RESUMEN
Phototherapy for non-invasive cancer treatment has been extensively studied. An urgent challenge in phototherapy application is to fabricate appropriate targeted agents to achieve efficient therapeutic effect. Herein, a molecular and supramolecular approach for targeting phototherapy was reasonably designed and realized through the axial sulfonate modification of silicon(IV) phthalocyanines (Pcs), followed by supramolecular interaction with albumin. This approach can not only improve the photoactivities (e.g., fluorescence emission and reactive oxygen species production) of the Pcs but also enhance their tumor targeting. Most importantly, one of the deigned Pcs (4) can target HepG2 cells through dual cell pathways, leading to an extremely high phototoxicity with an EC50 (i.e., concentration of Pcs to kill 50% of cells under light irradiation) value of 2.0 nM. This finding presents a feasible strategy to realize efficient targeting phototherapy.
Asunto(s)
Antineoplásicos , Fotoquimioterapia , Albúminas , Antineoplásicos/uso terapéutico , Línea Celular Tumoral , Indoles/metabolismo , Indoles/farmacología , Fármacos Fotosensibilizantes/uso terapéutico , FototerapiaRESUMEN
The response rate of anti-PD therapy in most cancer patients remains low. Therapeutic drug and tumor-infiltrating lymphocytes (TILs) are usually obstructed by the stromal region within tumor microenvironment (TME) rather than distributed around tumor cells, thus unable to induce the immune response of cytotoxic T cells. Here, we constructed the cationic thermosensitive lipid nanoparticles IR780/DPPC/BMS by introducing cationic NIR photosensitizer IR-780 iodide (IR780) modified lipid components, thermosensitive lipid DPPC and PD-1/PD-L1 inhibitor BMS202 (BMS). Upon laser irradiation, IR780/DPPC/BMS penetrated into deep tumor, and reduced cancer-associated fibroblasts (CAFs) around tumor cells to remodel the spatial distribution of TILs in TME. Interestingly, the cationic IR780/DPPC/BMS could capture released tumor-associated antigens (TAAs), thereby enhancing the antigen-presenting ability of DCs to activate cytotoxic T lymphocytes. Moreover, IR780/DPPC/BMS initiated gel-liquid crystal phase transition under laser irradiation, accelerating the disintegration of lipid bilayer structure and leading to the responsive release of BMS, which would reverse the tumor immunosuppression state by blocking PD-1/PD-L1 pathway for a long term. This combination treatment can synergistically exert the antitumor immune response and inhibit the tumor growth and metastasis.
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Antígeno B7-H1/inmunología , Liposomas/farmacología , Neoplasias/tratamiento farmacológico , Receptor de Muerte Celular Programada 1/inmunología , Acetamidas/química , Acetamidas/farmacología , Antígeno B7-H1/antagonistas & inhibidores , Linfocitos T CD8-positivos/efectos de los fármacos , Línea Celular Tumoral , Proliferación Celular/efectos de los fármacos , Humanos , Tolerancia Inmunológica/efectos de los fármacos , Inmunoterapia/métodos , Indoles/química , Indoles/farmacología , Liposomas/química , Terapia por Luz de Baja Intensidad , Linfocitos Infiltrantes de Tumor/efectos de los fármacos , Linfocitos Infiltrantes de Tumor/efectos de la radiación , Nanopartículas/química , Neoplasias/inmunología , Neoplasias/patología , Neoplasias/radioterapia , Receptor de Muerte Celular Programada 1/antagonistas & inhibidores , Piridinas/química , Piridinas/farmacología , Linfocitos T Citotóxicos/efectos de los fármacos , Linfocitos T Citotóxicos/efectos de la radiación , Microambiente Tumoral/efectos de los fármacosRESUMEN
Fabrication of a multifunctional near-infrared (NIR) theranostic nanoplatform has attracted increasing attention. Indocyanine green (ICG), a clinic-approved NIR fluorescence-imaging agent, is an excellent photothermal agent candidate. However, the stability and tumor targeting are still great obstacles for its wide application. In this work, C-phycocyanin (CPC) as a tumor-associated macrophages (TAMs) targeted vehicle was used to fabricate noncovalent ICG conjugate of CPC (ICG@CPC) via self-assembly in aqueous media. Compared to free ICG, ICG@CPC displays improved stabilities in aqueous solutions and under light irradiation and threefold increase in photothermal conversion efficiency. The in vitro results indicated that ICG@CPC could be selectively internalized into J774A.1 cells via SR-A-mediated endocytosis and lead to enhanced photocytotoxicity against J774A.1 cells. In vivo results showed that ICG@CPC had significantly improved drug accumulation in the tumor and photothermal therapeutic efficacy relative to ICG alone. This study for the first time utilizes CPC as a TAMs-targeted nanocarrier for ICG and may promote further rational design of ICG-based photothermal nanodrugs for precise and efficient cancer theranosis.
