The Experts below are selected from a list of 2682 Experts worldwide ranked by ideXlab platform
Joan E Roberts - One of the best experts on this subject based on the ideXlab platform.
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Hypericin mediated photooxidative damage of α crystallin in human lens epithelial cells
2013Co-Authors: Marilyn Ehrenshaft, Joan E Roberts, Ronald P MasonAbstract:St. John’s wort (Hypericum perforatum), a perennial herb native to Europe, is widely used for and seems to be effective in treatment of mild to moderate depression. Hypericin, a singlet oxygen-generating photosensitizer that absorbs in both the visible and the UVA range, is considered to be one of the bioactive ingredients of St. John’s wort, and commercial preparations are frequently calibrated to contain a standard concentration. Hypericin can accumulate in ocular tissues, including lenses, and can bind in vitro to α-crystallin, a major lens protein. α-crystallin is required for lens transparency and also acts as a chaperone to ensure its own integrity and the integrity of all lens proteins. Because there is no crystallin turnover, damage to α-crystallin is cumulative over the lifetime of the lens and can lead to cataracts, the principal cause of blindness worldwide. In this work we study Hypericin photosensitization of α-crystallin and detect extensive polymerization of bovine α-crystallin exposed in vitro to Hypericin and UVA. We use fluorescence confocal microscopy to visualize binding between Hypericin and α-crystallin in a human lens epithelial (HLE) cell line. Further, we show that UVA irradiation of Hypericin-treated HLE cells results in a dramatic decrease in α-crystallin detection concurrent with a dramatic accumulation of the tryptophan oxidation product N-formylkynurenine (NFK). Examination of actin in HLE cells indicates that this cytoskeleton protein accumulates NFK resulting from Hypericin-mediated photosensitization. This work also shows that filtration of wavelengths <400 nm provides incomplete protection against α-crystallin modification and NFK accumulation, suggesting that even by wearing UV-blocking sunglasses, routine users of St. John’s wort cannot adequately shield their lenses from Hypericin-mediated photosensitized damage.
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phototoxicity in human retinal pigment epithelial cells promoted by Hypericin a component of st john s wort
2007Co-Authors: Albert R Wielgus, Colin F Chignell, David S Miller, Ben Van Houten, Joel N Meyer, Joan E RobertsAbstract:St. John’s wort (SJW), an over-the-counter antidepressant, contains Hypericin, which absorbs light in the UV and visible ranges. In vivo studies have determined that Hypericin is phototoxic to skin and our previous in vitro studies with lens tissues have determined that it is potentially phototoxic to the human lens. To determine if Hypericin might also be phototoxic to the human retina, we exposed human retinal pigment epithelial (hRPE) cells to 10 )7 to 10 )5 M Hypericin. Fluorescence emission detected from the cells (kex = 488 nm; kem = 505 nm) confirmed Hypericin uptake by human RPE. Neither Hypericin exposure alone nor visible light exposure alone reduced cell viability. However when irradiated with 0.7 J cm )2 of visible light (k > 400 nm) there was loss of cell viability as measured by MTS and lactate dehydrogenase assays. The presence of Hypericin in irradiated hRPE cells significantly changed the redox equilibrium of glutathione and a decrease in the activity of glutathione reductase. Increased lipid peroxidation as measured by the thiobarbituric acid reactive substances assay correlated to Hypericin concentration in hRPE cells and visible light radiation. Thus, ingested SJW is potentially phototoxic to the retina and could contribute to retinal or early macular degeneration.
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phototoxicity in human lens epithelial cells promoted by st john s wort
2004Co-Authors: Colin F Chignell, David S Miller, Usha P Andley, Joan E RobertsAbstract:St. John’s Wort (SJW), an over-the-counter antidepressant, contains Hypericin, which absorbs light in the UV and visible ranges and is phototoxic to skin. To determine if it also could be phototoxic to the eye, we exposed human lens epithelial cells to 0.1–10 lM Hypericin and irradiated them with 4 J/cm 2 UV-A or 0.9 J/cm 2 visible light. Neither Hypericin exposure alone nor light exposure alone reduced cell viability. In contrast, cells exposed to Hypericin in combination with UV-A or visible light underwent necrosis and apoptosis. The ocular antioxidants lutein and N-acetyl cysteine did not prevent damage. Thus, ingested SJW is potentially phototoxic to the eye and could contribute to early cataractogenesis. Precautions should be taken to protect the eye from intense sunlight while taking SJW.
