RESUMO
Photodynamic therapy using Hypericin (Hy-PDT) is an alternative non-invasive treatment that enables selective tumor inhibition and angiogenesis derived from the differential recruitment of endothelial cells in the tumor microenvironment. Most PDT studies were performed on in vitro models without vascular biomechanical simulation. Our work strives to develop a microchip that generates a constant shear stress force to investigate the Hy-PDT efficiency on human umbilical vein endothelial cells (HUVECs). The microchip with a single straight microchannel was composed of the bottom layer (polystyrene), the middle layer (double-sided biocompatible adhesive tape), and the top layer (polyester film) and could produce shear stress in the range of 1.4 - 7.0 dyn cm-2. The quantification of vascular endothelial growth factor (VEGF), cell viability, and activities of caspases 3 and 7 were assayed to validate the microchip and Hy-PDT efficacy. After the endothelization, static and dynamic cell incubations with Hy were conducted in microchips. Compared to static systems, the shear stress displayed its effect on the increasing release of VEGF and promoted more cell damage and cell death via necrosis during Hy-PDT. In conclusion, the expressive shear stress-dependent manner during PDT treatments suggests that the microchip could be an essential approach in preclinical tests to evaluate the therapeutic outcome considering the endothelial shear stress microenvironment.
Assuntos
Perileno , Fotoquimioterapia , Humanos , Fármacos Fotossensibilizantes/farmacologia , Fator A de Crescimento do Endotélio Vascular , Células Endoteliais , Sistemas Microfisiológicos , AntracenosRESUMO
Perylene-based compounds, either naturally occurring or synthetic, have shown interesting biological activities. In this study, we report on the broad-spectrum antifungal properties of two lead amphiphilic perylene bisimides, compounds 4 and 5, which were synthesized from perylene-3,4,9,10-tetracarboxylic dianhydride by condensation with spermine and an ammonium salt formation. The antifungal activity was evaluated using a collection of fungal strains and clinical isolates from patients with onychomycosis or sporotrichosis. Both molecules displayed an interesting antifungal profile with MIC values in the range of 2-25 µM, being as active as several reference drugs, even more potent in some particular strains. The ammonium trifluoroacetate salt 5 showed the highest activity with a MIC value of 2.1 µM for all tested Candida spp., two Cryptococcus spp., two Fusarium spp., and one Neoscytalidium spp. strain. Therefore, these amphiphilic molecules with the perylene moiety and cationic ammonium side chains represent important structural features for the development of novel antifungals.
Assuntos
Compostos de Amônio , Perileno , Humanos , Antifúngicos/farmacologia , Perileno/farmacologia , Espermina , Ácido Trifluoracético , Testes de Sensibilidade MicrobianaRESUMO
This Review provides a critical analysis of the literature covering the naturally occurring partially reduced perylenequinones (PQs) from fungi without carbon substituents (which can be named class A perylenequinones) and discusses their structures, stereochemistry, biosynthesis, and biological activities as appropriate. Perylenequinones are natural pigments with a perylene skeleton produced by certain fungi, aphids, some plants, and animal species. These compounds display several biological activities, e.g., antimicrobial, anti-HIV, photosensitizers, cytotoxic, and phytotoxic. It describes 36 fungal PQs and cites 81 references, covering from 1956 to August 2022.
Assuntos
Fungos , Perileno , Pigmentos Biológicos , Quinonas , Animais , Fungos/química , Perileno/análogos & derivados , Perileno/química , Perileno/farmacologia , Fármacos Fotossensibilizantes , Pigmentos Biológicos/biossíntese , Pigmentos Biológicos/química , Pigmentos Biológicos/isolamento & purificação , Pigmentos Biológicos/farmacologia , Quinonas/química , Quinonas/farmacologiaRESUMO
Polycyclic aromatic hydrocarbons (PAHs) most likely derived from natural sources were observed in two sediment cores covering the last 100 years in an Amazon estuarine region. A considerable change in the PAHs main source was observed in the 1960s. Before the 1960s, the sources of PAHs seem to be related to biogenic and/or early-diagenetic processes. Concentrations of perylene were higher before the 1960s and suggest that its primary source to the sediments in the Amazon region is linked to a short-term diagenetic transformation of their biogenic precursors. The natural formation of alkylated PAHs in sediments was linked to the methylation of the parental aromatic hydrocarbons due to sediment maturation processes and the dehydrogenation of sterols in the sediments. The relatively rapid reaction occurring in recent sediments of the Amazon region suggests the importance of the microbial community in the transformation of biogenic precursors to alkylated-PAHs in the sediments.