Asunto(s)
Verde de Indocianina/química , Verde de Indocianina/metabolismo , Macrófagos/metabolismo , Fototerapia/métodos , Ficocianina/química , Línea Celular Tumoral , Endocitosis , Humanos , Terapia Molecular Dirigida , Agua/químicaRESUMEN
Owing to their unique, nanoscale related optical properties, nanostructures assembled from molecular photosensitizers (PSs) have interesting applications in phototheranostics. However, most nanostructured PS assemblies are super-quenched, thus, preventing their use in photodynamic therapy (PDT). Although some of these materials undergo stimuli-responsive disassembly, which leads to partial recovery of PDT activity, their therapeutic potentials are unsatisfactory owing to a limited ability to promote generation reactive oxygen species (ROS), especially via typeâ I photoreactions (i.e., not by 1 O2 generation). Herein we demonstrate that a new, nanostructured phthalocyanine assembly, NanoPcA, has the ability to promote highly efficient ROS generation via the typeâ I mechanism. The results of antibacterial studies demonstrate that NanoPcA has potential PDT applications.
Asunto(s)
Antibacterianos/farmacología , Indoles/farmacología , Nanoestructuras/química , Fotoquimioterapia , Fármacos Fotosensibilizantes/farmacología , Especies Reactivas de Oxígeno/antagonistas & inhibidores , Antibacterianos/síntesis química , Antibacterianos/química , Escherichia coli/efectos de los fármacos , Escherichia coli/metabolismo , Indoles/síntesis química , Indoles/química , Isoindoles , Pruebas de Sensibilidad Microbiana , Estructura Molecular , Tamaño de la Partícula , Procesos Fotoquímicos , Fármacos Fotosensibilizantes/síntesis química , Fármacos Fotosensibilizantes/química , Especies Reactivas de Oxígeno/metabolismo , Staphylococcus aureus/efectos de los fármacos , Staphylococcus aureus/metabolismo , Propiedades de SuperficieRESUMEN
Sono-Photodynamic therapy (SPDT) utilizing ultrasound and light has been demonstrated that this novel approach can lower dosage resulting in reduction of the potential side effects caused by sensitizers. Recently, a new formulation of rose bengal (RB) as an intralesional injection has completed clinical trials phase II for PDT treatment of melanoma cancer. However, the inherent unfavorable pharmacological properties of RB hindered its extensive clinical development. With the aim to identify new RB derivatives (RBDs) with enhanced photodynamic and sonodynamic anticancer efficiency, a series of amphiphilic RBDs have been designed, synthesized and biological characterized. Among them, RBD4 significantly improved cellular uptake and enhanced intracellular ROS generation efficiency upon light and ultrasound irradiation, resulting in dramatically improved anticancer potency. Notably, RBD4 has a relative potency similar to sinoporphyrin sodium (DVDMS), indicating its further potential application for SPDT.
Asunto(s)
Antineoplásicos/farmacología , Fotoquimioterapia , Rosa Bengala/farmacología , Animales , Antineoplásicos/síntesis química , Antineoplásicos/química , Proliferación Celular/efectos de los fármacos , Supervivencia Celular/efectos de los fármacos , Relación Dosis-Respuesta a Droga , Ensayos de Selección de Medicamentos Antitumorales , Células Hep G2 , Humanos , Interacciones Hidrofóbicas e Hidrofílicas , Ratones , Estructura Molecular , Especies Reactivas de Oxígeno/análisis , Especies Reactivas de Oxígeno/metabolismo , Rosa Bengala/síntesis química , Rosa Bengala/química , Relación Estructura-Actividad , Células Tumorales CultivadasRESUMEN
There is no effective drug to treat EV71 infection yet. Traditional Chinese herbs are great resources for novel antiviral compounds. Here we showed that Oblongifolin M (OM), an active compound isolated from Garcinia oblongifolia, potently inhibited EV71 infection in a dose dependent manner. To identify its potential effectors in the host cells, we successfully identified 18 proteins from 52 differentially expressed spots by comparative proteomics studies. Further studies showed that knockdown of ERp57 inhibited viral replication through downregulating viral IRES (internal ribosome entry site) activities, whereas ectopic expression of ERp57 increased IRES activity and partly rescued the inhibitory effects of OM on viral replication. We demonstrated that OM is an effective antiviral agent; and that ERp57 is one of its cellular effectors against EV71 infection.