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photooxidation of lens α crystallin by Hypericin active ingredient in st john s wort
2000Co-Authors: Kevin L Schey, Colin F Chignell, Severine A Patat, M Datillo, R H Wang, Joan E RobertsAbstract:Abstract Hypericin is the active ingredient in the over the counter antidepressant medication St. John's Wort. Hypericin produces singlet oxygen and other excited state intermediates that indicate it should be a very efficient phototoxic agent in the eye. Furthermore it absorbs in the UV and visible range, which means it can potentially damage both the lens and the retina. Lens α-crystallin, isolated from calf lenses, was irradiated in the presence of Hypericin (5 × 10−5 M, 10 mM ammonium bicarbonate, pH 7.0) and in the presence and absence of light (>300 nm, 24 mW/cm2). Hypericin-induced photosensitized photopolymerization as assessed by sodium dodecylsulfate-polyacrylamide gel electrophoresis. Further analysis of the oxidative changes occurring in α-crystallin using mass spectrometry showed specific oxidation of methionine, tryptophan and histidine residues, which increased with irradiation time. Hypericin did not damage the lens protein in the dark. Damage to α-crystallin could undermine the integrity ...
Peter De Witte - One of the best experts on this subject based on the ideXlab platform.
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topical treatment of disseminated superficial actinic porokeratosis with Hypericin photodynamic therapy a case report
2010Co-Authors: Annelies Boiy, Peter De Witte, Rik RoelandtsAbstract:Hypericin is a photo-active dye originating from the St. John's wort. Two patients with disseminated superficial actinic porokeratosis (DSAP) were treated with photodynamic therapy (PDT) using topical Hypericin. Although a partial response was obtained in one patient topical Hypericin-PDT does not emerge as a promising treatment for DSAP.
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The Multifaceted Photocytotoxic Profile of Hypericin
2009Co-Authors: Theodossis A. Theodossiou, Peter De Witte, John S. Hothersall, Alexandros Pantos, Patrizia AgostinisAbstract:Photodynamic therapy (PDT) is an established anticancer treatment employing a phototoxin (photosensitizer), visible light and oxygen. The latter is photochemically converted into reactive oxygen species, which are highly toxic to the cells. Hypericin, a natural pigment of hypericum plants, is prominent among photosensitizers. The unique perylenequinone structure of Hypericin is responsible for its intriguing multifaceted photochemical cytotoxicity. The diverse photodynamic action of Hypericin targets a range of subcellular organelles most importantly the mitochondria and the endoplasmic reticulum (ER)-Golgi complex. Hypericin exerts its phototoxicity through intricate mechanisms, implicating key proteins, vital enzymes, organelle membranes and changes in cellular homeostasis. This, depending on drug and light administration conditions, leads to cell death, which occurs mainly by the induction of apoptosis and/or necrosis. Cell photosensitization with Hypericin is also associated with the stimulation of macroautophagy, which may promote cell demise when the apoptotic machinery is defective. Herein, we aim to integrate the most important findings with regard to Hypericin photocytotoxicity, into a unified scenario, detailing its potential in cancer photomedicine.
