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Nutrition and Cancer 2021Cancer stem cells (CSCs), a subgroup of cancer cells, have self-renewal capacity and differentiation potential and drive tumor growth. CSCs are highly-resistant to...
Cancer stem cells (CSCs), a subgroup of cancer cells, have self-renewal capacity and differentiation potential and drive tumor growth. CSCs are highly-resistant to conventional chemo-radio therapy. Phytochemicals were shown to be able to eliminate CSCs. Phytol is a diterpene alcohol with demonstrated anticancer effects. The current study compared the effect of phytol with retinoic acid (RA) as a well-known inducers of CSC differentiation and cisplatin, a common chemotherapy drug, on CSC markers in human embryonic carcinoma NCCIT cells. NCCIT cells were exposed to 10 mM RA for 14 day to induce differentiation. Moreover, NCCIT cells were treated with IC dose of cisplatin (12 µM) and phytol (40 µM) for 7 day. Real-time PCR showed that phytol was more effective that RA and cisplatin in down-regulating the CSC markers , . Percentage of SP (13%) and ABCB1 (0.34%) in NCCIT cells decreased to 7% and 0.1% respectively after treatment with phytol. A very small proportion of NCCIT cells were positive for CD44 (0.2%) and CD133 (0.48%) and this fraction did not change significantly after treatment with three agents. In conclusion, phytol has the greatest inhibitory effect on CSC population and markers than RA and cisplatin.
Topics: Carcinoma; Cell Line, Tumor; Cisplatin; Humans; Neoplastic Stem Cells; Phytol
PubMed: 32700607
DOI: 10.1080/01635581.2020.1795695 -
The Plant Journal : For Cell and... Mar 2022During chlorophyll degradation, large amounts of the isoprenoid alcohol phytol are released. The pathway of phytol catabolism has been studied in humans, because...
During chlorophyll degradation, large amounts of the isoprenoid alcohol phytol are released. The pathway of phytol catabolism has been studied in humans, because chlorophyll is part of the human diet, but little is known for plants. In humans, phytanoyl-CoA derived from phytol is degraded via α-oxidation by phytanoyl-CoA hydroxylase (PAHX) and 2-hydroxy-phytanoyl-CoA lyase (HPCL). Arabidopsis contains two sequences homologous to the human proteins AtPAHX and AtHPCL. Insertional mutants of Arabidopsis (pahx, hpcl) were grown under N deprivation to stimulate chlorophyll breakdown or supplemented with phytol to increase the endogenous amount of phytol. During N deprivation, chlorophyll, phytol, phytenal, upstream metabolites of phytol breakdown, and tocopherol and fatty acid phytyl esters, alternative phytol-derived lipids, accumulated in pahx and hpcl mutants, in line with the scenario that the mutations interfere with phytol degradation. AtHPCL was localized to the peroxisomes. Expression analysis of the AtHPCL sequence in the yeast Δpxp1 or Δmpo1 mutants followed by supplementation with 2-hydroxy-palmitic acid and enzyme assays of peroxisomal proteins from Col-0 and hpcl plants with 2-hydroxy-stearoyl-CoA revealed that AtHPCL harbors 2-hydroxy-acyl-CoA lyase activity. The α-dioxygenases αDOX1 and αDOX2 are involved in α-oxidation of fatty acids and could be involved in an alternative pathway of phytol degradation. However, phytol-related lipids in the αdox1, αdox2, or αdox1 αdox2 mutants were not altered compared with Col-0, indicating that αDOX1 and αDOX2 are not involved in phytol degradation. These results demonstrate that phytol degradation in Arabidopsis involves α-oxidation by AtPAHX and AtHPCL, but that it is independent of αDOX1/αDOX2.
Topics: Arabidopsis; Chlorophyll; Coenzyme A; Fatty Acids; Lyases; Phytanic Acid; Phytol
PubMed: 34902195
DOI: 10.1111/tpj.15632 -
The Plant Cell Oct 2015
Topics: Carbon Isotopes; Chlorophyll; Phytol; Tocopherols
PubMed: 26475867
DOI: 10.1105/tpc.15.00860 -
Environmental Toxicology Apr 2019In the present study, the modulatory effect of phytol against benzo(a)pyrene [B(a)P] induced lung carcinogenesis was investigated in Swiss albino mice. During the...
