RESUMEN
Therapy-induced modulation of the tumor microenvironment (TME) to overcome the immunosuppressive TME is considered to be an opportunity for cancer treatment. However, monitoring of TME modulation during the therapeutic process to accurately determine immune responses and adjust treatment plans in a timely manner remains to be challenging. Herein, we report a carrier-free nanotheranostic system (CANPs) assembled by two boron dipyrromethene (BODIPY) dyes, a sonophotosensitizer C-BDP, and a nitric oxide (NO) probe amino-BODIPY (A-BDP). CANPs can exert combined sonophototherapeutic effects of C-BDP under ultrasound and light irradiation and simultaneously induce inflammatory TME, as well as emit bright fluorescence via A-BDP by monitoring tumor-associated macrophages (TAMs) repolarization through the released NO in vitro and in vivo. Of note, transforming growth factor-ß (TGF-ß) could be the key cytokine involved in the sonophototherapy-induced TME reprogramming. By virtue of high physiological stability, good biocompatibility, and effective tumor targetability, CANPs could be a potential nanotheranostic system for the simultaneous induction and detection of TME reprogramming triggered by sonophototherapy.
Asunto(s)
Nanomedicina Teranóstica , Microambiente Tumoral , Microambiente Tumoral/efectos de los fármacos , Microambiente Tumoral/inmunología , Animales , Ratones , Porfobilinógeno/análogos & derivados , Porfobilinógeno/química , Porfobilinógeno/farmacología , Humanos , Fármacos Fotosensibilizantes/química , Fármacos Fotosensibilizantes/farmacología , Compuestos de Boro/química , Compuestos de Boro/farmacología , Óxido Nítrico/metabolismo , Antineoplásicos/farmacología , Antineoplásicos/química , Femenino , Nanopartículas/química , Colorantes Fluorescentes/química , Colorantes Fluorescentes/farmacología , Células RAW 264.7RESUMEN
In this study, we report for the first time the use of four aza-dipyrromethenes (ADPMs) as photosensitizers for cancer PDT. The synthesis and characterization of the ADPMs and their photodynamic action against B16F10 melanoma cells were assessed. ADPM 2 is the best singlet oxygen generator and the most phototoxic (at 2.5 µM) towards B16F10 cells.
Asunto(s)
Antineoplásicos/farmacología , Compuestos Aza/farmacología , Melanoma/tratamiento farmacológico , Fotoquimioterapia , Fármacos Fotosensibilizantes/farmacología , Porfobilinógeno/análogos & derivados , Animales , Antineoplásicos/síntesis química , Antineoplásicos/química , Compuestos Aza/síntesis química , Compuestos Aza/química , Proliferación Celular/efectos de los fármacos , Supervivencia Celular/efectos de los fármacos , Relación Dosis-Respuesta a Droga , Ensayos de Selección de Medicamentos Antitumorales , Melanoma/patología , Ratones , Estructura Molecular , Fármacos Fotosensibilizantes/síntesis química , Fármacos Fotosensibilizantes/química , Porfobilinógeno/síntesis química , Porfobilinógeno/química , Porfobilinógeno/farmacología , Relación Estructura-Actividad , Células Tumorales CultivadasRESUMEN
Here, we have synthesized and characterized a novel activatable photosensitizer (PS) 8a in which two well-designed boron dipyrromethene (BODIPY) derivatives are utilized as the photosensitizing fluorophore and quencher respectively, which are connected by a disulfide linker via two successive Cu (Ð) catalyzed click reactions. The fluorescence emission and singlet oxygen production of 8a are suppressed via intramolecular fluorescence resonance energy transfer (FRET) from the excited BODIPY-based PS part to quencher unit, but both of them can be simultaneously switched on by cancer-related biothiol glutathione (GSH) in phosphate buffered saline (PBS) solution with 0.05% Tween 80 as a result of cleavage of disulfide. Also, 8a exhibits a bright fluorescence image and a substantial ROS production in A549 human lung adenocarcinoma, HeLa human cervical carcinoma and H22 mouse hepatoma cells having a relatively high concentration of GSH, thereby leading to a significant photocytotoxicity, with IC50 values as low as 0.44 µM, 0.67 µM and 0.48 µM, respectively. In addition, the photosensitizer can be effectively activated and imaged in H22 transplanted hepatoma tumors of mice and shows a strong inhibition on tumor growth. All these results suggest that such a GSH-responsive photosensitizer based on FRET mechanism may provide a new strategy for tumor-targeted and fluorescence imaging-guided cancer therapy.
