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ChemMedChem Aug 2014Phytol was chemically transformed into fifteen semi-synthetic derivatives, which were evaluated for their antibacterial and drug resistance reversal potential in...
Phytol was chemically transformed into fifteen semi-synthetic derivatives, which were evaluated for their antibacterial and drug resistance reversal potential in combination with nalidixic acid against E. coli strains CA8000 and DH5α. The pivaloyl (4), 3,4,5-trimethoxybenzoyl (9), 2,3-dichlorobenzoyl (10), cinnamoyl (11), and aldehyde (14) derivatives of phytol ((2E,7R,11R)-3,7,11,15-tetramethyl-2-hexadecen-1-ol) were evaluated by using another antibiotic, tetracycline, against the MDREC-KG4 clinical isolate of E. coli. Derivative 4 decreased the maximal inhibitory concentration (MIC) of the antibiotics by 16-fold, while derivatives 9, 10, 11, and 14 reduced MIC values of the antibiotics up to eightfold against the E. coli strains. Derivatives 4, 9, 10, 11, and 14 inhibited the ATP-dependent efflux pump; this was also supported by their in silico binding affinity and down-regulation of the efflux pump gene yojI, which encodes the multidrug ATP-binding cassette transporter protein. This study supports the possible use of phytol derivatives in the development of cost-effective antibacterial combinations.
Topics: ATP-Binding Cassette Transporters; Anti-Bacterial Agents; Binding Sites; Drug Resistance, Bacterial; Escherichia coli; Escherichia coli Proteins; Microbial Sensitivity Tests; Molecular Docking Simulation; Phytol; Protein Structure, Tertiary
PubMed: 24891085
DOI: 10.1002/cmdc.201402027 -
Journal of Lipid Research Jan 2007Phytol, a branched-chain fatty alcohol, is the naturally occurring precursor of phytanic and pristanic acid, branched-chain fatty acids that are both ligands for the...
Phytol, a branched-chain fatty alcohol, is the naturally occurring precursor of phytanic and pristanic acid, branched-chain fatty acids that are both ligands for the nuclear hormone receptor peroxisome proliferator-activated receptor alpha (PPARalpha). To investigate the metabolism of phytol and the role of PPARalpha in its regulation, wild-type and PPARalpha knockout (PPARalpha-/-) mice were fed a phytol-enriched diet or, for comparison, a diet enriched with Wy-14,643, a synthetic PPARalpha agonist. After the phytol-enriched diet, phytol could only be detected in small intestine, the site of uptake, and liver. Upon longer duration of the diet, the level of the (E)-isomer of phytol increased significantly in the liver of PPARalpha-/- mice compared with wild-type mice. Activity measurements of the enzymes involved in phytol metabolism showed that treatment with a PPARalpha agonist resulted in a PPARalpha-dependent induction of at least two steps of the phytol degradation pathway in liver. Furthermore, the enzymes involved showed a higher activity toward the (E)-isomer than the (Z)-isomer of their respective substrates, indicating a stereospecificity toward the metabolism of (E)-phytol. In conclusion, the results described here show that the conversion of phytol to phytanic acid is regulated via PPARalpha and is specific for the breakdown of (E)-phytol.
Topics: Animals; Homeostasis; Immunoblotting; Mice; Mice, Knockout; PPAR alpha; Peroxisome Proliferators; Phytic Acid; Phytol; Pyrimidines; Reverse Transcriptase Polymerase Chain Reaction
PubMed: 17015885
DOI: 10.1194/jlr.M600050-JLR200 -
Molecular Nutrition & Food Research Mar 2018Peroxisome proliferator-activated receptor alpha (PPAR-α) is a ligand-activated transcription factor that regulates lipid and carbohydrate metabolism. We investigate...
SCOPE
Peroxisome proliferator-activated receptor alpha (PPAR-α) is a ligand-activated transcription factor that regulates lipid and carbohydrate metabolism. We investigate the effects of naturally occurring PPAR-α agonists, phytol, and its metabolite phytanic acid, on obesity-induced metabolic disorders using a mouse model.