Asunto(s)
Infecciones por Enterovirus/prevención & control , Garcinia/química , Extractos Vegetales/farmacología , Proteína Disulfuro Isomerasas/metabolismo , Rabdomiosarcoma/prevención & control , Terpenos/farmacología , Replicación Viral/efectos de los fármacos , Antivirales/farmacología , Western Blotting , Electroforesis en Gel Bidimensional , Enterovirus Humano A/patogenicidad , Infecciones por Enterovirus/metabolismo , Infecciones por Enterovirus/patología , Infecciones por Enterovirus/virología , Genoma Viral , Humanos , Proteína Disulfuro Isomerasas/antagonistas & inhibidores , Proteína Disulfuro Isomerasas/genética , Proteómica , ARN Mensajero/genética , ARN Interferente Pequeño/genética , ARN Viral/genética , Reacción en Cadena en Tiempo Real de la Polimerasa , Reacción en Cadena de la Polimerasa de Transcriptasa Inversa , Rabdomiosarcoma/metabolismo , Rabdomiosarcoma/patología , Rabdomiosarcoma/virología , Espectrometría de Masa por Láser de Matriz Asistida de Ionización Desorción , Células Tumorales Cultivadas , Proteínas Virales/metabolismoRESUMEN
Sonodynamic therapy (SDT) is a new approach for cancer treatment, involving the synergistic effect of ultrasound and certain chemical compounds termed as sonosensitizers. A water-soluble phthalocyanine, namely tetra-α-(3-carboxyphenoxyl) zinc(II) phthalocyanine (ZnPcC4), has been prepared and characterized. The interactions between ZnPcC4 and bovine serum albumin (BSA) were also investigated by absorption and fluorescence spectroscopy. It was found that there were strong interactions between ZnPcC4 and BSA with a binding constant of 6.83×10(7)M(-1). A non-covalent BSA conjugate of ZnPcC4 (ZnPcC4-BSA) was prepared. Both ZnPcC4 and ZnPcC4-BSA exhibited efficient sonodynamic activities against HepG2 human hepatocarcinoma cells. Compared with ZnPcC4, conjugate ZnPcC4-BSA showed a higher sonodynamic activity with an IC50 value of 7.5µM. Upon illumination with ultrasound, ZnPcC4-BSA can induce an increase of intracellular reactive oxygen species (ROS) level, resulting in cellular apoptosis. The results suggest that the albumin conjugates of zinc(II) phthalocyanines functionalized with carboxyls can serve as promising sonosensitizers for sonodynamic therapy.
Asunto(s)
Complejos de Coordinación/metabolismo , Complejos de Coordinación/farmacología , Indoles/metabolismo , Indoles/farmacología , Fototerapia , Albúmina Sérica Bovina/metabolismo , Terapia por Ultrasonido , Agua/química , Animales , Antineoplásicos/síntesis química , Antineoplásicos/química , Antineoplásicos/metabolismo , Antineoplásicos/farmacología , Apoptosis/efectos de los fármacos , Apoptosis/efectos de la radiación , Bovinos , Línea Celular Tumoral , Complejos de Coordinación/síntesis química , Complejos de Coordinación/química , Células Hep G2 , Humanos , Indoles/síntesis química , Indoles/química , Isoindoles , Fármacos Fotosensibilizantes/síntesis química , Fármacos Fotosensibilizantes/química , Fármacos Fotosensibilizantes/metabolismo , Fármacos Fotosensibilizantes/farmacología , Especies Reactivas de Oxígeno/metabolismo , SolubilidadRESUMEN