Asunto(s)
Antineoplásicos/farmacología , Transferencia Resonante de Energía de Fluorescencia , Glutatión/química , Imagen Óptica , Fotoquimioterapia , Fármacos Fotosensibilizantes/farmacología , Animales , Antineoplásicos/síntesis química , Antineoplásicos/química , Compuestos de Boro/síntesis química , Compuestos de Boro/química , Compuestos de Boro/farmacología , Línea Celular Tumoral , Proliferación Celular/efectos de los fármacos , Relación Dosis-Respuesta a Droga , Ensayos de Selección de Medicamentos Antitumorales , Femenino , Humanos , Ratones , Ratones Endogámicos , Estructura Molecular , Neoplasias Experimentales/tratamiento farmacológico , Neoplasias Experimentales/patología , Fármacos Fotosensibilizantes/síntesis química , Fármacos Fotosensibilizantes/química , Porfobilinógeno/análogos & derivados , Porfobilinógeno/síntesis química , Porfobilinógeno/química , Porfobilinógeno/farmacología , Relación Estructura-ActividadRESUMEN
The ruthenium(II) complexes [RuCl(L1)(L3)]Cl (1), [RuCl(L1)(L4)]Cl (2), [RuCl(L2)(L4)]Cl (3), [RuCl(L1)(L5)]Cl (4), and [RuCl(L2)(L5)]Cl (5) of NNN-donor dipicolylamine (dpa) bases (L4, L5) having BODIPY (boron-dipyrromethene) moieties, NN-donor phenanthroline derivatives (L1, L2), and benzyldipicolylamine (bzdpa, L3) were prepared and characterized by spectroscopic techniques and their cellular localization/uptake and photocytotoxicity studied. Complex 1, as its PF6 salt (1a), has been structurally characterized with help of a single-crystal X-ray diffraction technique. It has a RuN5Cl core with the Cl bonded trans to the amine nitrogen atom of bzdpa. The complexes showed intense absorption spectral bands near 500 nm (ε ≈ 58000 M-1 cm-1) in 2 and 3 and 654 nm (ε ≈ 80000 M-1 cm-1) in 4 and 5 in 1/1 DMSO/DPBS (v/v). Complex 5 having biotin and PEGylated-disteryl BODIPY gave a singlet oxygen quantum yield (ΦΔ) of â¼0.65 in DMSO. Complex 5 exhibited remarkable PDT (photodynamic therapy) activity (IC50 ≈ 0.02 µM) with a photocytotoxicity index (PI) value of >5000 in red light of 600-720 nm in A549 cancer cells. The biotin-conjugated complexes showed better photocytotoxicity in comparison to nonbiotinylated analogues in A549 cells. The complexes displayed less toxicity in HPL1D normal cells in comparison to A549 cancer cells. The emissive BODIPY complexes 3 and 5 (ΦF ≈ 0.07 in DMSO) showed significant mitochondrial localization.
Asunto(s)
Antineoplásicos/farmacología , Complejos de Coordinación/farmacología , Luz , Fotoquimioterapia , Fármacos Fotosensibilizantes/farmacología , Células A549 , Antineoplásicos/síntesis química , Antineoplásicos/química , Biotina/química , Biotina/farmacología , Boro/química , Boro/farmacología , Línea Celular , Proliferación Celular/efectos de los fármacos , Supervivencia Celular/efectos de los fármacos , Complejos de Coordinación/síntesis química , Complejos de Coordinación/química , División del ADN/efectos de los fármacos , Teoría Funcional de la Densidad , Ensayos de Selección de Medicamentos Antitumorales , Humanos , Modelos Moleculares , Imagen Óptica , Fármacos Fotosensibilizantes/síntesis química , Fármacos Fotosensibilizantes/química , Porfobilinógeno/análogos & derivados , Porfobilinógeno/química , Porfobilinógeno/farmacología , Rutenio/química , Rutenio/farmacologíaRESUMEN
Cis-dichloro-oxovanadium(IV) complexes [VO(L1/L2)Cl2], where L1 is N-(4-(5,5-difluoro-1,3,7,9-tetramethyl-5H-4Ê4,5Ê4-dipyrrolo[1,2-c:2',1'-f][1,3,2]diazaborinin-10-yl)benzyl)-1-(pyridin-2-yl)-N-(pyridin-2-ylmethyl)methanamine in 1 and L2 is N-(4-(5,5-difluoro-2,8-diiodo-1,3,7,9-tetramethyl-5H-4Ê4,5Ê4-dipyrrolo[1,2-c:2',1'-f][1,3,2]diazaborinin-10-yl)benzyl)-1-(pyridin-2-yl)-N-(pyridin-2-ylmethyl)methanamine in 2) having 4,4-difluoro-4-bora-3a,4a-diaza-s-indacene as boron-dipyrromethene (BODIPY) appended dipicolylamine bases were prepared, characterized and their photocytotoxicity studied. X-ray crystal structure of 1 showed distorted octahedral geometry with a VIVON3Cl2 core having Cl-V-Cl angle of 91.93(4)°. The complexes showed variable solution conductivity properties. They were non-electrolytes in dry DMF at 25⯰C but showed 1:1 electrolytic behavior in an aqueous medium due to dissociation of one chloride ligand as evidenced from the mass spectral study. Complexes 1 and 2 showed absorption bands at 500 and 535â¯nm, respectively. The calf thymus DNA melting study revealed their interaction through DNA crosslinking on exposure to light which was further confirmed from the alkaline agarose gel electrophoresis using plasmid supercoiled pUC19 DNA. Complex 2 showed disruption of the mitochondrial membrane potential in the JC-1 (1,1',3,3'-tetraethyl-5,5',6,6'-tetrachloroimidacarbocyanine iodide) assay. The complexes were photocytotoxic in visible light (400-700â¯nm, power: 10â¯Jâ¯cm-2) in cervical cancer HeLa and breast cancer MCF-7 cells. Complex 2 having a photoactive diiodoboron-dipyrromethene moiety gave a singlet oxygen quantum yield (ΦΔ) value of ~0.6. It showed singlet oxygen mediated apoptotic photodynamic therapy activity with remarkably low IC50 (half maximal inhibitory concentration) value of ~0.15⯵M. The cis-disposition of chlorides gave a cis-divacant 4-coordinate intermediate structure from the density functional theory (DFT) study thus mimicking the DNA crosslinking property of cisplatin.