METHODS AND RESULTS
A luciferase reporter assay shows that phytanic acid potently activates PPAR-α among PPAR subtypes. In high-fat-diet-induced, severely obese mice, a phytol-enriched diet increases phytanic acid levels in the liver and adipose tissue, where PPAR-α is abundantly expressed. A phytol-enriched diet ameliorates severe obesity and the related metabolic abnormalities of white adipose tissue. Moreover, the expression of PPAR-α target genes in the liver and brown adipose tissue is enhanced by a phytol-enriched diet, suggesting that phytol and phytanic acid activate PPAR-α in these organs. We confirm that phytanic acid treatment induced PPAR-α target gene expression in both primary hepatocytes and brown adipocytes from wild-type mice, but not in these cells from PPAR-α-deficient mice.
CONCLUSION
A phytol-enriched diet may increase phytanic acid levels in the liver and brown adipocytes, thereby activating PPAR-α in these organs and ameliorating obesity-induced metabolic diseases.
Topics: Adipose Tissue, Brown; Animals; Cells, Cultured; Diet; Lipid Metabolism; Liver; Male; Metabolic Diseases; Mice; Mice, Inbred C57BL; Obesity; PPAR alpha; Phytanic Acid; Phytol; Uncoupling Protein 1
PubMed: 29377597
DOI: 10.1002/mnfr.201700688 -
Animal Science Journal = Nihon Chikusan... 2020Recent in vitro evidence suggests that the phytol-derived fatty acids, phytanic acid (PA) and pristanic acid (PrA), are components of animal products with the potential...
Recent in vitro evidence suggests that the phytol-derived fatty acids, phytanic acid (PA) and pristanic acid (PrA), are components of animal products with the potential to cause both beneficial and harmful effects on human health. In this study, we investigated the in vivo tissue accumulation of PA and PrA and the changes in tissue lipid profiles, using mice fed a phytol-containing diet. After 4 weeks of treatment with a diet containing 1.0% phytol, plasma, adipose tissue, liver, and brain were collected and their lipid profiles were biochemically and gas-chromatographically determined. Dietary phytol caused PA and PrA accumulation in the adipose tissue and liver but not in the brain, and reduced plasma and liver triacylglycerol levels. Phytol intake also decreased the fatty acid concentrations in the adipose tissue, especially polyunsaturated fatty acids such as linoleic acid, but increased the concentrations of these fatty acids in the liver. However, dietary phytol had a low impact on the brain lipid profile. This study suggests that dietary phytol intake caused accumulation of PA and PrA and modified lipid profiles in the adipose tissue and liver, but that the brain is an insusceptible tissue to dietary phytol-induced changes.
Topics: Adipose Tissue; Animals; Brain; Diet; Fatty Acids; Fatty Acids, Unsaturated; Female; Linoleic Acid; Lipid Metabolism; Liver; Mice, Inbred C57BL; Phytanic Acid; Phytol; Tissue Distribution
PubMed: 32618084
DOI: 10.1111/asj.13424 -
Anti-cancer Agents in Medicinal... 2024Non-Small Cell Lung Cancer (NSCLC) is a malignancy with a significant prevalence and aggressive nature, posing a considerable challenge in terms of therapeutic...
BACKGROUND
Non-Small Cell Lung Cancer (NSCLC) is a malignancy with a significant prevalence and aggressive nature, posing a considerable challenge in terms of therapeutic interventions. Autophagy and apoptosis, two intricate cellular processes, are integral to NSCLC pathophysiology, each affecting the other through shared signaling pathways. Phytol (Phy) and α-bisabolol (Bis) have shown promise as potential anticancer agents individually, but their combined effects in NSCLC have not been extensively investigated.
OBJECTIVE
The present study was to examine the synergistic impact of Phy and Bis on NSCLC cells, particularly in the context of autophagy modulation, and to elucidate the resulting differential protein expression using LCMS/ MS analysis.
METHODS
The A549 cell lines were subjected to the patented effective concentration of Phy and Bis, and subsequently, the viability of the cells was evaluated utilizing the MTT assay. The present study utilized real-time PCR analysis to assess the expression levels of crucial apoptotic genes, specifically Bcl-2, Bax, and Caspase-9, as well as autophagy-related genes, including Beclin-1, SQSTM1, Ulk1, and LC3B. The confirmation of autophagy marker expression (Beclin-1, LC3B) and the autophagy-regulating protein SQSTM1 was achieved through the utilization of Western blot analysis. Differentially expressed proteins were found using LC-MS/MS analysis.