In the present study, the modulatory effect of phytol against benzo(a)pyrene [B(a)P] induced lung carcinogenesis was investigated in Swiss albino mice. During the experimental period, phytol treatment showed no adverse toxic effect and mortality to the experimental animals. Lung tumor was observed in B(a)P treated group and also in animals post-treated with low concentration (50 mg/kg) of phytol. No neoplastic changes were observed in the lung tissue of the animals treated with the maximum dose of phytol (100 mg/kg). An elevated level of antioxidant enzymes combined with macromolecular damage (lipid peroxidation, protein carbonyl content) was observed upon B(a)P treatment whereas, phytol restored the level of antioxidant enzymes which were comparable to the vehicle control group. Moreover, administration of B(a)P induced apoptosis, as observed by the highest expression of Bax, caspase-3, and caspase-9 proteins in lung tissue of B(a)P alone treated animals. However, phytol treatment reduced the expression of Bax, caspase-3, and caspase-9 protein and maintained the constant expression of anti-apoptotic protein Bcl-2. These observations positively reveal that phytol regulates the antioxidant enzymes and thereby protects the cells against B(a)P induced carcinogenesis without showing any adverse toxic effect to the animals.
Topics: Animals; Anticarcinogenic Agents; Antioxidants; Apoptosis; Benzo(a)pyrene; Carcinogens, Environmental; Lipid Peroxidation; Lung Neoplasms; Male; Mice; Oxidative Stress; Phytol; Protein Carbonylation
PubMed: 30520250
DOI: 10.1002/tox.22690 -
Food and Chemical Toxicology : An... Jan 2010A toxicological and dermatologic review of phytol when used as a fragrance ingredient is presented. (Review)
Review
A toxicological and dermatologic review of phytol when used as a fragrance ingredient is presented.
Topics: Animals; Carcinogenicity Tests; Humans; Mucous Membrane; Mutagenicity Tests; Odorants; Phytol; Reproduction; Skin; Teratogens
PubMed: 20141879
DOI: 10.1016/j.fct.2009.11.012 -
Journal of Natural Products Apr 2020Phytol is a diterpene constituent of chlorophyll and has been shown to have several pharmacological properties, particularly in relation to the management of painful...
Phytol, a Chlorophyll Component, Produces Antihyperalgesic, Anti-inflammatory, and Antiarthritic Effects: Possible NFκB Pathway Involvement and Reduced Levels of the Proinflammatory Cytokines TNF-α and IL-6.
Phytol is a diterpene constituent of chlorophyll and has been shown to have several pharmacological properties, particularly in relation to the management of painful inflammatory diseases. Arthritis is one of the most common of these inflammatory diseases, mainly affecting the synovial membrane, cartilage, and bone in joints. Proinflammatory cytokines, such as TNF-α and IL-6, and the NFκB signaling pathway play a pivotal role in arthritis. However, as the mechanisms of action of phytol and its ability to reduce the levels of these cytokines are poorly understood, we decided to investigate its pharmacological effects using a mouse model of complete Freund's adjuvant (CFA)-induced arthritis. Our results showed that phytol was able to inhibit joint swelling and hyperalgesia throughout the whole treatment period. Moreover, phytol reduced myeloperoxidase (MPO) activity and proinflammatory cytokine release in synovial fluid and decreased IL-6 production as well as the COX-2 immunocontent in the spinal cord. It also downregulated the p38MAPK and NFκB signaling pathways. Therefore, our findings demonstrated that phytol can be an innovative antiarthritic agent due to its capacity to attenuate inflammatory reactions in joints and the spinal cord, mainly through the modulation of mediators that are key to the establishment of arthritic pain.