Asunto(s)
Compuestos de Boro , Citotoxinas , ADN , Fármacos Fotosensibilizantes , Porfobilinógeno/análogos & derivados , Vanadatos , Boro/química , Boro/farmacología , Compuestos de Boro/síntesis química , Compuestos de Boro/química , Compuestos de Boro/farmacología , Cristalografía por Rayos X , Citotoxinas/síntesis química , Citotoxinas/química , Citotoxinas/farmacología , ADN/química , ADN/metabolismo , Células HeLa , Humanos , Células MCF-7 , Fármacos Fotosensibilizantes/síntesis química , Fármacos Fotosensibilizantes/química , Fármacos Fotosensibilizantes/farmacología , Porfobilinógeno/síntesis química , Porfobilinógeno/química , Porfobilinógeno/farmacología , Vanadatos/química , Vanadatos/farmacologíaRESUMEN
A distyryl boron dipyrromethene based photosensitiser substituted with 1,2,4,5-tetrazine and alkyne moieties was prepared. Through site-specific bioorthogonal reactions with the complementary functional tags anchored on the membrane of A431 human epidermoid carcinoma cells, this versatile photosensitiser exhibited enhanced cellular uptake and photocytotoxicity. The bioorthogonal ligation was also demonstrated in tumour-bearing nude mice.
Asunto(s)
Antineoplásicos/farmacología , Compuestos de Boro/farmacología , Fotoquimioterapia , Fármacos Fotosensibilizantes/farmacología , Porfobilinógeno/análogos & derivados , Animales , Antineoplásicos/síntesis química , Antineoplásicos/química , Compuestos de Boro/síntesis química , Compuestos de Boro/química , Línea Celular Tumoral , Proliferación Celular/efectos de los fármacos , Supervivencia Celular/efectos de los fármacos , Relación Dosis-Respuesta a Droga , Ensayos de Selección de Medicamentos Antitumorales , Humanos , Ratones , Ratones Desnudos , Estructura Molecular , Neoplasias Experimentales/tratamiento farmacológico , Neoplasias Experimentales/metabolismo , Neoplasias Experimentales/patología , Imagen Óptica , Fármacos Fotosensibilizantes/síntesis química , Fármacos Fotosensibilizantes/química , Porfobilinógeno/síntesis química , Porfobilinógeno/química , Porfobilinógeno/farmacología , Especies Reactivas de Oxígeno/análisis , Especies Reactivas de Oxígeno/metabolismo , Relación Estructura-ActividadRESUMEN
A ferrocenyl boron dipyrromethene (BODIPY) has been developed and utilized as a dark quencher to construct a cathepsin B-responsive fluorescent probe and photosensitizer. The smart fluorescent probe and photosensitizer (Pc-FcQ) contains a zinc(II) phthalocyanine as the fluorescent and photosensitizing unit which is conjugated to the ferrocenyl BODIPY dark quencher via a cathepsin B-cleavable peptide substrate [Gly-Phe-Leu-Gly-Lys]. The photosensitizing properties of Pc-FcQ, including fluorescence and singlet oxygen generation, are significantly quenched through energy transfer to the BODIPY unit and subsequently by the photoinduced electron transfer from the nearby ferrocenyl moiety. Upon exposure of cathepsin B in human hepatocellular carcinoma HepG cells, the fluorescence emission of Pc-FcQ could be restored, indicating the cleavage of the peptide substrate and the separation of the phthalocyanine and ferrocenyl BODIPY unit. However, the intracellular fluorescence intensity of Pc-FcQ was largely diminished after the cells were pre-treated with cathepsin B inhibitor. Its intracellular fluorescence intensity was comparable to that of the control compound in which the peptide substrate was replaced by the non-cleavable one [Gly-Gly-Gly-Gly-Lys]. The singlet oxygen generation of Pc-FcQ was also examined in HepG2 cells as reflected by the cytotoxicity assay. The Pc-FcQ exhibited higher potency when compared with the non-cleavable analogue due to the cleavage of peptide substrate and the detachment of the BODIPY dark quencher from the phthalocyanine. The activation of the Pc-FcQ was also demonstrated in tumor-bearing nude mice. After intratumoral injection of Pc-FcQ, the fluorescence intensity at the tumor region increased gradually over 10â¯h as a result of the detachment of the dark quencher upon the action of cathepsin B. All the results suggest that this ferrocenyl BODIPY could serve as an efficient dark quencher and the resulting Pc-FcQ could act as the cathepsin B-responsive fluorescent probe and activatable photosensitizer.
