RESUMEN

The fascinating and dangerous colored pathogens contain unique chemically pigmented molecules, which give varied and efficient assistance as virulence factors to the crucial reproduction and growth of microbes. Therefore, multiple novel strategies and inhibitors have been developed in recent years that target virulence factor pigments. However, despite the importance and significance of this topic, it has not yet been comprehensively reviewed. Moreover, research groups around the world have made successful progress against antibacterial infections by targeting pigment production, including our serial works on the discovery of CrtN inhibitors against staphyloxanthin production in Staphylococcus aureus. On the basis of the previous achievements and recent progress of our group in this field, this article will be the first comprehensive review of pigment inhibitors against colored pathogens, especially S. aureus infections, and this article includes design strategies, representative case studies, advantages, limitations, and perspectives to guide future research.

Asunto(s)

Antiinfecciosos/farmacología , Pigmentos Biológicos/antagonistas & inhibidores , Factores de Virulencia/metabolismo , Animales , Antiinfecciosos/química , Productos Biológicos/química , Productos Biológicos/farmacología , Descubrimiento de Drogas , Reposicionamiento de Medicamentos , Humanos , Pigmentos Biológicos/química , Pigmentos Biológicos/metabolismo

RESUMEN

This work studies the adsorption of colored compounds in cane juice using a food-grade macroporous adsorber resin without functional groups. The adsorption equilibrium was studied through the adsorption isotherms at 30, 40, and 50 ℃. The absorbance at 420 nm was used to measure the concentration of colored compounds, which enables correlation of the residual concentration with the adsorbed concentration. Furthermore, the efficiency of the adsorption process was studied, from which it was observed that there was an improvement in efficiency with increasing resin content, while the increase in temperature was less important in the process. The kinetic study was performed using the Ibarz model and intraparticle diffusion model, which correctly account for the kinetics of the adsorption process. The adsorption kinetic constant was always greater than the desorption kinetic constant, indicating that the adsorption step predominates over the desorption step.

Asunto(s)

Bebidas/análisis , Manipulación de Alimentos , Indicadores y Reactivos/química , Modelos Moleculares , Pigmentos Biológicos/antagonistas & inhibidores , Tallos de la Planta/química , Saccharum/química , Adsorción , Algoritmos , Difusión , Almacenamiento de Alimentos , Calor , Indicadores y Reactivos/metabolismo , Cinética , Reacción de Maillard , Microesferas , Tamaño de la Partícula , Perú , Pigmentos Biológicos/química , Pigmentos Biológicos/metabolismo , Poliestirenos/química , Poliestirenos/metabolismo , Porosidad

RESUMEN

Decreased antimicrobial efficiency has become a global public health issue. The paucity of new antibacterial drugs is evident, and the arsenal against infectious diseases needs to be improved urgently. The selection of plants as a source of prototype compounds is appropriate, since plant species naturally produce a wide range of secondary metabolites that act as a chemical line of defense against microorganisms in the environment. Although traditional approaches to combat microbial infections remain effective, targeting microbial virulence rather than survival seems to be an exciting strategy, since the modulation of virulence factors might lead to a milder evolutionary pressure for the development of resistance. Additionally, anti-infective chemotherapies may be successfully achieved by combining antivirulence and conventional antimicrobials, extending the lifespan of these drugs. This review presents an updated discussion of natural compounds isolated from plants with chemically characterized structures and activity against the major bacterial virulence factors: quorum sensing, bacterial biofilms, bacterial motility, bacterial toxins, bacterial pigments, bacterial enzymes, and bacterial surfactants. Moreover, a critical analysis of the most promising virulence factors is presented, highlighting their potential as targets to attenuate bacterial virulence. The ongoing progress in the field of antivirulence therapy may therefore help to translate this promising concept into real intervention strategies in clinical areas.