Topics: Animals; Anti-Inflammatory Agents; Chlorophyll; Cytokines; Disease Models, Animal; Edema; Freund's Adjuvant; Hyperalgesia; Inflammation; Interleukin-6; Mice; Molecular Structure; NF-kappa B; Pain; Phytol; Synovial Membrane; Tumor Necrosis Factor-alpha
PubMed: 32091204
DOI: 10.1021/acs.jnatprod.9b01116 -
Cellular and Molecular Life Sciences :... Aug 2006Phytanic acid is a branched-chain fatty acid that accumulates in a variety of metabolic disorders. High levels of phytanic acid found in patients can exceed the... (Review)
Review
Phytanic acid is a branched-chain fatty acid that accumulates in a variety of metabolic disorders. High levels of phytanic acid found in patients can exceed the millimolar range and lead to severe symptoms. Degradation of phytanic acid takes place by alpha-oxidation inside the peroxisome. A deficiency of its breakdown, leading to elevated levels, can result from either a general peroxisomal dysfunction or from a defect in one of the enzymes involved in alpha-oxidation. Research on Refsum disease, belonging to the latter group of disorders and characterized by a deficiency of the first enzyme of alpha-oxidation, has extended our knowledge of phytanic acid metabolism and pathology of the disease greatly over the past few decades. This review will centre on this research on phytanic acid: its origin, the mechanism by which its alpha-oxidation takes place, its role in human disease and the way it is produced from phytol.
Topics: Aldehyde Oxidoreductases; Chondrodysplasia Punctata, Rhizomelic; Humans; Oxidation-Reduction; Peroxisomal Disorders; Peroxisomes; Phytanic Acid; Phytol; Protein Transport; Refsum Disease
PubMed: 16799769
DOI: 10.1007/s00018-005-5463-y -
Chemico-biological Interactions Apr 2018Phytol (3,7,11,15-tetramethyl-2-hexadecen-1-ol) is an acyclic monounsaturated diterpene alcohol generated from chlorophyll metabolism that exerts anti-inflammatory,...
Phytol (3,7,11,15-tetramethyl-2-hexadecen-1-ol) is an acyclic monounsaturated diterpene alcohol generated from chlorophyll metabolism that exerts anti-inflammatory, antithrombotic, antimicrobial, and antitumor effects. However, the effect of phytol on melanogenesis and the underlying molecular mechanisms of its inhibition remain unknown. Here, we found that phytol suppressed α-melanocyte-stimulating hormone-induced melanogenesis in B16F10 murine melanoma cells without any toxic effects. Phytol significantly attenuated melanin production by reducing the expression of tyrosinase and tyrosinase related protein 1. Treatment with phytol inhibited the expression of microphthalmia-associated transcription factor (MITF) by phosphorylating extracellular signal-regulated protein kinase (ERK). The ERK inhibitor PD98059 restored MITF expression and prevented the anti-melanogenic effect of phytol. We found that the ERK inhibitor coincidently abrogated MITF ubiquitination and degradation, suggesting that the ERK pathway is involved in phytol-induced ubiquitination of MITF. Furthermore, our data show that reactive oxygen species (ROS) production was increased in cells treated with phytol. Consistently, a ROS scavenger inhibited ERK phosphorylation and restored MITF degradation. Accordingly, the intermediary role of ROS was confirmed in phytol-induced MITF degradation. Taken together, these results demonstrate that phytol stimulates ROS production and modulates ERK-mediated proteasomal degradation of MITF in B16F10 murine melanoma cells. These findings suggest that phytol may have potential to be utilized as a whitening agent in cosmetics and as a therapy for skin hyperpigmentation.
Topics: Animals; Cell Line, Tumor; Cell Survival; Extracellular Signal-Regulated MAP Kinases; Flavonoids; Gene Expression; Melanins; Mice; Microphthalmia-Associated Transcription Factor; Monophenol Monooxygenase; Phosphorylation; Phytol; Proteasome Endopeptidase Complex; Reactive Oxygen Species; Signal Transduction; Ubiquitination; alpha-MSH
PubMed: 29486182
DOI: 10.1016/j.cbi.2018.02.033 -
Journal of Molecular Medicine (Berlin,... Oct 2018Multiple sclerosis (MS) is an inflammatory, demyelinating disease of the central nervous system. We investigated the effect of phytol in an animal model of MS,...