Assuntos
Perileno , Hidrocarbonetos Policíclicos Aromáticos , Poluentes Químicos da Água , China , Monitoramento Ambiental , Estuários , Sedimentos Geológicos , Hidrocarbonetos Policíclicos Aromáticos/análise , Esteróis , Poluentes Químicos da Água/análiseRESUMO
OBJECTIVE: Breast cancer (BC) currently has no effective treatment especially for the highly aggressive and metastatic triple negative breast cancer (TNBC). Here, we investigated the antitumoral and antimigratory effects of hypericin (HYP) encapsulated on Pluronic F127 (F127/HYP) photodynamic therapy (PDT) against TNBC cell line MDA-MB-231 compared to a nontumorigenic human breast ductal cell line (MCF-10A). METHODS: The phototoxicity/cytotoxicity was assessed by MTT assay, long-term cytotoxicity by clonogenic assay, cell uptake, subcellular distribution, and cellular oxidative stress by fluorescence microscopy, cell death with annexin V-FITC/propidium iodide, PDT mechanism using sodium azide and D-mannitol, and cell migration by wound-healing assay. RESULTS: The treatment promoted phototoxic effect on tumor cell line in a dose-dependent and selective manner. Internalization of F127/HYP was efficient and accumulation occurred in the endoplasmic reticulum and mitochondria, resulting in cellular oxidative stress mainly by the type II mechanism, induced by necrosis. Furthermore, F127/HYP decreased colony formation and reduced the cell migration ability in MDA-MB-231 cells. CONCLUSION: Our results suggest a potentially useful role of F127/HYP micelles as a platform for HYP delivery to more specifically and effectively treat TNBC.
Assuntos
Perileno , Fotoquimioterapia , Neoplasias de Mama Triplo Negativas , Antracenos , Humanos , Perileno/análogos & derivados , Perileno/metabolismo , Perileno/farmacologia , Poloxâmero , Neoplasias de Mama Triplo Negativas/tratamento farmacológicoRESUMO
Benzo[ghi]perylene (BghiP) is produced by the incomplete combustion of gasoline and it is a marker of high vehicular flow in big cities. Nowadays, it is known that BghiP functions as ligand for the aryl hydrocarbon receptor (AhR), which can cause several molecular responses. For this reason, the aim of the present study was to assess the in vitro effects of the exposure to BghiP, specifically, the induction of cellular dormancy and endoplasmic reticulum stress (ER stress) in NL-20 human cells. Our results proved that a 24 h exposure of BghiP, increased the expression of NR2F1 (p < 0.05). NR2F1 is the main activator of cell dormancy, therefore, we analyzed the expression of its target genes SOX9 and p27 showing an increase of the transcripts (p < 0.05), suggesting a pathway that could produce a cell cycle arrest. Interestingly, this effect was only observed with BghiP exposure, and not with a classic AhR ligand: benzo[a]pyrene. Moreover, in the presence of the AhR antagonist, CH223191, or when the expression of AhR was knock-down using dsiRNAs, the cellular dormancy signaling pathway was blocked. Morphological and ultrastructure analysis demonstrated that BghiP also induces ER stress, characterized by the dilated ER cisternae and the overexpression of PERK and CHOP genes (p < 0.05). Moreover, the halt of cell proliferation and the ER stress are both associated to the increase of pro-inflammatory cytokines (IL-6 and IL-8) and the cell survival in response to microenvironmental cues. These responses induced by BghiP on bronchial cells open new horizons on the research of other biological effects induced by environmental pollutants.
Assuntos
Perileno , Benzo(a)pireno , Estresse do Retículo Endoplasmático , Células Epiteliais/metabolismo , Humanos , Ligantes , Perileno/toxicidade , Receptores de Hidrocarboneto Arílico/genética , Receptores de Hidrocarboneto Arílico/metabolismoRESUMO
Hypericin (HYP) is an active compound of Hypericum perforatum. Associated with photodynamic therapy (PDT), HYP has shown a broad therapeutic potential against microorganisms and cancer cells. Due to the low water solubility of HYP, its application in the biological medium becomes limited. To solve this limitation, our research group has been used copolymeric micelles to carrier HYP with high efficiency. However, there is no elucidated mechanism for HYP delivery mediated by copolymeric micelles. In this sense, we believed that the study of binding-sites of copolymeric micelles and HYP is the first step to its understanding. For this purpose, in this work, we employed 1D and 2D NMR techniques to investigate the behaviour of HYP-loaded P84 micelles in different concentrations . 1D and 2D NMR analysis revealed that HYP molecules were arrangement in a π-stacked aggregation form with a specific location on the core of P84 micelles.