Asunto(s)

Antibacterianos/farmacología , Bacterias/efectos de los fármacos , Productos Biológicos/farmacología , Factores de Virulencia/antagonistas & inhibidores , Bacterias/metabolismo , Fenómenos Fisiológicos Bacterianos , Proteínas Bacterianas/antagonistas & inhibidores , Toxinas Bacterianas/antagonistas & inhibidores , Biopelículas/efectos de los fármacos , Productos Biológicos/aislamiento & purificación , Inhibidores Enzimáticos/farmacología , Pigmentos Biológicos/antagonistas & inhibidores , Plantas/química , Percepción de Quorum

RESUMEN

Anthocyanins are widely used as natural colorants in foods, but they are highly susceptible to chemical degradation during storage leading to color fading. This study examined the potential of natural quillaja saponin and polyphenols (vanillin, epigallocatechin gallate, green tea extract, and protocatechualdehyde) at inhibiting color fading of anthocyanins in model beverages. The purple carrot anthocyanin (0.025%) in model beverages (citric acid, pH 3.0) containing l-ascorbic acid (0.050%) degraded with a first-order reaction rate during storage (40°C/7days in light). The addition of polyphenols (0.2%) delayed color fading, with the most notable improvement observed with green tea extract addition. The half-life for anthocyanin color fading increased from 2.9 to 6.7days with green tea extract. Fluorescence quenching measurements showed that the green tea extract contained components that interacted with anthocyanins probably through hydrophobic interactions. Overall, this study provides valuable information about enhancing the stability of anthocyanins in beverage systems using polyphenols.

Asunto(s)

Antocianinas/análisis , Bebidas/análisis , Daucus carota , Suplementos Dietéticos/análisis , Pigmentos Biológicos/análisis , Polifenoles/análisis , Antocianinas/antagonistas & inhibidores , Antocianinas/metabolismo , Daucus carota/química , Almacenamiento de Alimentos/normas , Pigmentos Biológicos/antagonistas & inhibidores , Pigmentos Biológicos/metabolismo , Extractos Vegetales/análisis , Extractos Vegetales/antagonistas & inhibidores , Extractos Vegetales/metabolismo , Polifenoles/metabolismo

RESUMEN

Porphyrias are disorders of heme metabolism frequently characterized by extreme photosensitivity. This symptom results from accumulation of porphyrins, tetrapyrrole intermediates in heme biosynthesis that generate reactive oxygen species when exposed to light, in the skin of affected individuals. Here we report that in addition to producing an ommochrome body pigment, the planarian flatworm Schmidtea mediterranea generates porphyrins in its subepithelial pigment cells under physiological conditions, and that this leads to pigment cell loss when animals are exposed to intense visible light. Remarkably, porphyrin biosynthesis and light-induced depigmentation are enhanced by starvation, recapitulating a common feature of some porphyrias - decreased nutrient intake precipitates an acute manifestation of the disease. Our results establish planarians as an experimentally tractable animal model for research into the pathophysiology of acute porphyrias, and potentially for the identification of novel pharmacological interventions capable of alleviating porphyrin-mediated photosensitivity or decoupling dieting and fasting from disease pathogenesis.

Asunto(s)

Proteínas del Helminto/genética , Pigmentos Biológicos/genética , Planarias/efectos de la radiación , Porfiria Intermitente Aguda/fisiopatología , Porfirinas/genética , Animales , Modelos Animales de Enfermedad , Regulación de la Expresión Génica , Proteínas del Helminto/metabolismo , Hemo/genética , Hemo/metabolismo , Humanos , Luz , Fenotiazinas/metabolismo , Pigmentos Biológicos/antagonistas & inhibidores , Pigmentos Biológicos/biosíntesis , Planarias/genética , Planarias/metabolismo , Porfiria Intermitente Aguda/genética , Porfiria Intermitente Aguda/metabolismo , Porfirinas/antagonistas & inhibidores , Porfirinas/biosíntesis , Pigmentación de la Piel/genética , Pigmentación de la Piel/efectos de la radiación , Inanición/genética

RESUMEN

Fresh culinary-medicinal Shiitake mushrooms (Lentinus edodes) were pretreated by soaking in 0.1 mg/mL of L-cysteine solution for 1 hour; then the variation in formaldehyde content and browning degree were studied during hot air-drying and canning processes. The results indicated that L-cysteine pretreatment significantly inhibited the increase of formaldehyde content and browning during the drying process; these increases in the pretreatment groups ranged from 7.0% to 14.0% and 65.4% to 68.9%, respectively, of that of the control groups. While the L-cysteine pretreatment did not seem to have a significant effect on controlling the formaldehyde content during the canning process, the increase of the browning degree of the canned products of the pretreatment groups ranged from 64.8% to 78.5% of that of the control groups, indicating the inhibitive effect of L-cysteine on browning during the canning process of L. edodes. Overall, L-cysteine pretreatment improved the sensory quality of both dried and canned L. edodes.

