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Use of hypericin in photodynamic applications
Abstract
St. John's wort (Hypericum perforatum) is one of the medicinal plants used to treat a variety of conditions such as depression, obsessive-compulsive disorder and premenstrual syndrome. In recent years, a biologically active phytoconstituent of the plant, hypericin, a photosensitizer, has gained much attention because of its multiple pharmacological effects and these include antiviral, antitumour, photodynamic and photodiagnostic activities. Due to its promising photodynamic effects for some aging-related diseases such as cancer and age-related macular degeneration, this paper reviews the important aspects of photodynamic activities of hypericin in terms of its history, mechanism of action, advantages over conventional photosensitizers and clinical use. The relevant recent pharmaceutical approaches to improve the formulation of hypericin are also included. There is a potential for better-formulated hypericin for treating diseases and early diagnosis of cancers.
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... Due to its lipophilic properties it is possible to prevent aggregation of hypericin by addition of albumin and plasma lipoproteins that adsorb hypericin in aqueous environment [14] . Some macromolecular substances such as polyethyleneglycol [14], N-methylpyrrolidone [20] and polyvinylpyrrolidone [21, 22] can be used instead of serum proteins to solubilize hypericin in aqueous media. Thus, to obtain aqueous solutions of Hyperflav for cell tests, we used polyvinylpyrrolidone (PVP). ...
Background:
Application of hypericin (an alkaloid from Hypericum perforatum plants) as photodynamic agent may become the next successful step in photodynamic therapy of malignant tumors. Hyperflav - is a purified Hypericum extract designed for the purpose of photodynamic diagnosis.
Aim:
Present studies investigated the effectiveness in vitro of Hyperflav application as a photosensitizer for photodynamic therapy.
Methods:
Hyperflav photodynamic activity was assessed in phototoxic cell tests on Jurkat, MT-4 and Namalwa leukemic cell lines. Spectroscopic measurements of Hyperflav solutions were performed.
Results:
Hyperflav aqueous solubility was maintained in presence of polyvinylpyrrolidone with the most pronounced photodynamic activity at 1:5 (w/w) Hyperflav-PVP ratio. Hyperflav fluorescence spectrum in ethanol exhibits two main peaks around 597 and 647 nm, in accordance with the spectrum of pure hypericin. Fluorescence spectrum of aqueous solution exhibits peaks at 604 and 655 nm and indicates decreasing in fluorescence intensity. Hyperflav at drug dose range of 5 -25 μg/ml and light dose 15 J/cm(2) showed a dose-dependent cytotoxicity on tested cell cultures, while dark cytotoxicity was not observed. Light irradiation of cell samples preincubated with 15 μg/ml Hyperflav resulted in 69.9, 76.0 and 78.3% cell death of Jurkat, MT-4 and Namalwa cultures, respectively. Combined preparation of Hyperflav with gold nanoparticles showed low photocytotoxicity (24.2%) in comparison with Hyperflav alone (99.6%) on Namalwa cells.
Conclusion:
Hyperflav being solubilized in nontoxic aqueous media exhibits in vitro photodynamic activity at doses that do not have dark toxicity, and therefore it meets requirements as a perspective photosensitizer. Further studies, particularly in vivo, are warranted to fully evaluate photodynamic potential of Hyperflav.
An evaluation of the leishmanicidal activity in vitro and in vivo of hypericin, a second-generation photosensitizer found in Hypericum perforatum is presented. Hypericin was evaluated against intracellular amastigotes in vitro of Leishmania (Viannia) panamensis. A topical formulation containing 0.5% hypericin was developed and assayed in vivo in a hamster model of cutaneous leishmaniasis. Results demonstrate that hypericin induces a significant anti-amastigotes effect in vitro for L. panamensis by decreasing the number of parasites inside infected cells. The topical formulation of 0.5% hypericin allows healing of L. panamensis-induced lesions upon a topical application of 40 mg/day plus visible light irradiation (5 J/cm2, 15 minutes), twice a week during three weeks.