RESULTS
The combination of Phy and Bis demonstrated significant inhibition of NSCLC cell growth, indicating their synergistic effect. Real-time PCR analysis revealed a shift towards apoptosis, with downregulation of Bcl-2 and upregulation of Bax and Caspase-9, suggesting a shift towards apoptosis. Genes associated with autophagy regulation, including Beclin-1, SQSTM1 (p62), Ulk1, and LC3B, showed significant upregulation, indicating potential induction of autophagy. Western blot analysis confirmed increased expression of autophagy markers, such as Beclin-1 and LC3B, while the autophagy-regulating protein SQSTM1 exhibited a significant decrease. LC-MS/MS analysis revealed differential expression of 861 proteins, reflecting the modulation of cellular processes. Protein-protein interaction network analysis highlighted key proteins involved in apoptotic and autophagic pathways, including STOML2, YWHAB, POX2, B2M, CDA, CAPN2, TXN, ECHS1, PEBP1, PFN1, CDC42, TUBB1, HSPB1, PXN, FGF2, and BAG3, emphasizing their crucial roles. Additionally, PANTHER pathway analysis uncovered enriched pathways associated with the differentially expressed proteins, revealing their involvement in a diverse range of biological processes, encompassing cell signaling, metabolism, and cellular stress responses.
CONCLUSION
The combined treatment of Phy and Bis exerts a synergistic inhibitory effect on NSCLC cell growth, mediated through the interplay of apoptosis and autophagy. The differential protein expression observed, along with the identified proteins and enriched pathways, provides valuable insights into the underlying molecular mechanisms. These findings offer a foundation for further exploration of the therapeutic potential of Phy and Bis in the management of NSCLC.
Topics: Humans; Autophagy; Apoptosis; Tandem Mass Spectrometry; Cell Proliferation; Phytol; Drug Screening Assays, Antitumor; Cell Survival; Dose-Response Relationship, Drug; A549 Cells; Proteome; Chromatography, Liquid; Antineoplastic Agents, Phytogenic; Structure-Activity Relationship; Molecular Structure; Carcinoma, Non-Small-Cell Lung; Antineoplastic Agents; Drug Synergism; Lung Neoplasms; Tumor Cells, Cultured; Sesquiterpenes
PubMed: 38415491
DOI: 10.2174/0118715206289038240214102951 -
Biochimica Et Biophysica Acta.... Sep 20172-Hydroxyacyl-CoA lyase (HACL1) is a key enzyme of the peroxisomal α-oxidation of phytanic acid. To better understand its role in health and disease, a mouse model...
2-Hydroxyacyl-CoA lyase (HACL1) is a key enzyme of the peroxisomal α-oxidation of phytanic acid. To better understand its role in health and disease, a mouse model lacking HACL1 was investigated. Under normal conditions, these mice did not display a particular phenotype. However, upon dietary administration of phytol, phytanic acid accumulated in tissues, mainly in liver and serum of KO mice. As a consequence of phytanic acid (or a metabolite) toxicity, KO mice displayed a significant weight loss, absence of abdominal white adipose tissue, enlarged and mottled liver and reduced hepatic glycogen and triglycerides. In addition, hepatic PPARα was activated. The central nervous system of the phytol-treated mice was apparently not affected. In addition, 2OH-FA did not accumulate in the central nervous system of HACL1 deficient mice, likely due to the presence in the endoplasmic reticulum of an alternate HACL1-unrelated lyase. The latter may serve as a backup system in certain tissues and account for the formation of pristanic acid in the phytol-fed KO mice. As the degradation of pristanic acid is also impaired, both phytanoyl- and pristanoyl-CoA levels are increased in liver, and the ω-oxidized metabolites are excreted in urine. In conclusion, HACL1 deficiency is not associated with a severe phenotype, but in combination with phytanic acid intake, the normal situation in man, it might present with phytanic acid elevation and resemble a Refsum like disorder.