Asunto(s)

Cisteína/metabolismo , Desecación , Manipulación de Alimentos/métodos , Formaldehído/antagonistas & inhibidores , Pigmentos Biológicos/antagonistas & inhibidores , Hongos Shiitake/metabolismo , Almacenamiento de Alimentos/métodos , Humanos

RESUMEN

Penicillium marneffei, one of the most important thermal dimorphic fungi, is a severe threat to the life of immunocompromised patients. However, the pathogenic mechanisms of P. marneffei remain largely unknown. In this work, we developed a model host by using nematode Caenorhabditis elegans to investigate the virulence of P. marneffei. Using two P. marneffei clinical isolate strains 570 and 486, we revealed that in both liquid and solid media, the ingestion of live P. marneffei was lethal to C. elegans (P<0.001). Meanwhile, our results showed that the strain 570, which can produce red pigment, had stronger pathogenicity in C. elegans than the strain 486, which can't produce red pigment (P<0.001). Microscopy showed the formation of red pigment and hyphae within C. elegans after incubation with P. marneffei for 4 h, which are supposed to be two contributors in nematodes killing. In addition, we used C. elegans as an in vivo model to evaluate different antifungal agents against P. marneffei, and found that antifungal agents including amphotericin B, terbinafine, fluconazole, itraconazole and voriconazole successfully prolonged the survival of nematodesinfected by P. marneffei. Overall, this alternative model host can provide us an easy tool to study the virulence of P. marneffei and screen antifungal agents.

Asunto(s)

Antifúngicos/farmacología , Caenorhabditis elegans/microbiología , Hifa/efectos de los fármacos , Micosis/tratamiento farmacológico , Penicillium/efectos de los fármacos , Anfotericina B/farmacología , Animales , Modelos Animales de Enfermedad , Fluconazol/farmacología , Interacciones Huésped-Patógeno , Hifa/crecimiento & desarrollo , Hifa/metabolismo , Hifa/patogenicidad , Itraconazol/farmacología , Micosis/microbiología , Micosis/mortalidad , Naftalenos/farmacología , Penicillium/crecimiento & desarrollo , Penicillium/metabolismo , Penicillium/patogenicidad , Pigmentos Biológicos/antagonistas & inhibidores , Pigmentos Biológicos/biosíntesis , Pigmentos Biológicos/toxicidad , Análisis de Supervivencia , Terbinafina , Voriconazol/farmacología

RESUMEN

Artocarpus plants have been a focus of constant attention due to the potential for skin whitening agents. In the in vitro experiment, compounds from the Artocarpus plants, such as artocarpanone, norartocarpetin, artocarpesin, artogomezianol, andalasin, artocarbene, and chlorophorin showed tyrosinase inhibitory activity. Structure-activity investigations revealed that the 4-substituted resorcinol moiety in these compounds was responsible for their potent inhibitory activities on tyrosinase. In the in vitro assay, using B16 melanoma cells, the prenylated polyphenols isolated from Artocarpus plants, such as artocarpin, cudraflavone C, 6-prenylapigenin, kuwanon C, norartocarpin, albanin A, cudraflavone B, and brosimone I showed potent inhibitory activity on melanin formation. Structure-activity investigations revealed that the introduction of an isoprenoid moiety to a non-isoprenoid-substituted polyphenol enhanced the inhibitory activity of melanin production in B16 melanoma cells. In the in vivo investigation, the extract of the wood of Artocarpus incisus and a representative isolated compound from it, artocarpin had a lightening effect on the skin of guinea pigs' backs. Other in vivo experiments using human volunteers have shown that water extract of Artocarpus lakoocha reduced the melanin formation in the skin of volunteers. These results indicate that the extracts of Artocarpus plants are potential sources for skin whitening agents.