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Hypericin as a marker for determination of tissue viability after intratumoral ethanol injection in a murine liver tumor model
2008Co-Authors: Marie Van De Putte, Huaijun Wang, Feng Chen, Peter De WitteAbstract:Rationale and Objectives In this preclinical proof-of-principle study, the necrosis avid agent Hypericin was investigated as a potential early indicator for therapeutic response after ethanol-mediated chemical ablation in murine liver tumors. Materials and Methods Seven mice bearing intrahepatic radiation-induced fibrosarcoma-1 tumors were intravenously injected with Hypericin 1 hour before (n = 3) or 24 hours after (n = 4) intratumoral ethanol injection. Mice were euthanized 24 hours after Hypericin injection and, taking advantage of the fluorescent property of the compound, the excised livers were investigated qualitatively and quantitatively by means of fluoromacroscopic and fluoromicroscopic examinations, colocalized with conventional histomorphology. Results Significant differences in Hypericin fluorescence were found in necrosis, viable tumor and normal liver tissue in decreasing order (P Conclusions Hypericin specifically enhanced the imaging contrast between necrotic and viable tissues and nonspecifically distinguished viable tumor from normal liver. Injection of Hypericin shortly before ablation is more favorable than after ablation, because it circumvents difficulties with no-entry zones for Hypericin and requires shorter intervals between ethanol ablation and imaging.
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enhancing the photodynamic effect of Hypericin in human bladder transitional cell carcinoma spheroids by the use of the oxygen carrier perfluorodecalin
2006Co-Authors: Appolinary R Kamuhabwa, Ann Huygens, Tania Roskams, Peter De WitteAbstract:: In the present study, we evaluated the possibility of enhancing the photodynamic effect of Hypericin in transitional cell carcinoma (TCC) spheroids by the use of the oxygen carrier, perfluorodecalin. Following incubation with Hypericin, RT-112 TCC spheroids were irradiated in the presence or absence of perfluorodecalin, at light doses of 7 J/cm(2) or 28 J/cm(2) , delivered at a fluence rate of 15 mW/cm(2) . The photodynamic therapy (PDT) efficacy was evaluated and apoptotic cells were visualized. The results show that, in the absence of perfluorodecalin, spheroidal TCC cells are inadequately sensitive to Hypericin PDT. As was shown by fluorescence microscopy, this lack of activity was not due to insufficient photoactive concentrations of Hypericin reaching the inner parts of the spheroids. Conversely, enhanced oxygenation of spheroids by perfluorodecalin led to a dramatic enhancement of Hypericin PDT efficacy. The detection of nuclear shrinkage or fragmentation with DAPI staining and the assessment of cell morphology by light microscopy indicated that apoptosis was the most prominent response of spheroids to Hypericin PDT in the presence of perfluorodecalin. In conclusion, the results of this study suggest that perfluorocarbons, such as perfluorodecalin, are useful in enhancing the oxygenation of tumor tissue, resulting in highly efficient Hypericin PDT. Since Hypericin becomes concentrated specifically in human bladder urothelial carcinoma lesions and the bladder is very well suited to instillation with a perfluorocarbon, combining the techniques looks very promising for an efficient and selective whole bladder wall photodynamic antitumoral treatment in a urological clinical setting.
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the impact of aggregation on the biodistribution of Hypericin
2006Co-Authors: Marie Van De Putte, Tania Roskams, Guy Bormans, Alfons Verbruggen, Peter De WitteAbstract:Hypericin is a potent agent in the photodynamic therapy of cancers and accumulates to a large extent in tumor tissue. To better understand the impact of Hypericin aggregates present in the delivery vehicle on the biodistribution of the compound, we compared the in vivo tissue accumulation after administering Hypericin suspended as coarse aggregates in phosphate-buffered saline, with the biodistribution found after injection of a solution of Hypericin in a mixture of DMSO, polyethylene glycol and water. When administered as coarse aggregates, Hypericin showed a pronounced uptake in liver, spleen and lung and a slow body clearance with a complete decline in tumor/normal tissue ratios (far less than 1). In contrast, delivery of Hypericin as a solution resulted in dramatically improved tumor to normal tissue ratios and a relatively fast elimination from the body. To elucidate the exact localization of Hypericin in both conditions, a fluorescence microscopy study was performed on sections of spleen, liver, lung and tumor tissue. At 24 h after injection, fluorescence in spleen, liver and lung was faint and homogeneous for dissolved Hypericin, whereas bright fluorescent spots covering the entire tissue sections were found when coarse aggregates were injected. We found that aggregates get trapped within these tissues, followed by a gradual monomerization. A direct involvement of monocytes and macrophages, however, could not be demonstrated. In conclusion, it is of critical importance that the delivery vehicle prevents extensive aggregation of Hypericin before injection and assures an efficient transfer to serum lipoproteins upon injection. These results may also be extended to radiolabeled derivatives and other lipophilic photosensitizers, such as porphyrins, phthalocyanines, naphthalocyanines and chlorines, with similar aggregation properties.