Assuntos
Perileno , Fotoquimioterapia , Antracenos , Micelas , Perileno/análogos & derivados , Fotoquimioterapia/métodosRESUMO
This study evaluated the cytotoxic, genotoxic, and the modulatory effects on DNA damage of hypericin in Chinese hamster lung fibroblasts (V79 cells). The hypericin is a natural polycyclic quinone, mainly extracted from St. John's Wort (Hypericum perforatum L.). Along with hyperforin, the hypericins are responsible for the antidepressant activity of St. John's Wort. Cytotoxicity was assessed by the XTT colorimetric assay and the nuclear division index (NDI). The genotoxic activity was studied by the micronucleus test at concentrations of 30, 60, 120, and 240 µg/mL. Mutagenic agents, methyl methanesulfonate (MMS, 44 µg/mL), doxorubicin (DXR, 0.5 µg/mL), and etoposide (VP16, 1 µg/mL) were used in combination with different concentrations of hypericin in order to evaluate the modulatory effect on DNA damage. Results showed that the hypericin was cytotoxic at concentrations above 156.2 µg/mL and genotoxic above 120 µg/mL. The hypericin significantly reduced DNA damage frequency induced by DXR, at concentrations of 30 and 60 µg/mL, and MMS at a concentration of 30 µg/mL, but was unable to reduce damage when combined with VP-16. These results demonstrate the non-photoactivated hypericin toxicological safety limits, its protective effect on DNA damage and provide a basis for future studies that may characterize better its chemopreventive mechanism.
Assuntos
Hypericum , Antracenos/toxicidade , Dano ao DNA , Mutagênicos/toxicidade , Perileno/análogos & derivados , Extratos VegetaisRESUMO
Hypericin (Hy) is a hydrophobic photosensitizer used in photodynamic therapy for cancer therapeutic. In this study, Hy-loaded oil-in-water (O/W) nanoemulsions (NEs) were produced by the ultrasonication method combing different biocompatible oils and surfactants to enhance Hy aqueous solubility and bioavailability. Experimental parameters were optimized by the characterization of droplet size, zeta potential, and physicochemical properties. In vitro studies based on the release profile, cytotoxicity, cell morphology, and Hy intracellular accumulation were assayed. Hy at 100 mg L-1 was incorporated into the low viscosity (~0.005 Pa s) NEs with spherical droplets averaging 20-40 nm in size and polydispersity index <0.02. Hy release from the NE was significantly higher (4-fold) than its suspension (p < 0.001). The NEs demonstrated good physical stability during storage at 5 °C for at least six months. The Hy-loaded NEs exhibited an IC50 value 6-fold lower than Hy suspension during PDT against breast cancer cell lines (MCF-7). Cell microscopy imaging confirmed the increased cytotoxic effects of Hy-loaded NEs, showing damaged and apoptotic cells. Confocal laser scanning microscopy evidenced greater Hy delivery through NE into MCF-7 cells followed by improved intracellular ROS generation. Our results suggest that the Hy-loaded NEs can improve hypericin efficacy and assist Hy-PDT's preclinical development as a cancer treatment.
Assuntos
Antracenos/química , Emulsões/química , Nanoestruturas/química , Perileno/análogos & derivados , Fotoquimioterapia/métodos , Radiossensibilizantes/química , Antracenos/metabolismo , Antracenos/farmacologia , Apoptose/efeitos dos fármacos , Sobrevivência Celular/efeitos dos fármacos , Liberação Controlada de Fármacos/efeitos da radiação , Estabilidade de Medicamentos , Humanos , Luz , Células MCF-7 , Óleos/química , Perileno/química , Perileno/metabolismo , Perileno/farmacologia , Radiossensibilizantes/metabolismo , Radiossensibilizantes/farmacologia , Espécies Reativas de Oxigênio/metabolismo , Sonicação , Temperatura , Água/químicaRESUMO
BackgroundFusarium has been considered an opportunistic pathogen, causing several infections in humans, including onychomycosis. In addition, a high resistance to conventional antifungals has been linked to this genus. Photodynamic Therapy (PDT), known as a non-invasive therapy, can be an alternative treatment for fungal infections, based on the excitation of a photosensitizing compound (PS) by a specific length of light, causing damage to the target. The aim of this study was to evaluate the effects of a formulation of Hypericin (Hyp) encapsulated in Pluronic™ (P123), via photodynamic therapy (PDT), on planktonic cells and biofilms in Fusarium spp. using in vitro and ex vivo assays. Materials & Methods epidemiology studies about Fusarium spp. in onychomycosis was perfomed, carried out molecular identification, compared the antifungal activity of the conventional antifungals with PDT with encapsulated Hypericin (Hyp-P123), carried out detection of reactive oxygen species, and measured the antibiofilm effect of the Hyp-P123-PDT in vitro and in an ex vivo model of onychomycosis. Results Hyp-P123-PDT exhibited a fungicidal effect in vitro with reductions ≥ 3 log10. ROS generation increased post-Hyp-P123-PDT in Fusarium spp. Hyp-P123-PDT showed a potent inhibitory effect on adhesion-phase and mature biofilms in vitro tests and an ex vivo model of onychomycosis (p<0.0001). Conclusion Hyp-P123-PDT had a potent effect against Fusarium spp., suggesting that photodynamic therapy with Hyp-P123 is a safe and promising treatment for onychomycosis in clinical practice.