Asunto(s)

Artocarpus/química , Cosméticos/química , Extractos Vegetales/química , Extractos Vegetales/farmacología , Pigmentación de la Piel/efectos de los fármacos , Animales , Cobayas , Humanos , Melaninas/biosíntesis , Estructura Molecular , Pigmentos Biológicos/antagonistas & inhibidores , Tirosina/biosíntesis , Madera/química

RESUMEN

The 4'-(p-toluenesulfonylamino)-4-hydroxychalcone (TSAHC), which bears inhibitory chemotypes for both alpha-glucosidase and tyrosinase, was evaluated for tyrosinase activity and depigmenting ability relative to compounds designed to only target tyrosianse activity. TSAHC emerged to be a competitive reversible inhibitor of mushroom tyrosinase. More importantly, it was also able to return the melanin content of alpha-melanocyte stimulated by alpha-MSH to base levels unlike other inhibitors that only targeted tyrosinase. The Western blot for expression levels of proteins involved in melanogenesis showed that TSAHC significantly decreased three main tyrosinase related protein in melanin biosynthesis, tyrosinase, TRP-1 and TRP-2.

Asunto(s)

Chalcona/análogos & derivados , Inhibidores Enzimáticos/farmacología , Inhibidores de Glicósido Hidrolasas , Monofenol Monooxigenasa/antagonistas & inhibidores , Pigmentos Biológicos/antagonistas & inhibidores , Sulfonamidas/farmacología , Chalcona/química , Chalcona/farmacología , Diseño de Fármacos , Activación Enzimática/efectos de los fármacos , Inhibidores Enzimáticos/química , Estructura Molecular , Monofenol Monooxigenasa/metabolismo , Estereoisomerismo , Relación Estructura-Actividad , Sulfonamidas/química , alfa-Glucosidasas/metabolismo

RESUMEN

Six diphenolic compounds containing adamantane moiety were synthesized and evaluated as potent inhibitors on tyrosinase activity and melanin formation in Melan-A cells. The inhibitory activity of 4-adamantyl resorcinol 1 was similar to that of 4-n-butyl resorcinol in both assays. However, dihydroxyl benzamide derivatives 6a-e showed different inhibitory patterns. All derivatives significantly suppressed the cellular melanin formation without tyrosinase inhibitory activities. These behaviors indicated that the introduction of amide bond changes the binding mode of dihydroxyl groups to tyrosinase. Among derivatives, 6d (3,4-dihydroxyl compound) and 6e (2,3-dihydroxyl compound) showed stronger inhibitory activities (IC(50)=1.25 microM and 0.73 microM, respectively) as compared to 4-n-butyl resorcinol (IC(50)=21.64 microM) and hydroquinone (IC(50)=3.97 microM). This study showed that the position of dihydroxyl substituent at aromatic ring is important for the intercellular inhibition of melanin formation, and also amide linkage and adamantane moiety enhance the inhibition.

Asunto(s)

Adamantano/síntesis química , Benzamidas/síntesis química , Pigmentos Biológicos/antagonistas & inhibidores , Adamantano/farmacología , Agaricales , Animales , Benzamidas/farmacología , Células Cultivadas , Melaninas/antagonistas & inhibidores , Melaninas/biosíntesis , Melaninas/metabolismo , Melanocitos/efectos de los fármacos , Melanocitos/enzimología , Ratones , Ratones Endogámicos C57BL , Monofenol Monooxigenasa/biosíntesis , Pigmentos Biológicos/biosíntesis , Pigmentos Biológicos/metabolismo

RESUMEN

In this study, effect of different 2,4 -dichlorophenoxyacetic acid (2,4-D) concentrations (0.0, 9.10(-5), 9.10(-4), 9.10(-3) and 9.10(-2) mM) on growth rate, content of protein and chlorophyll-a in Chlorella vulgaris and Spirulina platensis cells was investigated. The most stimulatory effect on growth rate, protein and pigment ratio of C. vulgaris and S. platensis was observed at 9.10(-4) mM concentrations of 2,4-D. The results show that low concentrations of 2,4-D have hormonal effect due to being a synthetic auxin. Cell number protein and pigment rates were inhibited at 9.10(-2) mM concentration in C. vulgaris. Such parameters were inhibited in S. platensis, both at 9.10(-3) and 9.10(-2) mM 2,4-D concentrations. This is due to herbicidal effect of high concentrations of 2,4-D. S. platensis was found to be more sensitive than S. vulgaris to 2,4-D applications. The use of algae as bio-indicators in herbicide contaminated fresh water habitats, was discussed.