Huanglian-Jie-Du-Tang (HLJDT) is a famous traditional Chinese herbal formula that has been widely used clinically to treat cerebral ischemia. Recently, we found that berberine, a major alkaloid compound in HLJDT, reduced amyloid-ß (Aß) accumulation in an Alzheimer's disease (AD) mouse model. In this study, we compared the effects of HLJDT, four single component herbs of HLJDT (Rhizoma coptidis (RC), Radix scutellariae (RS), Cortex phellodendri (CP) and Fructus gardenia (FG)) and the modified formula of HLJDT (HLJDT-M, which is free of RS) on the regulatory processing of amyloid-ß precursor protein (APP) in an in vitro model of AD. Here we show that treatment with HLJDT-M and its components RC, CP, and the main compound berberine on N2a mouse neuroblastoma cells stably expressing human APP with the Swedish mutation (N2a-SwedAPP) significantly decreased the levels of full-length APP, phosphorylated APP at threonine 668, C-terminal fragments of APP, soluble APP (sAPP)-α and sAPPß-Swedish and reduced the generation of Aß peptide in the cell lysates of N2a-SwedAPP. HLJDT-M showed more significant APP- and Aß- reducing effects than berberine, RC or CP treatment alone. In contrast, HLJDT, its component RS and the main active compound of RS, baicalein, strongly increased the levels of all the metabolic products of APP in the cell lysates. The extract from FG, however, did not influence APP modulation. Interestingly, regular treatment of TgCRND8 APP transgenic mice with baicalein exacerbated the amyloid plaque burden, APP metabolism and Aß production. Taken together, these data provide convincing evidence that HLJDT and baicalein treatment can increase the amyloidogenic metabolism of APP which is at least partly responsible for the baicalein-mediated Aß plaque increase in the brains of TgCRND8 mice. On the other hand, HLJDT-M significantly decreased all the APP metabolic products including Aß. Further study of HLJDT-M for therapeutic use in treating AD is warranted.
Asunto(s)
Enfermedad de Alzheimer/tratamiento farmacológico , Precursor de Proteína beta-Amiloide/metabolismo , Medicamentos Herbarios Chinos/uso terapéutico , Procesamiento Proteico-Postraduccional , Enfermedad de Alzheimer/patología , Animales , Berberina/farmacología , Berberina/uso terapéutico , Supervivencia Celular/efectos de los fármacos , Modelos Animales de Enfermedad , Medicamentos Herbarios Chinos/química , Medicamentos Herbarios Chinos/farmacología , Flavanonas/farmacología , Flavanonas/uso terapéutico , Humanos , Espacio Intracelular/metabolismo , Ratones Transgénicos , Mutación/genética , Placa Amiloide/metabolismo , Placa Amiloide/patología , Procesamiento Proteico-Postraduccional/efectos de los fármacosRESUMEN
Conflicting findings exist regarding the link between environmental factors and development of Alzheimer's disease (AD) in a variety of transgenic mouse models of AD. In the present study, we investigated the effect of behavioral stress on the onset and progression of Aß pathology in the brains of TgCRND8 mice, a transgenic mouse model of AD. One group of TgCRND8 mice was subjected to restraint stress starting at 1 month of age until they were 3 months old, while restraint stress in the second group started at 4 months of age until they were 6 months old. After 2 months of treatment, no differences in the soluble, formic acid extracted, or histologically detected Aß deposition in the cortical and hippocampal levels were found between non-stressed and stressed mice. These results showed that restraint stress alone failed to aggravate amyloid pathology when initiated either before or after the age of amyloid plaque deposition in TgCRND8 mice, suggesting that if stress aggravated AD phenotype, it may not be via an amyloid-related mechanism in the TgCRND8 mice. These findings are indicative that plaque load per se may not be used as a significant criterion for evaluating the effect of stress on AD patients.