UNLABELLED
Multiple sclerosis (MS) is an inflammatory, demyelinating disease of the central nervous system. We investigated the effect of phytol in an animal model of MS, experimental autoimmune encephalomyelitis (EAE), as phytol, a plant-derived diterpene alcohol, exerts anti-inflammatory and redox-protective actions. We observed a significant amelioration of clinical symptoms in EAE C57BL/6N mice fed prophylactically with a phytol-enriched diet. Demyelination, DNA damage, and infiltration of immune cells, specifically T1 cells, into the central nervous system were reduced in phytol-fed EAE mice. Furthermore, phytol reduced T-cell proliferation ex vivo. Phytanic acid - a metabolite of phytol - also reduced T-cell proliferation, specifically that of T1 cells. Additionally, phytol-enriched diet increased the mRNA expression of nicotinamide adenine dinucleotide phosphate oxidase (NOX) 2 in white blood cells in the lymph nodes. Accordingly, phytol lost its anti-inflammatory effects in chimeric EAE C57BL/6N mice whose peripheral cells lack NOX2, indicating that phytol mediates its effects in peripheral cells via NOX2. Moreover, the effects of phytol on T-cell proliferation were also NOX2-dependent. In contrast, the T-cell subtype alterations and changes in proliferation induced by phytanic acid, the primary metabolite of phytol, were NOX2-independent. In conclusion, phytol supplementation of the diet leads to amelioration of EAE pathology in both a NOX2-dependent and a NOX2-independent manner via yet unknown mechanisms.
KEY MESSAGES
Phytol diet ameliorates EAE pathology. Phytol diet reduces demyelination, immune cell infiltration, and T-cell proliferation. Phytol diet increases NOX2 mRNA expression in white blood cells in the lymph nodes. Phytol mediates its effects in peripheral cells via NOX2. Effects of phytol on T-cell proliferation were NOX2-dependent.
Topics: Animals; Cell Proliferation; Dietary Supplements; Encephalomyelitis, Autoimmune, Experimental; Female; Lymph Nodes; Mice, Inbred C57BL; NADPH Oxidase 2; Phytol; Spinal Cord; T-Lymphocytes
PubMed: 30151738
DOI: 10.1007/s00109-018-1689-7 -
Journal of Food Science Jun 2023Phytol is a diterpene alcohol found abundantly in nature as the phytyl side chain of chlorophylls. Free form of phytol and its metabolites have been attracting attention...
Phytol is a diterpene alcohol found abundantly in nature as the phytyl side chain of chlorophylls. Free form of phytol and its metabolites have been attracting attention because they have a potential to improve the lipid and glucose metabolism. On the other hand, phytol is unfavorable for those who suffering from Refsum's disease. However, there is little information on the phytol contents in leafy vegetables rich in chlorophylls. This study indicated that raw spinach leaves contain phytol of 0.4-1.5 mg/100 g fresh weight. Furthermore, crude enzyme extracted from the leaves showed the enzyme activities involved in dephytylation of chlorophyll derivatives and they were high at mild alkaline pH and around 45°C, and lowered at 55°C or above. Under the optimum pH and temperature for such enzymes determined in the model reaction using the crude enzyme, phytol content in the smoothie made from raw spinach leaves increased with an increase of chlorophyllide, another reaction product. Comparison between the increased amounts of phytol and chlorophyllide showed that the enzymatic dephytylation of chlorophylls was critically responsible for the increase of phytol in the smoothie. PRACTICAL APPLICATION: Phytol, which is released by the enzymes related to chlorophyll metabolism in plants, has been investigated because of its potential abilities to improve the lipid metabolism and blood glucose level. In contrast to such health benefits, they are known to be toxic for patients suffering from Refsum's disease. This research for the first time reports the phytol content in raw spinach leaves and that phytol can be increased in the smoothie made from spinach leaves by the action of endogenous enzymes on chlorophyll derivatives under a certain condition. These results help control phytol content in the smoothies.
Topics: Humans; Chlorophyllides; Spinacia oleracea; Refsum Disease; Phytol; Chlorophyll
PubMed: 37122139
DOI: 10.1111/1750-3841.16588