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Pharmaceuticals (Basel, Switzerland) Sep 2022In this study, incorporation of the cytotoxic agent paclitaxel and the P-glycoprotein inhibitor elacridar in hyaluronic acid (HA)-modified nanoemulsions was studied for...
In this study, incorporation of the cytotoxic agent paclitaxel and the P-glycoprotein inhibitor elacridar in hyaluronic acid (HA)-modified nanoemulsions was studied for intraductal delivery and breast cancer localized treatment. To improve cytotoxicity, we investigated the incorporation of perillyl alcohol or tributyrin as components of the nanoemulsion oil phase. The nanoemulsions presented size <180 nm and negative zeta potential. Both tributyrin and perillyl alcohol increased nanoemulsion cytotoxicity in MCF-7 cells, but not in MDA-MB-231. However, perillyl alcohol reduced nanoemulsion stability in the presence of the drugs. Concomitant incorporation of paclitaxel and elacridar in HA- and tributyrin-containing nanoemulsions (PE-NETri) increased cytotoxicity and reduced IC50 by 1.6 to 3-fold in MCF-7 and MDA-MB-231 cells compared to the nanoemulsion containing only paclitaxel (P-NE). This nanoemulsion also produced a 3.3-fold reduction in the viability of MDA-MB-231 spheroids. Elacridar incorporated in the nanoemulsion was capable of inhibiting P-glycoprotein in membranes. In vivo intraductal administration of the NE containing HA resulted in a three-fold higher retention of a fluorescent marker compared to a solution or nanoemulsion without HA, demonstrating the importance of HA. The nanoemulsion produced no histological changes in the mammary tissue. These results support the potential applicability of the nanoemulsion for local breast cancer management.
PubMed: 36145331
DOI: 10.3390/ph15091110 -
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 -
Phytomedicine : International Journal... Nov 2022Ulcerative colitis (UC) is the most prevalent chronic inflammatory immune bowel disease. The modernization of lifestyle accompanied by the stress to cope with the...
Perillyl alcohol attenuates chronic restraint stress aggravated dextran sulfate sodium-induced ulcerative colitis by modulating TLR4/NF-κB and JAK2/STAT3 signaling pathways.
BACKGROUND
Ulcerative colitis (UC) is the most prevalent chronic inflammatory immune bowel disease. The modernization of lifestyle accompanied by the stress to cope with the competition has resulted in a new range of complications where stress became a critical contributing factor for many diseases, including UC. Hence there is an urgent need to develop a dual role in curtailing both systemic and neuroinflammation. Perillyl alcohol (POH) is a natural essential oil found in lavender, peppermint, cherries etc and has been widely studied for its strong anti-inflammatory, antioxidant and anti-stress properties.
HYPOTHESIS/PURPOSE
POH regulates the various inflammatory signaling cascades involved in chronic inflammation by inhibiting farnesyltransferase enzyme. Several studies reported that POH could inhibit the phosphorylation of NF-κB, STAT3 and promote the endogenous antioxidant enzymes like Nrf2 via farnesyltransferase enzyme inhibition. Also, the effects of POH against UC is not known yet. Thus, this study aims to explore the anti-ulcerative properties of POH on stress aggravated ulcerative colitis in C57BL/6 mice.
METHODS
Ulcerative colitis was induced by duel exposure of chronic restraint stress (day 1 to day 28) and 2.5% dextran sulphate sodium (day8 to day14) in mice. POH treatment 100 and 200 mg/kg was administred from day14 ti day28 following oral route of administration. Disease activity index, colonoscopy, western blot analysis and histological analysis, neurotransmitter analysis and Gene expression studies were perofomerd to asses the anti-colitis effects of POH.
RESULTS
The treatment reversed the oxidative stress and inflammatory response by inhibiting TLR4/NF-kB pathway, and IL-6/JAK2/STAT3 pathway in both isolated mice colons and brains. The inhibition of these pathways resulted in a decrease in pro-inflammatory cytokines like IL-6, IL-1β and TNF-α. The treatment improved the physiological and histological changes with decreased ulcerations as examined by colonic endoscopy and Haematoxylin and Eosin staining. The treatment also improved the behavior response as it increased mobility time which was reduced by chronic restrained stress. This was due to increased satiety neurotransmitters like dopamine and serotonin and decreased cortisol in mice brains.
CONCLUSION
These results infer that POH has significant anti-colitis activity on chronic restraint stress aggravated DSS-induced UC in mice.
Topics: Animals; Anti-Inflammatory Agents; Antioxidants; Colitis, Ulcerative; Cytokines; Dextran Sulfate; Dopamine; Eosine Yellowish-(YS); Farnesyltranstransferase; Hydrocortisone; Interleukin-6; Mice; Mice, Inbred C57BL; Monoterpenes; NF-E2-Related Factor 2; NF-kappa B; Oils, Volatile; Serotonin; Signal Transduction; Toll-Like Receptor 4; Tumor Necrosis Factor-alpha
PubMed: 36070663
DOI: 10.1016/j.phymed.2022.154415 -
Brazilian Oral Research 2022This study evaluated the orofacial antinociceptive effect of (S)-(-)-perillyl alcohol (PA) associated with codeine (C) and investigated the possible molecular anchorage...