Asunto(s)
Enfermedad de Alzheimer/patología , Enfermedad de Alzheimer/psicología , Conducta Animal , Encéfalo/patología , Progresión de la Enfermedad , Placa Amiloide/patología , Estrés Psicológico/patología , Envejecimiento/patología , Enfermedad de Alzheimer/sangre , Enfermedad de Alzheimer/complicaciones , Péptidos beta-Amiloides/metabolismo , Animales , Encéfalo/metabolismo , Corteza Cerebral/metabolismo , Corteza Cerebral/patología , Corticosterona/sangre , Modelos Animales de Enfermedad , Humanos , Hipotálamo/metabolismo , Hipotálamo/patología , Ratones , Ratones Transgénicos , Neuronas/metabolismo , Neuronas/patología , Placa Amiloide/sangre , Placa Amiloide/complicaciones , Proteínas Proto-Oncogénicas c-fos/metabolismo , Restricción Física , Estrés Psicológico/sangre , Estrés Psicológico/complicacionesRESUMEN
Using bacteria as therapeutic agents against solid tumors is emerging as an area of great potential in the treatment of cancer. Obligate and facultative anaerobic bacteria have been shown to infiltrate the hypoxic regions of solid tumors, thereby reducing their growth rate or causing regression. However, a major challenge for bacterial therapy of cancer with facultative anaerobes is avoiding damage to normal tissues. Consequently the virulence of bacteria must be adequately attenuated for therapeutic use. By placing an essential gene under a hypoxia conditioned promoter, SalmonellaTyphimurium strain SL7207 was engineered to survive only in anaerobic conditions (strain YB1) without otherwise affecting its functions. In breast tumor bearing nude mice, YB1 grew within the tumor, retarding its growth, while being rapidly eliminated from normal tissues. YB1 provides a safe bacterial vector for anti-tumor therapies without compromising the other functions or tumor fitness of the bacterium as attenuation methods normally do.
Asunto(s)
Bacterias Anaerobias/fisiología , Interacciones Huésped-Patógeno , Neoplasias/microbiología , Salmonella typhimurium/fisiología , Animales , Bacterias Anaerobias/genética , Bacterias Anaerobias/patogenicidad , Vacunas Bacterianas/farmacología , Terapia Biológica/métodos , Neoplasias de la Mama/microbiología , Neoplasias de la Mama/patología , Neoplasias de la Mama/terapia , Línea Celular Tumoral , Femenino , Ingeniería Genética/métodos , Humanos , Hipoxia , Ratones , Ratones Desnudos , Neoplasias/patología , Neoplasias/terapia , Salmonella typhimurium/genética , Salmonella typhimurium/patogenicidad , Carga Tumoral/efectos de los fármacos , Virulencia/genética , Ensayos Antitumor por Modelo de Xenoinjerto/métodosRESUMEN
The accumulation of ß-amyloid (Aß) peptide derived from abnormal processing of amyloid precursor protein (APP) is a common pathological hallmark of Alzheimer's disease (AD) brains. In this study, we evaluated the therapeutic effect of berberine (BBR) extracted from Coptis chinensis Franch, a Chinese medicinal herb, on the neuropathology and cognitive impairment in TgCRND8 mice, a well established transgenic mouse model of AD. Two-month-old TgCRND8 mice received a low (25 mg/kg per day) or a high dose of BBR (100 mg/kg per day) by oral gavage until 6 months old. BBR treatment significantly ameliorated learning deficits, long-term spatial memory retention, as well as plaque load compared with vehicle control treatment. In addition, enzyme-linked immunosorbent assay (ELISA) measurement showed that there was a profound reduction in levels of detergent-soluble and -insoluble ß-amyloid in brain homogenates of BBR-treated mice. Glycogen synthase kinase (GSK)3, a major kinase involved in APP and tau phosphorylation, was significantly inhibited by BBR treatment. We also found that BBR significantly decreased the levels of C-terminal fragments of APP and the hyperphosphorylation of APP and tau via the Akt/glycogen synthase kinase 3 signaling pathway in N2a mouse neuroblastoma cells stably expressing human Swedish mutant APP695 (N2a-SwedAPP). Our results suggest that BBR provides neuroprotective effects in TgCRND8 mice through regulating APP processing and that further investigation of the BBR for therapeutic use in treating AD is warranted.