Copyright © 2015, American Society for Microbiology. All Rights Reserved.
Plants used in traditional medicine have stood up to the test of time and contributed many novel compounds for preventive
and curative medicine to modern science. India is sitting on a gold mine of well recorded and traditionally well practiced
knowledge of herbal medicine. Specially, plants growing at high altitude in Himalayan pastures are time-honored sources of
health and general well being of local inhabitants. As of today, Himalayan plants are a major contributor to the herbal pharmaceutical
industry both of India and other countries. Plants growing at higher altitudes are subjected to an assault of diverse testing
situations including higher doses of mutagenic UV-radiation, physiological drought, desiccation and strong winds. Plants interact
with stressful environments by physiological adaptation and altering the biochemical profile of plant tissues and producing
a spectrum of secondary metabolites. Secondary metabolites are of special interest to scientists because of their unique pharmacophores
and medicinal properties. Secondary metabolites like polyphenols, terpenes and alkaloids have been reported to possess antimutagenic
and anticancer properties in many studies. The fundamental aspiration of the current review is to divulge the antimutagenic/anticancer
potential of five alpine plants used as food or medicine by the populations living at high altitudes.
Keywords
Arnebia euchroma
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Hippophae rhamnoides
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Hypericum perforatum
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Podophyllum hexandrum
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Rheum emodi
Hypericin is used as a powerful naturally occurring photosensitizer in photodynamic therapy (PDT). Activated by visible light, it kills tumour cells and tissues via generation of reactive oxygen species (ROS). Depending on the protocol, apoptotic cell death can be achieved very effectively by hypericin-PDT. To analyze the fundamental molecular mechanisms leading to apoptosis induced by photodamage especially with regard to human skin cancer cells, we studied the alteration of the gene expression pattern in the human squamous cell carcinoma cell line A-431 at 1.5, 3, 5 and 8 h after hypericin-PDT by cDNA-macroarray technique. Radioactively labelled samples were hybridized onto macroarray filters containing PCR products of 9738 ESTs of the Incyte Human UniGEM Microarray clone set. In total, 168 genes were found to be differentially upregulated and 45 down-regulated. Verification of expression changes of 45 genes of interest was performed by quantitative real-time PCR. Due to the observed significant expression changes the following can be concluded: lipoprotein receptor-mediated endocytosis could play a role in the uptake of lipophilic hypericin. Extracellular signal transduction to the cell is reduced, cell detachment facilitated, changes of the morphology, cytoskeleton and formation of apoptotic bodies occur. The promotion of p38MAPK, ERK, JNK and Ras signalling pathways supports survival and/or apoptosis. Switches between life and death could be the strongly upregulated transcription factors c-jun and FOSB as well as the MAPK-phosphatase 1 DUSP-1, possibly activated via H3 histone modifications. ROS activate ER-stress pathways or adaptive response, and provoke damage protection against ROS, partly in a cell-type specific way.
Direct enantiomer separation of hypericin, pseudohypericin, and protohypericin was accomplished by high-performance liquid chromatography (HPLC) using immobilized polysaccharide-type chiral stationary phases (CSPs). Enantioselectivities up to 1.30 were obtained in the polar-organic elution mode whereby for hypericin and pseudohypericin Chiralpak IC [chiral selector being cellulose tris(3,5-dichlorophenylcarbamate)] and for protohypericin Chiralpak IA (chiral selector being the 3,5-dimethylphenylcarbamate of amylose) gave favorable results. Enantiomers were distinguished by on-line electronic circular dichroism detection. Optimized enantioselective chromatographic conditions were the basis for determining stereodynamic parameters of the enantiomer interconversion process of hypericin and pseudohypericin. Rate constants delivered by computational simulation of dynamic HPLC elution profiles (stochastic model, consideration of peak tailing) were used to calculate averaged enantiomerization barriers (DeltaG(enant)(#)) of 97.6-99.6 kJ/mol for both compounds (investigated temperature range 25-45 degrees C). Complementary variable temperature off-column (i.e., in solution) racemization experiments delivered DeltaG(enant)(#) = 97.1-98.0 kJ/mol (27-45 degrees C) for hypericin and DeltaG(enant)(#) = 98.9-101.4 kJ/mol (25-55 degrees C) for pseudohypericin. An activation enthalpy of DeltaH(#) = 86.0 kJ/mol and an activation entropy of DeltaS(#) = -37.7 J/(K mol) were calculated from hypericin racemization kinetics in solution, whereas for pseudohypericin these figures amounted to 74.1 kJ/mol and -82.6 J/(K mol), respectively. Although the natural phenanthroperylene quinone pigments hypericin and pseudohypericin as well as their biological precursor protohypericin are chiral and can be separated by enantioselective HPLC low enantiomerization barriers seem to prevent the occurrence of an excess of one enantiomer under typical physiological conditions--at least as long as stereoselective intermolecular interactions with other chiral entities are absent.