Asunto(s)
Boro/farmacología , Catepsina B/farmacología , Compuestos Ferrosos/farmacología , Colorantes Fluorescentes/farmacología , Fármacos Fotosensibilizantes/farmacología , Porfobilinógeno/análogos & derivados , Animales , Boro/química , Catepsina B/química , Supervivencia Celular/efectos de los fármacos , Relación Dosis-Respuesta a Droga , Femenino , Compuestos Ferrosos/química , Colorantes Fluorescentes/química , Células HT29 , Células Hep G2 , Humanos , Ratones , Ratones Endogámicos BALB C , Ratones Desnudos , Estructura Molecular , Imagen Óptica , Fármacos Fotosensibilizantes/química , Porfobilinógeno/química , Porfobilinógeno/farmacología , Relación Estructura-Actividad , Células Tumorales CultivadasRESUMEN
As traditional phototherapy agents, boron dipyrromethene (BODIPY) photosensitizers have attracted increasing attention due to their high molar extinction coefficients, high phototherapy efficacy, and excellent photostability. After being formed into nanostructures, BODIPY-containing nano-photosensitizers show enhanced water solubility and biocompatibility as well as efficient tumor accumulation compared to BODIPY molecules. Hence, BODIPY nano-photosensitizers demonstrate a promising potential for fighting cancer. This review contains three sections, classifying photodynamic therapy (PDT), photothermal therapy (PTT), and the combination of PDT and PTT based on BODIPY nano-photosensitizers. It summarizes various BODIPY nano-photosensitizers, which are prepared via different approaches including molecular precipitation, supramolecular interactions, and polymer encapsulation. In each section, the design strategies and working principles of these BODIPY nano-photosensitizers are highlighted. In addition, the detailed in vitro and in vivo applications of these recently developed nano-photosensitizers are discussed together with future challenges in this field, highlighting the potential of these promising nanoagents for new tumor phototherapies.
Asunto(s)
Antineoplásicos/farmacología , Boro/farmacología , Neoplasias/terapia , Fármacos Fotosensibilizantes/farmacología , Fototerapia , Porfobilinógeno/análogos & derivados , Animales , Antineoplásicos/química , Humanos , Fármacos Fotosensibilizantes/química , Porfobilinógeno/química , Porfobilinógeno/farmacologíaRESUMEN
Monofunctional pyriplatin analogues cis-[Pt(NH3)2(L)Cl](NO3) (1-3) having boron-dipyrromethene (BODIPY) pendants (L) with 1,3,5,7-tetramethyl-8-(4-pyridyl)-4,4'-difluoroboradiazaindacene moieties were designed and synthesized, and their photocytotoxic properties were studied. The Pt-BODIPY conjugates displayed an absorption band within 505-550 nm and a green emissive band near 535 nm in 1% DMSO/DMEM (Dulbecco's modified Eagle's medium) buffer. Complex cis-[Pt(NH3)2(4-Me-py)Cl](NO3) (4) was used as a control for determining the structural aspects by X-ray crystallography. The mono- and diiodinated BODIPY complexes 2 and 3 showed generation of singlet oxygen on light activation as evidenced from the 1,3-diphenylisobenzofuran (DPBF) titration experiments. The cytotoxicity of the BODIPY complexes was tested against A549 (human lung cancer), MCF-7 (human breast cancer), and HaCaT (human skin keratinocyte) cells in dark and visible light (400-700 nm, 10 J cm-2). While complexes 2 and 3 showed excellent photocytotoxicity (IC50 ≈ 0.05 µM), they remained essentially nontoxic in the dark (IC50 > 100 µM). The emissive bands of 1 and 2 were used for cellular imaging by confocal microscopy study, which showed their mitochondrial localization. This was further supported by platinum estimation from isolated mitochondria and mitochondrial depolarization through a JC-1 assay. The photomediated apoptotic cell death was evidenced from flow cytometric assays, annexin-V/FITC-PI (fluorescein isothiocyanate-propidium iodide) and cell cycle arrest in sub-G1 and G2/M phases. The complexes bind to 9-ethylguanine as a model nucleobase to form monoadducts. A mechanistic study on DNA photocleavage activity using pUC19 DNA showed singlet oxygen as the reactive oxygen species (ROS). The combination of photodynamic therapy with DNA cross-linking property enhanced the anticancer potential of the monofunctional BODIPY-conjugates of pyriplatins.