Topics: Animals; Disease Models, Animal; Endoplasmic Reticulum; Enoyl-CoA Hydratase; Fatty Acids; Female; Liver; Lyases; Male; Mice; Mice, Knockout; Oxidation-Reduction; PPAR alpha; Phytanic Acid; Phytol
PubMed: 28629946
DOI: 10.1016/j.bbalip.2017.06.004 -
Anti-cancer Agents in Medicinal... 2018Phytol have various pharmacological activities such as antimicrobial, cytotoxic, antitumoral, antimutagenic, anti-atherogenic, antidiabetic, lipid-lowering,... (Meta-Analysis)
Meta-Analysis
BACKGROUND
Phytol have various pharmacological activities such as antimicrobial, cytotoxic, antitumoral, antimutagenic, anti-atherogenic, antidiabetic, lipid-lowering, antispasmodic, antiepileptic, antinociceptive, antioxidant, anti-inflammatory, anxiolytic, antidepressant and immunoadjuvant. Several studies point to an association of phytol with implications for apoptosis and necrosis at cellular levels in cancer, yet no clear conclusions were drawn.
METHOD
To clarify this, we conducted a meta-analysis of non-clinical studies of phytol and its associations with toxicity and cytotoxicity emphasizing the mechanisms of apoptosis and necrosis induction and its importance in tumor therapy. Relevant studies were systematically searched in PubMed and Web of Science. The association between phytol and cyto-/toxicity was assessed by odds ratio (ORs) and 95% confidence intervals (CI). Twentythree studies were finally included in the meta-analysis. A significant association between phytol and toxicity (OR: 1.47; 95% CI = 0.86-2.48) was found among studies and cytotoxicity (OR: 1.81; 95% CI = 1.12- 2.65, p<0.05) in and studies. In studies, 24% of them indicate that phytol at high doses induces apoptosis by several mechanisms; while about 40% of studies indicate that phytol induces reactive oxygen species generation. But, Phytol does not act as a direct oxidant, unlike its metabolite phytanic acid. The 24% of studies also highlighted the mechanisms for apoptosis-like including expression of Bcl2 protein or mutations in pro-apoptotic protein Bax. Of them, 8% studies show necrosis and hepatotoxicity. However, in 24% of the articles, the mechanisms of toxicity and cytotoxicity are still not well elucidated.
CONCLUSION
This study confirms that the association between phytol and cyto-/toxicity depends on the dose/concentration used in the given experimental conditions. Thus, there are still great prospects for new research aimed at the use of phytol and its metabolite as anticancer agents.
Topics: Antineoplastic Agents; Apoptosis; Cell Proliferation; Humans; Neoplasms; Phytol
PubMed: 30129418
DOI: 10.2174/1871520618666180821113830 -
Water Research Apr 2022With a growing consciousness of the importance of nature stewardship, researchers are focusing their efforts on utilizing renewable energy, particularly solar energy, to...
Sunlight-active phytol-ZnO@TiO nanocomposite for photocatalytic water remediation and bacterial-fouling control in aquaculture: A comprehensive study on safety-level assessment.
With a growing consciousness of the importance of nature stewardship, researchers are focusing their efforts on utilizing renewable energy, particularly solar energy, to address environmental concerns. In this context, photocatalysis has long been viewed as one of the most promising cleaning methods. Hence, we have prepared a sunlight-active phytol-assisted ZnO-TiO nanocomposite (PZTN) for photocatalytic bacterial deactivation and dye degradation process. The PZTN-photocatalysis effectively deactivated the bacterial pathogens as well as malachite green dye within 240 min under direct-sunlight. Moreover, this will be the first complete study on safety level assessment of photocatalytically-remediated water through toxicity studies. The obtained results evidenced that photocatalytically-deactivated bacteria and MG-dye showed to have no toxic effects, signifying that the PZTN-photocatalyzed water seems to be extremely safe for the environment. As a result of this research, we suggest that the PZTN could be a promising sunlight-active photocatalyst for environmental water treatment. On the other hand, biofouling is a ubiquitous phenomenon in the marine environment. Bacteria are the first organisms to foul surfaces and produce biofilms on man-made submerged materials. Interestingly, PZTN-coated PVC plastic-films effectively disallowed biofilms on their surface. This part of this research suggests that PZTN coated PVC-plastics are the best alternative for biofouling management.