Asunto(s)

Ácido 2,4-Diclorofenoxiacético/toxicidad , Chlorella vulgaris/efectos de los fármacos , Clorofila/metabolismo , Herbicidas/toxicidad , Proteínas Nucleares/metabolismo , Spirulina/efectos de los fármacos , Contaminantes Químicos del Agua/toxicidad , Ácido 2,4-Diclorofenoxiacético/metabolismo , Chlorella vulgaris/citología , Chlorella vulgaris/crecimiento & desarrollo , Chlorella vulgaris/metabolismo , Clorofila A , Relación Dosis-Respuesta a Droga , Agua Dulce , Herbicidas/metabolismo , Cinética , Pigmentos Biológicos/antagonistas & inhibidores , Pigmentos Biológicos/metabolismo , Spirulina/citología , Spirulina/crecimiento & desarrollo , Spirulina/metabolismo , Contaminantes Químicos del Agua/metabolismo

RESUMEN

We have previously reported effective gene silencing of a transgene and endogenous plant genes in tobacco and tomato plants using a modified viral satellite DNA associated with Tomato yellow leaf curl China virus (TYLCCNV). In this study, we constructed a similar gene silencing vector (DNADeltaC12beta) based on the satellite DNAbeta associated with Tobacco curly shoot virus (TbCSV) by replacing its betaC1 gene with a multiple cloning site. Strong and stable silencing of cognate genes was achieved when this vector, carrying a fragment of the green fluorescent protein (GFP) transgene or a sulfur (Su) endogenous gene encoding one unit of the chloroplast enzyme magnesium chelatase required for chlorophyll II production, was co-agroinoculated with TbCSV used as a helper virus. GFP silenced transgenic Nicotiana benthamiana plants appear red under UV illumination due to loss of green fluorescence, while the Su silenced plants appear white as a result of failure to synthesize chlorophyll. Our results show that the efficiency of Su silencing is independent of the insert orientation in both N. benthamiana and N. glutinosa plants. Most significant however, is the observation that in association with heterologous begomoviruses, such as TYLCCNV or Malvastrum yellow vein virus, the DNADeltaC12beta vector could still effectively induce transgene and endogenous gene silencing in tobacco plants. These observations suggest that the modified viral satellite DNA vector can be applied as a reverse genetics tool for the study, analysis and discovery of gene function in more plants.

Asunto(s)

Geminiviridae/genética , Silenciador del Gen , Vectores Genéticos , Nicotiana/genética , Nicotiana/virología , Southern Blotting , ADN Viral/análisis , Genes Reporteros , Proteínas Fluorescentes Verdes/genética , Liasas/antagonistas & inhibidores , Liasas/genética , Pigmentos Biológicos/antagonistas & inhibidores , Plantas Modificadas Genéticamente , ARN Mensajero/análisis , ARN de Planta/análisis , Reacción en Cadena de la Polimerasa de Transcriptasa Inversa , Nicotiana/metabolismo , Transformación Genética

RESUMEN

By using fosmidomycin and mevinolin (inhibitors of the synthesis of isoprenoid pigments), spectrophotometry, and mass spectrometry, the presence of isoprenoid pigments is shown in 71 of the 78 strains under study. All of these strains belong to 11 genera of the family Microbacteriaceae. Yellow, orange, and red pigments are found to have absorption spectra typical of C40-carotenoids. Eight out of the sixteen strains of the genus Microbacterium are able to synthesize neurosporene, a precursor of lycopene and beta-carotene. The biosynthesis of carotenoids in some representatives of the genera Agromyces, Leifsonia, and Microbacterium is induced by light. Inhibition of the biosynthesis of isoprenoid pigments by fosmidomycin suggests that they are synthesized via the nonmevalonate pathway. Twelve strains are found to exhibit both the nonmevalonate and mevalonate pathways of isoprenoid synthesis. These data, together with the difference in the inhibitory concentration of fosmidomycin, can be used for differentiating various taxa within the family Microbacteriaceae.