This study evaluated the orofacial antinociceptive effect of (S)-(-)-perillyl alcohol (PA) associated with codeine (C) and investigated the possible molecular anchorage mechanisms of PA. Mice (n = 5 per group) were treated with PA alone and associated with codeine and assigned to the following groups: 75.0 mg/kg PA; 75.0 mg/kg PA + C 30 mg/kg; PA 37.5 mg/kg + C 15.0 mg/kg; C 30.0 mg/kg; and control. Nociception was induced by formalin, capsaicin, and glutamate, and was quantified based on the duration (in seconds) of face grooming. The possible mechanisms of action were evaluated by molecular docking study. In the formalin test, PA75/C30 presented an effect in the neurogenic (p < 0.0001) and inflammatory (p < 0.005) phases. Mice treated with PA75 (p < 0.0001) and PA75/C30 (p < 0.0005) showed a reduced nociceptive behavior in the capsaicin test. Glutamate-induced nociception also was blocked by PA75 (p < 0.0005) and C30 (p < 0.0005). The molecular anchorage analysis indicated high negative binding energy values for the evaluated receptors, especially glutamate receptors (AMPA -79.57 Kcal/mol, mGLUR6 -71.25, and NMDA -66.33 Kcal/mol). PA associated with codeine showed orofacial antinociceptive activity, with theoretical evidence of interaction with glutamate receptors.
Topics: Analgesics; Animals; Capsaicin; Codeine; Facial Pain; Glutamic Acid; Mice; Molecular Docking Simulation; Monoterpenes; Receptors, Glutamate
PubMed: 35946737
DOI: 10.1590/1807-3107bor-2022.vol36.0109 -
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 -
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 -
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 -
Journal of Materials Chemistry. B Jun 2022Elemental sulfur (), a by-product of the petroleum refining industries, possesses many favourable properties including photocatalytic activity and antibacterial...
Elemental sulfur (), a by-product of the petroleum refining industries, possesses many favourable properties including photocatalytic activity and antibacterial activity, in addition to being intrinsically hydrophobic. Despite this, there is a relative lack of research employing elemental sulfur and/or sulfur copolymers within superhydrophobic materials design. In this work, we present the use of sulfur copolymers to produce superhydrophobic materials with advanced functionalities. Using inverse vulcanization and the use of a natural organic crosslinker, perillyl alcohol (PER), stable S-PER copolymers were synthesised and later combined with silica (SiO) nanoparticles, to achieve highly water repellent composites that displayed both antimicrobial and photocatalytic properties, in the absence of carcinogenic and/or expensive materials. Here, we investigated the antibacterial performance of coatings against the Staphylococcus aureus bacterial strain, where coatings displayed great promise for use in antifouling applications, as they were found to limit surface adhesion by more than 99%, when compared to uncoated glass samples. Furthermore, UV dye degradation tests were performed, utilizing the commercially available dye resazurin, and it was shown that coatings had the potential to simultaneously exhibit surface hydrophobicity and photoactivity, demonstrating a great advancement in the field of superhydrophobic materials.
Topics: Anti-Bacterial Agents; Anti-Infective Agents; Polymers; Silicon Dioxide; Sulfur; Water
PubMed: 35438120
DOI: 10.1039/d2tb00319h -
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 -
Non-coding RNA Research Mar 2022Non-coding RNAs, including long non-coding RNAs (lncRNAs) and microRNAs (miRNAs), play critical roles in the pathogenesis and progression of pulmonary artery...
BACKGROUND
Non-coding RNAs, including long non-coding RNAs (lncRNAs) and microRNAs (miRNAs), play critical roles in the pathogenesis and progression of pulmonary artery hypertension (PAH). LncRNA H19, myocardial infarction-associated transcript (MIAT), miR-29a, and miR-33a have been suggested as potential targets for treating arterial hypertension. We explored the expression pattern of non-coding RNAs H19, MIAT, miR-29a, and miR-33a in monocrotaline (MCT)-induced PAH rats. Moreover, we investigated whether perillyl alcohol (PA) and quercetin (QS), two plant derivatives with beneficial effects on PAH-induced abnormalities, act through regulating the expression of these non-coding RNAs.
METHODS
Male Wistar rats ( = 30) were divided into five groups. MCT (60 mg/kg) was injected subcutaneously to induce PAH. PA (50 mg/kg daily) and QS (30 mg/kg daily) were administered three weeks after induction of PAH. H&E staining and qRT-PCR were performed to assess arteriole wall thickness and gene expression, respectively.
RESULTS
Right ventricular systolic pressure (RVSP) and right ventricular hypertrophy (RVH) increased in MCT and MCT + Veh. groups compared to the control group (in both < 0.001). QS and PA decreased RVSP and RVH significantly. Wall thickness and fibrosis score in the MCT group (score 3) increased compared to the control group (score 0). PA and QS ameliorated wall thickness and fibrosis to score 1 (mild). Also, the expression of miR-29a and miR-33a decreased in the PAH group (in both, < 0.001). Treatment with PA and QS decreased the expression of H19 ( < 0.001) and MIAT ( < 0.01) and increased the expression of miR-29a ( < 0.01) and miR-33a significantly ( < 0.05 for QS and < 0.001 for PA).
CONCLUSIONS
The beneficial effects of PA and QS on PAH-induced abnormalities were exerted through returning the dysregulated expression of H19, MIAT, miR-29a, and miR-33a to normal levels in rats with MTC-induced PAH. This study emphasized the therapeutic potential of PA and QS in PAH. However, more detailed investigations are needed to clarify the underlying molecular mechanisms.
PubMed: 35155877
DOI: 10.1016/j.ncrna.2022.01.005