarized, with a special focus on their potential as therapeutic agents for malignant melanoma.
Topics: Humans; Terpenes; Limonene; Antineoplastic Agents; Melanoma; Skin Neoplasms; Melanoma, Cutaneous Malignant
PubMed: 37515699
DOI: 10.1007/s43440-023-00512-1 -
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 -
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 -
Oncotarget May 2023
Topics: Humans; Blood-Brain Barrier; Groin; Brain; Glioma; Brain Neoplasms; Monoterpenes
PubMed: 37141417
DOI: 10.18632/oncotarget.28414 -
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