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Foreign object ingestions are a common occurrence in pediatrics, often necessitating endoscopic or surgical intervention. The ingestion of multiple magnets poses an increased risk for serious complications. Our article presents a case of a five-year-old boy who swallowed two pennies and four magnets. The latter failed to pass spontaneously and were lodged in the appendiceal orifice resulting in a challenging and unsuccessful endoscopic retrieval and hence required laparoscopic exploration, appendectomy, and partial cecal resection.
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BACKGROUND: Pyrrolizidine alkaloids (PAs) are naturally occurring plant toxins associated with potential hepatic and carcinogenic diseases in humans and animals. The concern over PAs has increased as the consumption of herbal medicines has increased. OBJECTIVE: This study aimed to develop and validate a sensitive analytical method to determine 28 PAs in five herbal medicines using liquid chromatography (LC)-electrospray ionization (ESI)-tandem mass spectrometry (MS/MS). Additionally, this study identified and quantified the amount of PAs in 10 samples of each herbal medicine. METHODS: The pretreatment in the proposed LC-MS/MS analysis comprised solvent extraction using 0.05M H2SO4 in 50% methanol and clean-up step using an mixed-mode cationic exchange (MCX)-solid-phase extraction (SPE) cartridge. The PA contents in herbal medicines were measured by using the developed method. RESULTS: The proposed method had recoveries ranging from 72.5-123.7% for the Atractylodis Rhizoma Alba, 70.6-151.7% for Alba Chrysanthmi Flos, 80.6-130.9% for Leonuri Herba, 70.3-122.9% for Gastrodiae Rhizoma, and 67.1-106.9% for Glycyrrhizae Radix. Even though a few samples showed recoveries in unsatisfactory values, the proposed method indicated entirely sufficient recoveries and precision in most samples. In monitoring results, only Leonuri Herba contained two PAs, which indicated Retrorsine (4/10) of 84.7-120.9 µg/kg and Senkirkine (10/10) of 60.9-170.7 µg/kg. CONCLUSION: The results obtained from this study demonstrate that the proposed method is fit for purpose to determine 28 PAs in herbal medicines. Therefore it could serve as a regulatory method capable of being used for controlling the risks of PAs in certain medicinal plants and dietary supplements. HIGHLIGHTS: An LC-MS/MS method for the determination of 28 pyrrolizidine alkaloids in herbal medicines was developed and validated through this study. The proposed method is considered as an useful method for monitoring pyroolizidine alkaloids in herbal medicines.
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Plantas Medicinales , Alcaloides de Pirrolicidina , Cationes , Cromatografía Líquida de Alta Presión , Cromatografía Liquida , Humanos , Alcaloides de Pirrolicidina/análisis , Extracción en Fase Sólida , Espectrometría de Masa por Ionización de Electrospray , Espectrometría de Masas en TándemRESUMEN
Curcuma longa, C. wenyujin and C. phaeocaulis are important herbal medicine which of rhizomatous herbaceous perennial plant of the family Zingiberaceae. This study generated a complete chloroplast genome sequence of three medicinal species were characterized by de novo assembly with whole genome sequencing data. The length of complete chloroplast genome were 162,180 bp (C. longa), 162,266 bp (C. wenyujin), and 162,133 bp (C. phaeocaulis), respectively, with four structures that were included in large single copy region (87,001 bp, 87,042 bp, and 87,013 bp), small single copy region (15,681 bp, 15,710 bp, and 15,622 bp), and duplicated inverted regions (29,749 bp, 29,757 bp and 29,749 bp of each). Based on phylogenetic trees, C. longa, C. wenyujin, and C. phaeocaulis were grouped by high bootstrap value with Curcuma species. This result approved that C. longa, C. wenyujin and C. phaeocaulis were comprised in Alpinia and Wurfbainia. Therefore, this chloroplast genome data firstly generated valuable genetic resource in discrimination of herbal materials, phylogeny and development DNA marker.