Asunto(s)
Enfermedad de Alzheimer/complicaciones , Péptidos beta-Amiloides/metabolismo , Berberina/uso terapéutico , Encéfalo , Trastornos del Conocimiento , Gliosis , Proteínas ADAM/metabolismo , Proteína ADAM10 , Enfermedad de Alzheimer/tratamiento farmacológico , Enfermedad de Alzheimer/genética , Secretasas de la Proteína Precursora del Amiloide/metabolismo , Precursor de Proteína beta-Amiloide/genética , Análisis de Varianza , Animales , Ácido Aspártico Endopeptidasas/metabolismo , Encéfalo/efectos de los fármacos , Encéfalo/metabolismo , Encéfalo/patología , Línea Celular Tumoral , Cromonas/farmacología , Trastornos del Conocimiento/tratamiento farmacológico , Trastornos del Conocimiento/etiología , Trastornos del Conocimiento/patología , Modelos Animales de Enfermedad , Inhibidores Enzimáticos/farmacología , Ensayo de Inmunoadsorción Enzimática , Regulación de la Expresión Génica/efectos de los fármacos , Regulación de la Expresión Génica/genética , Proteína Ácida Fibrilar de la Glía/metabolismo , Gliosis/tratamiento farmacológico , Gliosis/etiología , Gliosis/patología , Glucógeno Sintasa Quinasa 3/metabolismo , Humanos , Aprendizaje por Laberinto/efectos de los fármacos , Proteínas de la Membrana/metabolismo , Memoria/efectos de los fármacos , Ratones , Ratones Endogámicos C57BL , Ratones Transgénicos , Morfolinas/farmacología , Mutación/genética , Fragmentos de Péptidos/metabolismo , TransfecciónRESUMEN
Abnormal protein aggregation in the brain is linked to the pathogenesis of neurodegenerative diseases, including Alzheimer's disease (AD) and Parkinson's disease (PD). Recent studies revealed that the oligomeric form of aggregates is most likely the toxic species, and thus could be a good therapeutic target. To screen for potent inhibitors that can inhibit both oligomerisation and fibrillation of α-synuclein (α-syn), we systematically compared the antioligomeric and antifibrillar activities of eight compounds that were extracted from Chinese herbal medicines through three platforms that can monitor the formation of α-syn fibrils and oligomers in cell-free or cellular systems. Our results revealed that baicalein, a flavonoid extracted from the Chinese herbal medicine Scutellaria baicalensis Georgi ("huang qin" in Chinese), is a potent inhibitor of α-syn oligomerisation both in cell-free and cellular systems, and is also an effective inhibitor of α-syn fibrillation in cell-free systems. We further tested the protective effect of baicalein against α-syn-oligomer-induced toxicity in neuronal cells. Our data showed that baicalein inhibited the formation of α-syn oligomers in SH-SY5Y and Hela cells, and protected SH-SY5Y cells from α-syn-oligomer-induced toxicity. We also explored the effect of baicalein on amyloid-ß peptide (Aß) aggregation and toxicity. We found that baicalein can also inhibit Aß fibrillation and oligomerisation, disaggregate pre-formed Aß amyloid fibrils and prevent Aß fibril-induced toxicity in PC12 cells. Our study indicates that baicalein is a good inhibitor of amyloid protein aggregation and toxicity. Given the role of these processes in neurodegenerative diseases such as AD and PD, our results suggest that baicalein has potential as a therapeutic agent for the treatment of these devastating disorders.
Asunto(s)
Medicamentos Herbarios Chinos/química , Inhibidores Enzimáticos , Flavanonas/química , Flavanonas/farmacología , alfa-Sinucleína/antagonistas & inhibidores , Amiloide/biosíntesis , Supervivencia Celular/efectos de los fármacos , Células Cultivadas , Medicamentos Herbarios Chinos/farmacología , Inhibidores Enzimáticos/química , Inhibidores Enzimáticos/farmacología , Células HeLa , Humanos , Estructura Molecular , alfa-Sinucleína/químicaRESUMEN
A systematic review was conducted to assess the efficacy and safety of herbal medications (HM), as either monotherapy or adjunct to orthodox medications (cholinesterase inhibitors and nootropic agents, OM) for Alzheimer's disease (AD). Sixteen studies testing different HM were included. Out of the 15 HM monotherapy studies, 13 reported HM to be significantly better than OM or placebo; one reported similar efficacy between HM and OM. Only the HM adjuvant study reported significant efficacy. No major adverse events for HM were reported and HMs were found to reduce the adverse effects arising from OM. Imbalance in ethnicity among participants was observed; gender distribution was unclear. Heterogeneity in diagnostic criteria, interventions and outcome measures hindered comprehensive data analysis. Studies comparing HM with OM suggest that HM can be a safe, effective treatment for AD, either alone or in conjunction with OM. Methodological flaws in the design of the studies, however, limited the extent to which the results could be interpreted. Among various HMs, the safety and tolerability of EGb761 was best established. Further multi-center trials with large sample size, high methodological qualities and standardized HM ingredients are necessary for clinical recommendations on the use of HM in treating AD.