Topics: Aquaculture; Bacteria; Catalysis; Humans; Nanocomposites; Phytol; Sunlight; Titanium; Zinc Oxide
PubMed: 35077939
DOI: 10.1016/j.watres.2022.118081 -
The Plant Cell Oct 2015Phytol from chlorophyll degradation can be phosphorylated to phytyl-phosphate and phytyl-diphosphate, the substrate for tocopherol (vitamin E) synthesis. A candidate for...
Phytol from chlorophyll degradation can be phosphorylated to phytyl-phosphate and phytyl-diphosphate, the substrate for tocopherol (vitamin E) synthesis. A candidate for the phytyl-phosphate kinase from Arabidopsis thaliana (At1g78620) was identified via a phylogeny-based approach. This gene was designated VITAMIN E DEFICIENT6 (VTE6) because the leaves of the Arabidopsis vte6 mutants are tocopherol deficient. The vte6 mutant plants are incapable of photoautotrophic growth. Phytol and phytyl-phosphate accumulate, and the phytyl-diphosphate content is strongly decreased in vte6 leaves. Phytol feeding and enzyme assays with Arabidopsis and recombinant Escherichia coli cells demonstrated that VTE6 has phytyl-P kinase activity. Overexpression of VTE6 resulted in increased phytyl-diphosphate and tocopherol contents in seeds, indicating that VTE6 encodes phytyl-phosphate kinase. The severe growth retardation of vte6 mutants was partially rescued by introducing the phytol kinase mutation vte5. Double mutant plants (vte5 vte6) are tocopherol deficient and contain more chlorophyll, but reduced amounts of phytol and phytyl-phosphate compared with vte6 mutants, suggesting that phytol or phytyl-phosphate are detrimental to plant growth. Therefore, VTE6 represents the missing phytyl-phosphate kinase, linking phytol release from chlorophyll with tocopherol synthesis. Moreover, tocopherol synthesis in leaves depends on phytol derived from chlorophyll, not on de novo synthesis of phytyl-diphosphate from geranylgeranyl-diphosphate.
Topics: Arabidopsis; Arabidopsis Proteins; Biological Transport; Biosynthetic Pathways; Chlorophyll; Diphosphates; Mutation; Phosphorylation; Phosphotransferases; Phylogeny; Phytol; Plant Leaves; Seeds; Tocopherols
PubMed: 26452599
DOI: 10.1105/tpc.15.00395 -
Molecules (Basel, Switzerland) Oct 2022In this study, a novel galloyl phytol antioxidant was developed by incorporating the branched phytol chain with gallic acid through mild Steglich esterification. The...
In this study, a novel galloyl phytol antioxidant was developed by incorporating the branched phytol chain with gallic acid through mild Steglich esterification. The evaluation of the radical scavenging activity, lipid oxidation in a liposomal model, and glycerol trioleate revealed its superior antioxidant activities in both dispersed and bulk oils. Then, the antioxidant capacity enhancement of galloyl phytol was further explored using thermal gravimetry/differential thermal analysis (TG/DTA), transmission electron microscopy (TEM), and molecular modeling. The EC50 values of GP, GPa, and GE were 0.256, 0.262, and 0.263 mM, respectively, which exhibited comparable DPPH scavenging activities. These investigations unveiled that the branched aliphatic chain enforced the coiled molecular conformation and the unsaturated double bond in the phytol portion further fixed the coiled conformation, which contributed to a diminished aggregation tendency and enhanced antioxidant activities in dispersed and bulk oils. The remarkable antioxidant performance of galloyl phytol suggested intriguing and non-toxic natural antioxidant applications in the food industry, such as effectively inhibiting the oxidation of oil and improvement of the quality and shelf life of the oil, which would contribute to the use of tea resources and extending the tea industry chain.
Topics: Phytol; Antioxidants; Esterification; Plant Oils; Tea
PubMed: 36364126
DOI: 10.3390/molecules27217301