Peter Fedorocko - One of the best experts on this subject based on the ideXlab platform.
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Hypericin in the light and in the dark two sides of the same coin
2016Co-Authors: Zuzana Jendželovska, Rastislav Jendželovský, Barbora Kucharova, Peter FedorockoAbstract:Hypericin (4,5,7,4',5',7'-hexahydroxy-2,2'-dimethylnaphtodianthrone) is a naturally occurring chromophore found in some species of the genus Hypericum, especially Hypericum perforatum L. (St. John's wort), and in some basidiomycetes (Dermocybe spp.) or endophytic fungi (Thielavia subthermophila). In recent decades, Hypericin has been intensively studied for its broad pharmacological spectrum. Among its antidepressant and light-dependent antiviral actions, Hypericin is a powerful natural photosensitizer that is applicable in the photodynamic therapy (PDT) of various oncological diseases. As the accumulation of Hypericin is significantly higher in neoplastic tissue than in normal tissue, it can be used in photodynamic diagnosis (PDD) as an effective fluorescence marker for tumor detection and visualization. In addition, light-activated Hypericin acts as a strong pro-oxidant agent with antineoplastic and antiangiogenic properties, since it effectively induces the apoptosis, necrosis or autophagy of cancer cells. Moreover, a strong affinity of Hypericin for necrotic tissue was discovered. Thus, Hypericin and its radiolabeled derivatives have been recently investigated as potential biomarkers for the non-invasive targeting of tissue necrosis in numerous disorders, including solid tumors. On the other hand, several light-independent actions of Hypericin have also been described, even though its effects in the dark have not been studied as intensively as those of photoactivated Hypericin. Various experimental studies have revealed no cytotoxicity of Hypericin in the dark; however, it can serve as a potential antimetastatic and antiangiogenic agent. On the contrary, Hypericin can induce the expression of some ABC transporters, which are often associated with the multidrug resistance (MDR) of cancer cells. Moreover, the Hypericin-mediated attenuation of the cytotoxicity of some chemotherapeutics was revealed. Therefore, Hypericin might represent another St. John's wort metabolite that is potentially responsible for negative herb-drug interactions. The main aim of this review is to summarize the benefits of photoactivated and non-activated Hypericin, mainly in preclinical and clinical applications, and to uncover the "dark side" of this secondary metabolite, focusing on MDR mechanisms.
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Enhanced Antiproliferative and Apoptotic Response of HT-29 Adenocarcinoma Cells to Combination of Photoactivated
2011Co-Authors: Farnesyltransferase Inhibitor Manumycin A, Veronika Sačková, Lucia Kuliková, Martin Kello, Ivana Uhrinová, Peter FedorockoAbstract:Abstract: Several photodynamically-active substances and farnesyltransferase inhibitors are currently being investigated as promising anticancer drugs. In this study, the combined effect of Hypericin (the photodynamically-active pigment from Hypericum perforatum) and selective farnesyltransferase inhibitor manumycin (manumycin A; the selective farnesyltransferase inhibitor from Streptomyces parvulus) on HT-29 adenocarcinoma cells was examined. We found that the combination treatment of cells with photoactivated Hypericin and manumycin resulted in enhanced antiproliferative and apoptotic response compared to the effect of single treatments. This was associated with increased suppression of clonogenic growth, S phase cell cycle arrest, elevated caspase-3/7 activity and time-dependent total cleavage of procaspase-3 and lamin B, cleavage of p21Bax into p18Bax and massive PARP cleavage. Moreover, we found that the apoptosis-inducing factor is implicated in signaling events triggered by photoactivated Hypericin. Our results showed the relocalization of apoptosis-inducing factor (AIF) to the nuclei after Hypericin treatment. In addition, we discovered that not only manumycin but also photoactivated Hypericin induced the reduction of total Ras protein level. Manumycin decreased th
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down regulation of bcl 2 and akt induced by combination of photoactivated Hypericin and genistein in human breast cancer cells