Asunto(s)

Actinomycetales/metabolismo , Pigmentos Biológicos/biosíntesis , Terpenos/metabolismo , Actinomycetales/efectos de los fármacos , Actinomycetales/crecimiento & desarrollo , Fosfomicina/análogos & derivados , Fosfomicina/farmacología , Lovastatina/farmacología , Espectrometría de Masas , Pigmentos Biológicos/antagonistas & inhibidores , Espectrofotometría , Terpenos/antagonistas & inhibidores

RESUMEN

At present the use-rate of modern herbicides is in the range of 100-300 g AI ha-1, with a tendency to decline. The low use-rate (ca 10 g AI ha-1) of the original sulfonylurea and cyclic imide herbicides prompted agrochemical scientists to look for even more active compounds which led to the successive discoveries of many new herbicidal acetolactate synthase inhibitors and no less than 18 cyclic imides in the class of protoporphyrinogen-IX oxidase inhibitors in the 1990s. In this paper, mechanisms of action related to function and biosynthesis of chlorophylls, carotenoids, plastoquinone, amino acids, fatty acids and photosynthetic electron transport and other metabolic processes are discussed as plant-specific herbicidal target domains.

Asunto(s)

Herbicidas/farmacología , Proteínas del Complejo del Centro de Reacción Fotosintética/antagonistas & inhibidores , Pigmentos Biológicos/antagonistas & inhibidores , Acetolactato Sintasa/antagonistas & inhibidores , Aminoácidos/antagonistas & inhibidores , Aminoácidos/biosíntesis , Amoníaco/antagonistas & inhibidores , Amoníaco/metabolismo , Carotenoides/antagonistas & inhibidores , Carotenoides/biosíntesis , Pared Celular/efectos de los fármacos , Pared Celular/metabolismo , Celulosa/antagonistas & inhibidores , Celulosa/biosíntesis , Clorofila/antagonistas & inhibidores , Clorofila/biosíntesis , Transporte de Electrón/efectos de los fármacos , Transporte de Electrón/fisiología , Complejos de Proteína Captadores de Luz , Lípidos/antagonistas & inhibidores , Lípidos/biosíntesis , Fotosíntesis/efectos de los fármacos , Fotosíntesis/fisiología , Proteínas del Complejo del Centro de Reacción Fotosintética/metabolismo , Pigmentos Biológicos/biosíntesis , Plastoquinona/antagonistas & inhibidores , Plastoquinona/metabolismo , Especificidad de la Especie

RESUMEN

The dark green pigmented marine bacterium Pseudoalteromonas tunicata colonizes living surfaces and produces a range of extracellular compounds that inhibit common fouling organisms, including marine invertebrate larvae, algae, bacteria, and fungi. We have observed a positive correlation between the antifouling activity of P. tunicata strain D2 and the expression of pigmentation. To address the hypothesis that pigmentation and antifouling may be jointly regulated in this organism and to begin to identify potential regulatory elements, we used transposon mutagenesis to generate a strain of P. tunicata deficient in antifouling activity. The data presented here describe the phenotypic and molecular characterization of a nonpigmented transposon mutant strain of P. tunicata (D2W2). Analyses of the antifouling capabilities of D2W2 demonstrate that this strain is deficient in the ability to inhibit each of the target fouling organisms. Genetic analysis of D2W2 identified a gene, designated wmpR (white mutant phenotype), with high sequence similarity to transcriptional regulators ToxR from Vibrio cholerae and CadC from Escherichia coli. Two-dimensional polyacrylamide gel electrophoresis analysis revealed that WmpR is essential for the expression of a significant subset of stationary-phase-induced proteins likely to be important for the synthesis of fouling inhibitors. The identification of a gene involved in the regulation of expression of antifouling phenotypes will contribute to the understanding of the interactions between bacteria and other surface-colonizing organisms in the marine environment.