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BACKGROUND: COVID-19 has disrupted the 2020-2021 residency application cycle with the cancellation of away rotations and in-person interviews. This study seeks to investigate the feasibility and utility of video conferencing technology (VCT) as an opportunity for applicants to interact with faculty from outside programs. METHODS: 18 prospective urology applicants were randomized to 6 urology programs to give a virtual grand rounds (VGR) talk. Presentations were recorded and analyzed to determine audience engagement. Students were surveyed regarding perceived utility of VGR. Faculty were surveyed to determine system usability of VCT and ability to evaluate the applicant. RESULTS: 17 students completed the survey, reporting a 100% satisfaction rate with VGR. A majority felt this was a useful way to learn about outside programs. 85 physicians completed the faculty survey, with nearly half feeling confident in their ability to evaluate the applicant. Video transcription data shows sessions were interactive with minimal distractions. CONCLUSIONS: VGR can be a useful means for medical students to express interest in programs as well as an additional marker for faculty to evaluate applicants.
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COVID-19/epidemiología , Internado y Residencia , Solicitud de Empleo , Pandemias , Rondas de Enseñanza/métodos , Realidad Virtual , Adulto , Docentes Médicos , Retroalimentación , Femenino , Humanos , Masculino , Maryland , Persona de Mediana Edad , SARS-CoV-2RESUMEN
We report a prodrug, Glu-DAPPD, to overcome the shortcomings of an anti-neuroinflammatory molecule, N,N'-diacetyl-p-phenylenediamine (DAPPD), in biological applicability for potential therapeutic applications. We suspect that Glu-DAPPD can release DAPPD through endogenous enzymatic bioconversion. Consequently, Glu-DAPPD exhibits in vivo efficacies in alleviating neuroinflammation, reducing amyloid-ß aggregate accumulation, and improving cognitive function in Alzheimer's disease transgenic mice. Our studies demonstrate that the prodrug approach is suitable and effective toward developing drug candidates against neurodegeneration.
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Enfermedad de Alzheimer/tratamiento farmacológico , Cognición/efectos de los fármacos , Disfunción Cognitiva/tratamiento farmacológico , Inflamación/tratamiento farmacológico , Neuronas/efectos de los fármacos , Profármacos/farmacología , Enfermedad de Alzheimer/metabolismo , Péptidos beta-Amiloides/metabolismo , Precursor de Proteína beta-Amiloide/metabolismo , Animales , Línea Celular Tumoral , Disfunción Cognitiva/metabolismo , Modelos Animales de Enfermedad , Humanos , Inflamación/metabolismo , Masculino , Ratones , Ratones Endogámicos C57BL , Ratones Transgénicos , Microglía/efectos de los fármacos , Microglía/metabolismo , Neuronas/metabolismo , Fenilendiaminas/farmacologíaRESUMEN
Multiple pathogenic elements, including reactive oxygen species, amyloidogenic proteins, and metal ions, are associated with the development of neurodegenerative disorders. We report minimalistic redox-based principles for preparing compact aromatic compounds by derivatizing the phenylene moiety with various functional groups. These molecular agents display enhanced reactivities against multiple targets such as free radicals, metal-free amyloid-ß (Aß), and metal-bound Aß that are implicated in the most common form of dementia, Alzheimer's disease (AD). Mechanistic studies reveal that the redox properties of these reagents are essential for their function. Specifically, they engage in oxidative reactions with metal-free and metal-bound Aß, leading to chemical modifications of the Aß peptides to form covalent adducts that alter the aggregation of Aß. Moreover, the administration of the most promising candidate significantly attenuates the amyloid pathology in the brains of AD transgenic mice and improves their cognitive defects. Our studies demonstrate an efficient and effective redox-based strategy for incorporating multiple functions into simple molecular reagents.