2010Co-Authors: Peter Ferenc, Jaromir Mikes, Peter Solar, Jan Kleban, Peter FedorockoAbstract:Presented experiment considers combination of genistein and photodynamic therapy with Hypericin with a view to achieve higher therapeutic outcome in human breast adenocarcinoma cell lines MCF-7 and MDA-MB-231, both identified in our conditions as photodynamic therapy resistant. Since genistein is known to suppress Bcl-2 expression, we predicted that photodynamic therapy with Hypericin might benefit from mutual therapeutic combination. In line with our expectations, combined treatment led to down-regulation of Bcl-2 and up-regulation of Bax in both cell lines as well as to suppression of Akt and Erk1/2 phosphorylation induced by photoactivated Hypericin in MCF-7 cells. Although Akt and Erk1/2 phosphorylation was not stimulated by photodynamic therapy with Hypericin in MDA-MB-231 cells, it was effectively suppressed in combination. Variations in cell death signaling favoring apoptosis were indeed accompanied by cell cycle arrest in G(2)/M-phase, activation of caspase-7, PARP cleavage and increased occurrence of cells with apoptotic morphology of nucleus. All these events corresponded with suppression of proliferation and significantly lowered clonogenic ability of treated cells. In conclusion, our results indicate that pre-treatment with tyrosine kinase inhibitor genistein may significantly improve the effectiveness of photodynamic therapy with Hypericin in MCF-7 and MDA-MB-231 breast cancer cells.
Manfred Pavlík - One of the best experts on this subject based on the ideXlab platform.
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Hypericin and hyperforin production in st john s wort in vitro culture influence of saccharose polyethylene glycol methyl jasmonate and agrobacterium tumefaciens
2007Co-Authors: Manfred Pavlík, Jan Vacek, Bořivoj Klejdus, Vlastimil KubáňAbstract:Influence of saccharose in the presence or absence of polyethylene glycol (PEG), methyl jasmonate, and an inactivated bacterial culture of Agrobacterium tumefaciens in cultivation medium on morphology of Hypericum perforatum L. and production of Hypericin and hyperforin was studied under in vitro conditions. Production of Hypericin and hyperforin was influenced by the presence of different concentrations of saccharose (10−30 g L-1) in cultivation medium. Addition of PEG (1.25−5 g L-1) in the presence of saccharose (10−30 g L-1) increased production of Hypericin and hyperforin in the H. perforatum in vitro culture. Synthesis of Hypericin and hyperforin was unchanged or reduced for most of the experimental plants at higher contents of PEG (10 and 15 g L-1). Concentrations of Hypericin and hyperforin in the H. perforatum were on the order 100 and 103 μg g-1 of dry plant material, respectively. Production of Hypericin and hyperforin was stimulated either in the presence of a chemical elicitor (methyl jasmonat...
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Hypericin and hyperforin production in st john s wort in vitro culture influence of saccharose polyethylene glycol methyl jasmonate and agrobacterium tumefaciens
2007Co-Authors: Manfred Pavlík, Jan Vacek, Bořivoj Klejdus, Vlastimil KubanAbstract:Influence of saccharose in the presence or absence of polyethylene glycol (PEG), methyl jasmonate, and an inactivated bacterial culture of Agrobacterium tumefaciens in cultivation medium on morphology of Hypericum perforatum L. and production of Hypericin and hyperforin was studied under in vitro conditions. Production of Hypericin and hyperforin was influenced by the presence of different concentrations of saccharose (10-30 g L(-1)) in cultivation medium. Addition of PEG (1.25-5 g L(-1)) in the presence of saccharose (10-30 g L(-1)) increased production of Hypericin and hyperforin in the H. perforatum in vitro culture. Synthesis of Hypericin and hyperforin was unchanged or reduced for most of the experimental plants at higher contents of PEG (10 and 15 g L(-1)). Concentrations of Hypericin and hyperforin in the H. perforatum were on the order 100 and 103 microg g(-1) of dry plant material, respectively. Production of Hypericin and hyperforin was stimulated either in the presence of a chemical elicitor (methyl jasmonate) or an inactivated bacterial culture of A. tumefaciens. Morphological changes induced by the abovementioned substances were observed and described in detail. The obtained results will be applied in experimental botany and in the technology of H. perforatum cultivation for pharmaceutical applications.