Asunto(s)
Antineoplásicos/farmacología , Compuestos de Boro/farmacología , Mitocondrias/metabolismo , Compuestos Organoplatinos/farmacología , Fármacos Fotosensibilizantes/farmacología , Porfobilinógeno/análogos & derivados , Animales , Antineoplásicos/síntesis química , Antineoplásicos/química , Antineoplásicos/efectos de la radiación , Apoptosis/efectos de los fármacos , Compuestos de Boro/síntesis química , Compuestos de Boro/química , Compuestos de Boro/efectos de la radiación , Bovinos , Línea Celular Tumoral , ADN/química , Puntos de Control de la Fase G1 del Ciclo Celular/efectos de los fármacos , Puntos de Control de la Fase G2 del Ciclo Celular/efectos de los fármacos , Humanos , Luz , Potencial de la Membrana Mitocondrial/efectos de los fármacos , Microscopía Confocal , Microscopía Fluorescente , Mitocondrias/efectos de los fármacos , Compuestos Organoplatinos/síntesis química , Compuestos Organoplatinos/química , Compuestos Organoplatinos/efectos de la radiación , Fármacos Fotosensibilizantes/síntesis química , Fármacos Fotosensibilizantes/química , Fármacos Fotosensibilizantes/efectos de la radiación , Porfobilinógeno/síntesis química , Porfobilinógeno/química , Porfobilinógeno/farmacología , Porfobilinógeno/efectos de la radiación , Oxígeno Singlete/metabolismoRESUMEN
BACKGROUND: Acute Intermittent Porphyria (AIP) is an inherited disease produced by a deficiency of Porphobilinogen deaminase (PBG-D). The aim of this work was to evaluate the effects of Isoflurane and Sevoflurane on heme metabolism in a mouse genetic model of AIP to further support our previous proposal for avoiding their use in porphyric patients. A comparative study was performed administering the porphyrinogenic drugs allylisopropylacetamide (AIA), barbital and ethanol, and also between sex and mutation using AIP (PBG-D activity 70% reduced) and T1 (PBG-D activity 50% diminished) mice. METHODS: The activities of 5-Aminolevulinic synthetase (ALA-S), PBG-D, Heme oxygenase (HO) and CYP2E1; the expression of ALA-S and the levels of 5-aminolevulinic acid (ALA) were measured in different tissues of mice treated with the drugs mentioned. RESULTS: Isoflurane increased liver, kidney and brain ALA-S activity of AIP females but only affected kidney AIP males. Sevoflurane induced ALA-S activity in kidney and brain of female AIP group. PBG-D activity was further reduced by Isoflurane in liver male T1; in AIP male mice activity remained in its low basal levels. Ethanol and barbital also caused biochemical alterations. Only AIA triggered neurological signs similar to those observed during human acute attacks in male AIP being the symptoms less pronounced in females although ALA-S induction was greater. Heme degradation was affected. DISCUSSION: Biochemical alterations caused by the porphyrinogenic drugs assayed were different in male and female mice and also between T1 and AIP being more affected the females of AIP group. GENERAL SIGNIFICANCE: This is the first study using volatile anaesthetics in an AIP genetic model confirming Isoflurane and Sevoflurane porphyrinogenicity.
Asunto(s)
Anestésicos/farmacología , Hemo/metabolismo , Hidroximetilbilano Sintasa/fisiología , Modelos Genéticos , Porfobilinógeno/farmacología , Porfiria Intermitente Aguda/tratamiento farmacológico , Compuestos Orgánicos Volátiles/farmacocinética , Animales , Femenino , Masculino , Ratones , Ratones Endogámicos C57BL , Ratones Noqueados , Porfobilinógeno/química , Porfiria Intermitente Aguda/genética , Porfiria Intermitente Aguda/metabolismo , Porfiria Intermitente Aguda/patologíaRESUMEN
A general approach toward highly fluorogenic probes across the visible spectrum for various analytes offers significant potential for engineering a wide range of bioprobes with diverse sensing and imaging functions. Here we show a facile and general strategy that involves introducing a new fluorogenic mechanism in boron dipyrromethene (BODIPY) dyes, based on the principle of stimuli-triggered dramatic reduction in the electron-withdrawing capabilities of the meso-substituents of BODIPYs. The fluorogenic mechanism has been demonstrated to be applicable in various BODIPYs with emission maxima ranging from green to far red (509, 585, and 660 nm), and the synthetic strategy allows access to a panel of highly fluorogenic bioprobes for various biomolecules and enzymes (H2O2, H2S, and protease) via introducing specific triggering motifs. The potency of the general design strategy is exemplified by its application to develop a mitochondria-targeting far-red probe capable of imaging of endogenous H2O2 in living cells.