Asunto(s)
Enfermedad de Alzheimer/tratamiento farmacológico , Fitoterapia , Preparaciones de Plantas/uso terapéutico , Plantas Medicinales , Inhibidores de la Colinesterasa/uso terapéutico , Quimioterapia Combinada , Humanos , Nootrópicos/uso terapéutico , Preparaciones de Plantas/efectos adversos , Ensayos Clínicos Controlados Aleatorios como Asunto , Resultado del TratamientoRESUMEN
One of the major pathological features of Alzheimer's disease (AD) is the appearance of senile plaques characterized by extracellular aggregation of amyloid beta-peptide (Abeta) fibrils. Inhibition of Abeta fibril aggregation is therefore viewed as one possible method to halt the progression of AD. Salvianolic acid B (Sal B) is an active ingredient isolated from Salvia miltiorrhiza, a Chinese herbal medicine commonly used for the treatment of cardiovascular and cerebrovascular disorders. Recent findings show that Sal B prevents Abeta-induced cytotoxicity in a rat neural cell line. To understand the mechanism of Sal B-mediated neuroprotection, its effects on the inhibition of Abeta1-40 fibril formation and destabilization of the preformed Abeta1-40 fibrils were studied. The results were obtained using Thioflavin T fluorescence assay and Abeta aggregating immunoassay. We found that Sal B can inhibit fibril aggregation (IC(50): 1.54-5.37 microM) as well as destabilize preformed Abeta fibril (IC(50): 5.00-5.19 microM) in a dose- and time-dependent manner. Sal B is a better aggregation inhibitor than ferulic acid but less active than curcumin in the inhibition of Abeta1-40 aggregation. In electron microscope study, Sal B-treated Abeta1-40 fibrils are seen in various stages of shortening or wrinkling with numerous deformed aggregates of amorphous structure. Circular dichroism data indicate that Sal B dose dependently prevents the formation of beta-structured aggregates of Abeta1-40. Addition of preincubated Sal B with Abeta1-42 significantly reduces its cytotoxic effects on human neuroblastoma SH-SY5Y cells. These results suggest that Sal B has therapeutic potential in the treatment of AD, and warrant its study in animal models.
Asunto(s)
Péptidos beta-Amiloides/antagonistas & inhibidores , Péptidos beta-Amiloides/toxicidad , Antioxidantes/farmacología , Benzofuranos/farmacología , Microfibrillas/efectos de los fármacos , Péptidos beta-Amiloides/biosíntesis , Benzotiazoles , Agregación Celular/efectos de los fármacos , Línea Celular Tumoral , Dicroismo Circular , Interpretación Estadística de Datos , Ensayo de Inmunoadsorción Enzimática , Humanos , Microfibrillas/ultraestructura , Microscopía Electrónica , Sales de Tetrazolio , Tiazoles/farmacologíaRESUMEN
BACKGROUND: Salvianolic acid B (Sal B) is one of the most bioactive components of Salvia miltiorrhiza, a traditional Chinese herbal medicine that has been commonly used for prevention and treatment of cerebrovascular disorders. However, the mechanism responsible for such protective effects remains largely unknown. It has been considered that cerebral endothelium apoptosis caused by reactive oxygen species including hydrogen peroxide (H(2)O(2)) is implicated in the pathogenesis of cerebrovascular disorders. METHODOLOGY AND PRINCIPAL FINDINGS: By examining the effect of Sal B on H(2)O(2)-induced apoptosis in rat cerebral microvascular endothelial cells (rCMECs), we found that Sal B pretreatment significantly attenuated H(2)O(2)-induced apoptosis in rCMECs. We next examined the signaling cascade(s) involved in Sal B-mediated anti-apoptotic effects. We showed that H(2)O(2) induces rCMECs apoptosis mainly through the PI3K/ERK pathway, since a PI3K inhibitor (LY294002) blocked ERK activation caused by H(2)O(2 )and a specific inhibitor of MEK (U0126) protected cells from apoptosis. On the other hand, blockage of the PI3K/Akt pathway abrogated the protective effect conferred by Sal B and potentated H(2)O(2)-induced apoptosis, suggesting that Sal B prevents H(2)O(2)-induced apoptosis predominantly through the PI3K/Akt (upstream of ERK) pathway. SIGNIFICANCE: Our findings provide the first evidence that H(2)O(2) induces rCMECs apoptosis via the PI3K/MEK/ERK pathway and that Sal B protects rCMECs against H(2)O(2)-induced apoptosis through the PI3K/Akt/Raf/MEK/ERK pathway.