Colin F Chignell - One of the best experts on this subject based on the ideXlab platform.
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phototoxicity in human retinal pigment epithelial cells promoted by Hypericin a component of st john s wort
2007Co-Authors: Albert R Wielgus, Colin F Chignell, David S Miller, Ben Van Houten, Joel N Meyer, Joan E RobertsAbstract:St. John’s wort (SJW), an over-the-counter antidepressant, contains Hypericin, which absorbs light in the UV and visible ranges. In vivo studies have determined that Hypericin is phototoxic to skin and our previous in vitro studies with lens tissues have determined that it is potentially phototoxic to the human lens. To determine if Hypericin might also be phototoxic to the human retina, we exposed human retinal pigment epithelial (hRPE) cells to 10 )7 to 10 )5 M Hypericin. Fluorescence emission detected from the cells (kex = 488 nm; kem = 505 nm) confirmed Hypericin uptake by human RPE. Neither Hypericin exposure alone nor visible light exposure alone reduced cell viability. However when irradiated with 0.7 J cm )2 of visible light (k > 400 nm) there was loss of cell viability as measured by MTS and lactate dehydrogenase assays. The presence of Hypericin in irradiated hRPE cells significantly changed the redox equilibrium of glutathione and a decrease in the activity of glutathione reductase. Increased lipid peroxidation as measured by the thiobarbituric acid reactive substances assay correlated to Hypericin concentration in hRPE cells and visible light radiation. Thus, ingested SJW is potentially phototoxic to the retina and could contribute to retinal or early macular degeneration.
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phototoxicity in human lens epithelial cells promoted by st john s wort
2004Co-Authors: Colin F Chignell, David S Miller, Usha P Andley, Joan E RobertsAbstract:St. John’s Wort (SJW), an over-the-counter antidepressant, contains Hypericin, which absorbs light in the UV and visible ranges and is phototoxic to skin. To determine if it also could be phototoxic to the eye, we exposed human lens epithelial cells to 0.1–10 lM Hypericin and irradiated them with 4 J/cm 2 UV-A or 0.9 J/cm 2 visible light. Neither Hypericin exposure alone nor light exposure alone reduced cell viability. In contrast, cells exposed to Hypericin in combination with UV-A or visible light underwent necrosis and apoptosis. The ocular antioxidants lutein and N-acetyl cysteine did not prevent damage. Thus, ingested SJW is potentially phototoxic to the eye and could contribute to early cataractogenesis. Precautions should be taken to protect the eye from intense sunlight while taking SJW.
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photooxidation of lens α crystallin by Hypericin active ingredient in st john s wort
2000Co-Authors: Kevin L Schey, Colin F Chignell, Severine A Patat, M Datillo, R H Wang, Joan E RobertsAbstract:Abstract Hypericin is the active ingredient in the over the counter antidepressant medication St. John's Wort. Hypericin produces singlet oxygen and other excited state intermediates that indicate it should be a very efficient phototoxic agent in the eye. Furthermore it absorbs in the UV and visible range, which means it can potentially damage both the lens and the retina. Lens α-crystallin, isolated from calf lenses, was irradiated in the presence of Hypericin (5 × 10−5 M, 10 mM ammonium bicarbonate, pH 7.0) and in the presence and absence of light (>300 nm, 24 mW/cm2). Hypericin-induced photosensitized photopolymerization as assessed by sodium dodecylsulfate-polyacrylamide gel electrophoresis. Further analysis of the oxidative changes occurring in α-crystallin using mass spectrometry showed specific oxidation of methionine, tryptophan and histidine residues, which increased with irradiation time. Hypericin did not damage the lens protein in the dark. Damage to α-crystallin could undermine the integrity ...