Asunto(s)
Técnicas Biosensibles , Compuestos de Boro/química , Colorantes Fluorescentes/química , Peróxido de Hidrógeno/análisis , Imagen Óptica , Péptido Hidrolasas/análisis , Porfobilinógeno/análogos & derivados , Compuestos de Boro/farmacología , Supervivencia Celular , Electrones , Colorantes Fluorescentes/farmacología , Células HeLa , Humanos , Mitocondrias/química , Mitocondrias/metabolismo , Estructura Molecular , Péptido Hidrolasas/metabolismo , Porfobilinógeno/química , Porfobilinógeno/farmacología , Espectrometría de Fluorescencia , Espectrofotometría UltravioletaRESUMEN
Peroxynitrite has been implicated in type 2 diabetes and diabetic complications. As a follow-up study to our previous work on SR-135 (Arch Biochem Biophys 577-578: 49-59, 2015), we provide evidence that this series of compounds are effective when administered orally, and their mechanisms of actions extend to the peripheral tissues. A more soluble analogue of SR-135, SR-110 (from a new class of Mn(III) bis(hydroxyphenyl)-dipyrromethene complexes) was orally administered for 2 weeks to B6D2F1 mice fed a high fat-diet (HFD). Mice fed a HFD for 4 months gained significantly higher body weights compared to lean diet-fed mice (52 ± 1.5 g vs 34 ± 1.3 g). SR-110 (10 mg/kg daily) treatment significantly reduced fasting blood glucose and insulin levels, and enhanced glucose tolerance as compared to HFD control or vehicle (peanut butter) group. SR-110 treatment enhanced insulin signaling in the peripheral organs, liver, heart, and skeletal muscle, and reduced lipid accumulation in the liver. Furthermore, SR-110 increased insulin content, restored islet architecture, decreased islet size, and reduced tyrosine nitration. These results suggest that a peroxynitrite decomposing catalyst is effective in improving glucose homeostasis and restoring islet morphology and ß-cell insulin content under nutrient overload.
Asunto(s)
Grasas de la Dieta/efectos adversos , Células Secretoras de Insulina/metabolismo , Insulina/metabolismo , Ácido Peroxinitroso/metabolismo , Porfobilinógeno/análogos & derivados , Transducción de Señal/efectos de los fármacos , Administración Oral , Animales , Glucemia/metabolismo , Grasas de la Dieta/farmacología , Homeostasis/efectos de los fármacos , Ratones , Porfobilinógeno/química , Porfobilinógeno/farmacología , Ratas , Ratas Sprague-DawleyRESUMEN
Peroxynitrite has been implicated in ß-cell dysfunction and insulin resistance in obesity. Chemical catalysts that destroy peroxynitrite, therefore, may have therapeutic value for treating type 2 diabetes. To this end, we have recently demonstrated that Mn(III) bis(hydroxyphenyl)-dipyrromethene complexes, SR-135 and its analogs, can effectively catalyze the decomposition of peroxynitrite in vitro and in vivo through a 2-electron mechanism (Rausaria et al., 2011). To study the effects of SR-135 on glucose homeostasis in obesity, B6D2F1 mice were fed with a high fat-diet (HFD) for 12 weeks and treated with vehicle, SR-135 (5mg/kg), or a control drug SRB for 2 weeks. SR-135 significantly reduced fasting blood glucose and insulin levels, and enhanced glucose tolerance as compared to HFD control, vehicle or SRB. SR-135 also enhanced glucose-stimulated insulin secretion based on ex vivo studies. Moreover, SR-135 increased insulin content, restored islet architecture, decreased islet size, and reduced tyrosine nitration and apoptosis. These results suggest that a peroxynitrite decomposing catalyst enhances ß-cell function and survival under nutrient overload.
Asunto(s)
Diabetes Mellitus Tipo 2/etiología , Hipoglucemiantes/farmacología , Células Secretoras de Insulina/efectos de los fármacos , Manganeso/farmacología , Obesidad/complicaciones , Ácido Peroxinitroso/metabolismo , Porfobilinógeno/análogos & derivados , Animales , Apoptosis/efectos de los fármacos , Glucemia/análisis , Glucemia/metabolismo , Supervivencia Celular/efectos de los fármacos , Diabetes Mellitus Tipo 2/sangre , Diabetes Mellitus Tipo 2/tratamiento farmacológico , Diabetes Mellitus Tipo 2/metabolismo , Dieta Alta en Grasa/efectos adversos , Prueba de Tolerancia a la Glucosa , Hipoglucemiantes/química , Insulina/sangre , Células Secretoras de Insulina/citología , Células Secretoras de Insulina/metabolismo , Masculino , Manganeso/química , Ratones , Ratones Endogámicos C57BL , Obesidad/sangre , Obesidad/metabolismo , Porfobilinógeno/química , Porfobilinógeno/farmacologíaRESUMEN
Acute intermittent porphyria (AIP) is a genetic disorder of the synthesis of heme caused by a deficiency in hydroxymethylbilane synthase (HMBS), leading to the overproduction of the porphyrin precursors δ-aminolevulinic acid and porphobilinogen. The aim of this study is to describe the clinical and biological characteristics, the renal pathology, and the cellular mechanisms of chronic kidney disease associated with AIP. A total of 415 patients with HMBS deficiency followed up in the French Porphyria Center were enrolled in 2003 in a population-based study. A follow-up study was conducted in 2013, assessing patients for clinical, biological, and histological parameters. In vitro models were used to determine whether porphyrin precursors promote tubular and endothelial cytotoxicity. Chronic kidney disease occurred in up to 59% of the symptomatic AIP patients, with a decline in the glomerular filtration rate of ~1 ml/min per 1.73 m(2) annually. Proteinuria was absent in the vast majority of the cases. The renal pathology was a chronic tubulointerstitial nephropathy, associated with a fibrous intimal hyperplasia and focal cortical atrophy. Our experimental data provide evidence that porphyrin precursors promote endoplasmic reticulum stress, apoptosis, and epithelial phenotypic changes in proximal tubular cells. In conclusion, the diagnosis of chronic kidney disease associated with AIP should be considered in cases of chronic tubulointerstitial nephropathy and/or focal cortical atrophy with severe proliferative arteriosclerosis.