Asunto(s)

Antibacterianos/biosíntesis , Proteínas Bacterianas/genética , Gammaproteobacteria/genética , Regulación Bacteriana de la Expresión Génica , Factores de Transcripción/genética , Animales , Antibacterianos/antagonistas & inhibidores , Bacterias/crecimiento & desarrollo , Proteínas Bacterianas/metabolismo , Crustáceos/crecimiento & desarrollo , Elementos Transponibles de ADN , Eucariontes/crecimiento & desarrollo , Hongos/crecimiento & desarrollo , Gammaproteobacteria/metabolismo , Datos de Secuencia Molecular , Mutagénesis Insercional , Pigmentos Biológicos/antagonistas & inhibidores , Pigmentos Biológicos/biosíntesis , Análisis de Secuencia de ADN , Factores de Transcripción/metabolismo , Transcripción Genética , Urocordados/crecimiento & desarrollo

RESUMEN

The polymerization of hemoglobin-derived ferric-protoporphyrin IX [Fe(III)PPIX] to inert hemozoin (malaria pigment) is a crucial and unique process for intraerythrocytic plasmodia to prevent heme toxicity and thus a good target for new antimalarials. Quinoline drugs, i.e., chloroquine, and non-iron porphyrins have been shown to block polymerization by forming electronic pi-pi interactions with heme monomers. Here, we report the identification of ferrous-protoporphyrin IX [Fe(II)PPIX] as a novel endogenous anti-malarial. Fe(II)PPIX molecules, released from the proteolysis of hemoglobin, are first oxidized and then polymerized to hemozoin. We obtained Fe(II)PPIX on preparative scale by electrochemical reduction of Fe(III)PPIX, and the reaction was monitored by cyclic voltammetry. Polymerization assays at acidic pH were conducted with the resulting Fe(II)PPIX using a spectrophotometric microassay of heme polymerization adapted to anaerobic conditions and the products characterized by infrared spectroscopy. Fe(II)PPIX (a) did not polymerize and (b) produced a dose-dependent inhibition of Fe(III)PPIX polymerization (IC(50) = 0.4 molar equiv). Moreover, Fe(II)PPIX produced by chemical reduction with thiol-containing compounds gave similar results: a dose-dependent inhibition of heme polymerization was observed using either L-cysteine, N-acetylcysteine, or DL-homocysteine, but not with L-cystine. Cyclic voltammetry confirmed that the inhibition of heme polymerization was due to the Fe(II)PPIX molecules generated by the thiol-mediated reduction of Fe(III)PPIX. These results point to Fe(II)PPIX as a potential endogenous antimalarial and to Fe(III)PPIX reduction as a potential new pharmacological target.

Asunto(s)

Antimaláricos/farmacología , Compuestos Ferrosos/farmacología , Hemo/fisiología , Hemina/antagonistas & inhibidores , Pigmentos Biológicos/antagonistas & inhibidores , Plasmodium falciparum/crecimiento & desarrollo , Protoporfirinas/fisiología , Animales , Antimaláricos/química , Electroquímica , Eritrocitos/fisiología , Compuestos Ferrosos/sangre , Hemina/metabolismo , Humanos , Oxidación-Reducción , Pigmentos Biológicos/sangre , Plasmodium falciparum/efectos de los fármacos , Polímeros/metabolismo , Protoporfirinas/sangre , Protoporfirinas/toxicidad , Compuestos de Sulfhidrilo/farmacología