Photodynamic therapy has emerged as a promising alternative to current cancer treatment. However, conventional photosensitizers have several limitations due to their unsuitable pharmaceutical formulations and lack of selectivity. Our strategy was to exploit the advantages of nanoparticles and the quenching-induced deactivation of the model photosensitizer hypericin to produce "activatable" drug delivery systems. Efficient fluorescence and activity quenching were achieved by increasing the drug-loading rate of nanoparticles. In vitro assays confirmed the reversibility of hypericin deactivation, as the hypericin fluorescence and photodynamic activity were recovered upon cell internalization.
In urology, fluorescence-based imaging methods have been proven to significantly improve the detection of small, barely visible tumors and reduce the recurrence rate. Under ethical and economical pressure, new effective screening systems have to be developed to exploit and assess novel strategies for fluorescence photodetection in other areas. For this purpose, the chorioallantoic membrane (CAM) of the developing chick embryo is an attractive alternative model to the mammalian models.
Hypericin encapsulated into nanoparticles for the photodetection of ovarian metastases was evaluated in the CAM model with respect to vascular extravazation and tumor targeting and compared with free drug following intravenous administration.
To validate the CAM model as a valuable screening system for photodetection of cancer, we drew a comparison with results obtained on a conventional rodent model.
Rodent and CAM models led to the same conclusion regarding the benefits of nanoencapsulation to improve selective accumulation of drug in ovarian micrometastases.
Recently, we have shown that hypericin-mediated photodynamic therapy (PDT) is a promising modality for the treatment of nasopharyngeal cancer (NPC). The present study evaluated the expression of matrix metalloproteinase-9 (MMP-9) following hypericin-PDT in well-differentiated HK1 NPC cells. Down-regulation of MMP-9 by hypericin-PDT was observed at the mRNA level in HK1 cells in vitro and in vivo and at the protein level in vitro. Transcriptional activities of the activator protein-1 (AP-1) and nuclear factor (NF)-kappaB regulatory elements were inhibited by PDT. We also found that PDT reduced secreted granulocyte-macrophage colony stimulating factor (GM-CSF), which is known to activate transcription of NK-kappaB and AP-1. However, incubation of untreated HK1 cells with exogenous GM-CSF abrogated the reduction of MMP-9 production in hypericin-PDT-treated cells. It would appear that PDT downregulates MMP-9 expression via inhibition of GM-CSF production, which in turn modulates AP1/NF-kappaB transcriptional activities. Suppression of MMP-9 by hypericin-PDT may have therapeutic implications.
Early cancer detection is critical in improving disease management outcomes. Cancer diagnosis presents unique difficulties mainly due to its pathological presentation and poor accessibility that could limit the usefulness of conventional white light endoscopy in early cancer detection. Fluorescence endoscopy has been proven to improve the sensitivity and specificity of early cancer detection. Hypericin (HY) has been found to be superior to 5-aminolevulinic acid (5-ALA) and its ester derivative hexaminolevulinate (HA) as a fluorescence diagnostic agent, hence its development for delivery in vitro and in vivo, is the subject of this review.