Asunto(s)
Células Epiteliales/efectos de los fármacos , Nefritis Intersticial/complicaciones , Porfiria Intermitente Aguda/complicaciones , Insuficiencia Renal Crónica/epidemiología , Insuficiencia Renal Crónica/etiología , Túnica Íntima/patología , Anciano , Ácido Aminolevulínico/farmacología , Apoptosis/efectos de los fármacos , Células Cultivadas , Estrés del Retículo Endoplásmico , Células Epiteliales/ultraestructura , Epitelio/patología , Femenino , Fibrosis , Francia/epidemiología , Tasa de Filtración Glomerular , Células Endoteliales de la Vena Umbilical Humana/efectos de los fármacos , Humanos , Hidroximetilbilano Sintasa , Hipertensión/epidemiología , Túbulos Renales/patología , Masculino , Persona de Mediana Edad , Fenotipo , Porfobilinógeno/farmacología , Porfiria Intermitente Aguda/epidemiología , Prevalencia , Insuficiencia Renal Crónica/patologíaRESUMEN
The photosensitized generation of reactive oxygen species, and particularly of singlet oxygen [O2 (a(1) Δg )], is the essence of photodynamic action exploited in photodynamic therapy. The ability to switch singlet oxygen generation on/off would be highly valuable, especially when it is linked to a cancer-related cellular parameter. Building on recent findings related to intersystem crossing efficiency, we designed a dimeric BODIPY dye with reduced symmetry, which is ineffective as a photosensitizer unless it is activated by a reaction with intracellular glutathione (GSH). The reaction alters the properties of both the ground and excited states, consequently enabling the efficient generation of singlet oxygen. Remarkably, the designed photosensitizer can discriminate between different concentrations of GSH in normal and cancer cells and thus remains inefficient as a photosensitizer inside a normal cell while being transformed into a lethal singlet oxygen source in cancer cells. This is the first demonstration of such a difference in the intracellular activity of a photosensitizer.
Asunto(s)
Apoptosis , Colorantes Fluorescentes/síntesis química , Glutatión/metabolismo , Fármacos Fotosensibilizantes/síntesis química , Porfobilinógeno/análogos & derivados , Oxígeno Singlete/metabolismo , Animales , Apoptosis/efectos de los fármacos , Apoptosis/efectos de la radiación , Supervivencia Celular/efectos de los fármacos , Supervivencia Celular/efectos de la radiación , Dimerización , Citometría de Flujo , Colorantes Fluorescentes/química , Colorantes Fluorescentes/farmacología , Células HeLa , Humanos , Luz , Ratones , Microscopía Confocal , Modelos Moleculares , Estructura Molecular , Células 3T3 NIH , Fármacos Fotosensibilizantes/química , Fármacos Fotosensibilizantes/farmacología , Porfobilinógeno/síntesis química , Porfobilinógeno/química , Porfobilinógeno/farmacología , Oxígeno Singlete/químicaRESUMEN
Photodynamic therapy (PDT) combines the use of organic dyes (photosensitizers, PSs) and visible light in order to elicit a photo-oxidative stress which causes bacterial death. GD11, a recently synthesized PS belonging to the boron-dipyrromethene (BODIPY) class, was demonstrated to be efficient against planktonic cultures of Pseudomonas aeruginosa, causing a 7 log unit reduction of viable cells when administered at 2.5 µM. The effectiveness of GD11 against P. aeruginosa biofilms grown in flow-cells and microtiter trays was also demonstrated. Confocal laser scanning microscopy of flow-cell-grown biofilms suggests that the treatment has a biocidal effect against bacterial biofilm cells.
Asunto(s)
Antibacterianos/farmacología , Biopelículas/efectos de los fármacos , Fármacos Fotosensibilizantes/farmacología , Pseudomonas aeruginosa/efectos de los fármacos , Pseudomonas aeruginosa/fisiología , Biopelículas/efectos de la radiación , Boro/farmacología , Microscopía Confocal , Porfobilinógeno/análogos & derivados , Porfobilinógeno/farmacología , Pseudomonas aeruginosa/efectos de la radiaciónRESUMEN
Mammalian cells acquire cholesterol, a major membrane constituent, via low-density lipoprotein (LDL) uptake. However, the mechanisms by which LDL cholesterol reaches the plasma membrane (PM) have remained obscure. Here, we applied LDL labeled with BODIPY cholesteryl linoleate to identify this pathway in living cells. The egress of BODIPY cholesterol (BC) from late endosomal (LE) organelles was dependent on acid lipase and Niemann-Pick C1 (NPC1) protein, as for natural cholesterol. We show that NPC1 was needed to recruit Rab8a to BC-containing LEs, and Rab8a enhanced the motility and segregation of BC- and CD63-positive organelles from lysosomes. The BC carriers docked to the cortical actin by a Rab8a- and Myosin5b (Myo5b)-dependent mechanism, typically in the proximity of focal adhesions (FAs). LDL increased the number and dynamics of FAs and stimulated cell migration in an acid lipase, NPC1, and Rab8a-dependent fashion, providing evidence that this cholesterol delivery route to the PM is important for cell movement.