RESUMEN

It was documented that ageing is associated with a progressive and highly significant proliferation of the total number of light microscopically visible lipofuscin granules in the grey substance of sections of the cervical spinal cord of Balb/c mice. The mean total numbers (+/- standard errors) of lipofuscin granules in standard sections of the glutaraldehyde-osmium fixed, epon embedded spinal cords that were examined with a phase contrast light microscope in 1 week, 1 month, 8 months and 18 months old mice were 0, 269 +/- 56, 1101 +/- 82 and 2464 +/- 318, respectively. The population densities of multiglobular lipofuscin units as seen with the electron microscope in random spinal cord neurons of the same 4 age groups corresponded well with the above quantitative, light microscopic data. Continuous treatment for 8 months with either the natural anti-oxidant Vitamin E (alpha-tocopherol) at 40 mg/mouse/week or the synthetic anti-oxidant butylated hydroxytoluene at about 100 mg/mouse/week diminished significantly the proliferation of lipofuscin granules in spinal cord neurons that developed during that period of ageing. No toxicity of any sort was caused by these two treatments. These results provide support for the peroxide theory of lipofuscin biogenesis and encourage further exploration of the possibilities of obtaining greater anti-lipofuscin effects with less molecular bulk of antioxidants.

Asunto(s)

Antioxidantes/farmacología , Lipofuscina/antagonistas & inhibidores , Neuronas/metabolismo , Pigmentos Biológicos/antagonistas & inhibidores , Vitamina E/farmacología , Envejecimiento , Animales , Supervivencia Celular , Gránulos Citoplasmáticos/metabolismo , Gránulos Citoplasmáticos/ultraestructura , Lipofuscina/metabolismo , Masculino , Ratones , Ratones Endogámicos BALB C , Neuronas/ultraestructura , Médula Espinal/metabolismo , Médula Espinal/ultraestructura

RESUMEN

The total numbers and sizes of the lipofuscin granules in buccal ganglia of the pond snail Planorbis corneus were measured by light microscope morphometry of serial sections in different groups of animals. One group, weight range 0.5-5.0 g (age 1-4 years), was maintained on a lettuce diet (low Vitamin E content). Lipofuscin content increased with age by over a 100 times in this group. The lipofuscin deposits accumulate in the glial cells at the periphery of the ganglia. The other group, weight range 0.5-5.0 g was fed a supplemented Vitamin E diet for 4 months before quantitisation of the lipofuscin. This diet prevented lipofuscin appearance in the young animals, and reduced the lipofuscin content by 50% in the old animals. The findings provide direct evidence that Vitamin E reduces lipofuscin accumulation in glial cells in intact nervous tissue. The buccal ganglia of Planorbis provide a useful model system for studying age and dietary related alterations of lipofuscin in nervous tissue.

Asunto(s)

Ganglios/metabolismo , Lipofuscina/antagonistas & inhibidores , Tejido Nervioso/metabolismo , Pigmentos Biológicos/antagonistas & inhibidores , Vitamina E/farmacología , Envejecimiento , Animales , Mejilla/inervación , Ganglios/ultraestructura , Histocitoquímica , Lipofuscina/metabolismo , Microscopía Electrónica , Caracoles

Asunto(s)

Melanoma , Neoplasias Cutáneas , Dihidroxifenilalanina/metabolismo , Epinefrina/biosíntesis , Humanos , Melaninas/biosíntesis , Melanocitos/efectos de los fármacos , Melanocitos/crecimiento & desarrollo , Melanocitos/metabolismo , Melanocitos/fisiología , Melanoma/tratamiento farmacológico , Melanoma/metabolismo , Compuestos de Mostaza/uso terapéutico , Metástasis de la Neoplasia , Neuronas/metabolismo , Fenilalanina/metabolismo , Fenilalanina/uso terapéutico , Pigmentos Biológicos/antagonistas & inhibidores , Pigmentos Biológicos/biosíntesis , Neoplasias Cutáneas/tratamiento farmacológico , Neoplasias Cutáneas/metabolismo , Tirosina/metabolismo

Asunto(s)

Microsporum/análisis , Mitocondrias Hepáticas/metabolismo , Naftoquinonas/farmacología , Fosforilación Oxidativa/efectos de los fármacos , Pigmentos Biológicos/farmacología , Adenosina Trifosfatasas/metabolismo , Animales , Técnicas In Vitro , Lactonas/antagonistas & inhibidores , Lactonas/farmacología , Mitocondrias Hepáticas/enzimología , Dilatación Mitocondrial/efectos de los fármacos , Naftoquinonas/antagonistas & inhibidores , Consumo de Oxígeno , Pigmentos Biológicos/antagonistas & inhibidores , Polarografía , Ratas , Albúmina Sérica Bovina/farmacología