Asunto(s)
Actinas/metabolismo , Membrana Celular/metabolismo , LDL-Colesterol/metabolismo , Miosinas/metabolismo , Proteínas de Unión al GTP rab/metabolismo , Transporte Biológico , Proteínas Portadoras/metabolismo , Movimiento Celular/efectos de los fármacos , Movimiento Celular/fisiología , Células Cultivadas , Endosomas/efectos de los fármacos , Endosomas/metabolismo , Técnica del Anticuerpo Fluorescente , Adhesiones Focales/fisiología , Humanos , Péptidos y Proteínas de Señalización Intracelular , Glicoproteínas de Membrana/metabolismo , Microscopía Inmunoelectrónica , Proteína Niemann-Pick C1 , Porfobilinógeno/análogos & derivados , Porfobilinógeno/farmacología , Tetraspanina 30/metabolismo , Cicatrización de Heridas/efectos de los fármacosRESUMEN
The synthesis of four novel heteroleptic dipyrrinato complexes [(η(6)-arene)RuCl(2-pcdpm)] (η(6)-arene = C6H6, 1; C10H14, 2) and [(η(5)-C5Me5)MCl(2-pcdpm)] (M = Rh, 3; Ir, 4) containing a new chelating ligand 4-(2-methoxypyridyl)-phenyldipyrromethene (2-pcdpm) have been described. The complexes 1-4 have been fully characterized by various physicochemical techniques, namely, elemental analyses, spectral (ESI-MS, IR, (1)H, (13)C NMR, UV/vis) and electrochemical studies (cyclic voltammetry (CV) and differential pulse voltammetry (DPV)). Structures of 3 and 4 have been determined crystallographically. In vitro antiproliferative and cytotoxic activity of these complexes has been evaluated by trypan blue exclusion assay, cell morphology, apoptosis, acridine orange/ethidium bromide (AO/EtBr) fluorescence staining, and DNA fragmentation assay in Dalton lymphoma (DL) cell lines. Interaction of 1-4 with calf thymus DNA (CT DNA) has also been supported by absorption titration and electrochemical studies. Our results suggest that in vitro antitumor activity of 1-4 lies in the order 2 > 1 > 4 > 3.
Asunto(s)
Antineoplásicos/síntesis química , Quelantes/síntesis química , Complejos de Coordinación/síntesis química , Porfobilinógeno/análogos & derivados , Animales , Antineoplásicos/farmacología , Apoptosis/efectos de los fármacos , Bovinos , Línea Celular Tumoral , Quelantes/farmacología , Complejos de Coordinación/farmacología , Cristalografía por Rayos X , ADN/química , Fragmentación del ADN , Técnicas Electroquímicas , Humanos , Iridio/química , Espectroscopía de Resonancia Magnética , Modelos Moleculares , Oxidación-Reducción , Porfobilinógeno/síntesis química , Porfobilinógeno/farmacología , Rodio/química , Rutenio/químicaRESUMEN
We have developed a new reversible fluorescence probe MPhSe-BOD for the redox cycle process between hypochlorous acid and hydrogen sulfide in solution and in living cells. Confocal microscopy imaging using RAW264.7 cell lines shows that the probe has good cell membrane permeability, and can monitor intracellular HClO/H(2)S redox cycles continuously.
Asunto(s)
Colorantes Fluorescentes/química , Sulfuro de Hidrógeno/metabolismo , Ácido Hipocloroso/metabolismo , Porfobilinógeno/análogos & derivados , Selenio/química , Animales , Línea Celular , Permeabilidad de la Membrana Celular/efectos de los fármacos , Colorantes Fluorescentes/síntesis química , Colorantes Fluorescentes/farmacología , Sulfuro de Hidrógeno/química , Ácido Hipocloroso/química , Ratones , Estructura Molecular , Oxidación-Reducción , Estrés Oxidativo , Porfobilinógeno/química , Porfobilinógeno/farmacología , Selenio/farmacologíaRESUMEN
To understand the effects of substitution patterns on photosensitizing the ability of boron dipyrromethene (BODIPY), two structural variations that either investigate the effectiveness of various iodinated derivatives to maximize the "heavy atom effect" or focus on the effect of extended conjugation at the 4-pyrrolic position to red-shift their activation wavelengths were investigated. Compounds with conjugation at the 4-pyrrolic position were less photocytotoxic than the parent unconjugated compound, while those with an iodinated BODIPY core presented better photocytotoxicity than compounds with iodoaryl groups at the meso-positions. The potency of the derivatives generally correlated well with their singlet oxygen generation level. Further studies of compound 5 on HSC-2 cells showed almost exclusive localization to mitochondria, induction of G(2)/M-phase cell cycle block, and onset of apoptosis. Compound 5 also extensively occluded the vasculature of the chick chorioallantoic membrane. Iodinated BODIPY structures such as compound 5 may have potential as new photodynamic therapy agents for cancer.