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Enfermedad de Alzheimer/tratamiento farmacológico , Péptidos beta-Amiloides/antagonistas & inhibidores , Hidrocarburos Aromáticos/farmacología , Bibliotecas de Moléculas Pequeñas/farmacología , Animales , Radicales Libres/antagonistas & inhibidores , Hidrocarburos Aromáticos/química , Ratones , Ratones Transgénicos , Estructura Molecular , Oxidación-Reducción , Agregado de Proteínas/efectos de los fármacos , Bibliotecas de Moléculas Pequeñas/químicaRESUMEN
Amyloid-ß (Aß) accumulation, metal ion dyshomeostasis, oxidative stress, and cholinergic deficit are four major characteristics of Alzheimer's disease (AD). Herein, we report the reactivities of 12 flavonoids against four pathogenic elements of AD: metal-free and metal-bound Aß, free radicals, and acetylcholinesterase. A series of 12 flavonoids was selected based on the molecular structures that are responsible for multiple reactivities including hydroxyl substitution and transfer of the B ring from C2 to C3. Our experimental and computational studies reveal that the catechol moiety, the hydroxyl groups at C3 and C7, and the position of the B ring are important for instilling multiple functions in flavonoids. We establish a structure-activity relationship of flavonoids that should be useful for designing chemical reagents with multiple reactivities against the pathological factors of AD.
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As a central feature of neuroinflammation, microglial dysfunction has been increasingly considered a causative factor of neurodegeneration implicating an intertwined pathology with amyloidogenic proteins. Herein, we report the smallest synthetic molecule (N,N'-diacetyl-p-phenylenediamine [DAPPD]), simply composed of a benzene ring with 2 acetamide groups at the para position, known to date as a chemical reagent that is able to promote the phagocytic aptitude of microglia and subsequently ameliorate cognitive defects. Based on our mechanistic investigations in vitro and in vivo, 1) the capability of DAPPD to restore microglial phagocytosis is responsible for diminishing the accumulation of amyloid-ß (Aß) species and significantly improving cognitive function in the brains of 2 types of Alzheimer's disease (AD) transgenic mice, and 2) the rectification of microglial function by DAPPD is a result of its ability to suppress the expression of NLRP3 inflammasome-associated proteins through its impact on the NF-κB pathway. Overall, our in vitro and in vivo investigations on efficacies and molecular-level mechanisms demonstrate the ability of DAPPD to regulate microglial function, suppress neuroinflammation, foster cerebral Aß clearance, and attenuate cognitive deficits in AD transgenic mouse models. Discovery of such antineuroinflammatory compounds signifies the potential in discovering effective therapeutic molecules against AD-associated neurodegeneration.
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Enfermedad de Alzheimer/tratamiento farmacológico , Antiinflamatorios/farmacología , Cognición/efectos de los fármacos , Microglía/efectos de los fármacos , Fármacos Neuroprotectores/farmacología , Fagocitosis/efectos de los fármacos , Fenilendiaminas/farmacología , Enfermedad de Alzheimer/psicología , Péptidos beta-Amiloides/metabolismo , Precursor de Proteína beta-Amiloide/genética , Animales , Antiinflamatorios/uso terapéutico , Evaluación Preclínica de Medicamentos , Regulación de la Expresión Génica/efectos de los fármacos , Humanos , Inflamasomas/efectos de los fármacos , Inflamasomas/genética , Aprendizaje por Laberinto , Ratones , Ratones Transgénicos , Microglía/fisiología , Estructura Molecular , Proteínas del Tejido Nervioso/biosíntesis , Proteínas del Tejido Nervioso/genética , Fármacos Neuroprotectores/uso terapéutico , Fragmentos de Péptidos/genética , Fenilendiaminas/química , Fenilendiaminas/uso terapéutico , Presenilina-1/genética , Memoria Espacial/efectos de los fármacosRESUMEN
Amyloidogenic peptides are considered central pathological contributors towards neurodegeneration as observed in neurodegenerative disorders [e.g., amyloid-ß (Aß) peptides in Alzheimer's disease (AD)]; however, their roles in the pathologies of such diseases have not been fully elucidated since they are challenging targets to be studied due to their heterogeneous nature and intrinsically disordered structure. Chemical approaches to modify amyloidogenic peptides would be valuable in advancing our molecular-level understanding of their involvement in neurodegeneration. Herein, we report effective chemical strategies for modification of Aß peptides (i.e., coordination and coordination-/photo-mediated oxidation) implemented by a single Ir(iii) complex in a photo-dependent manner. Such peptide variations can be achieved by our rationally designed Ir(iii) complexes (Ir-Me, Ir-H, Ir-F, and Ir-F2) leading to significantly modulating the aggregation pathways of two main Aß isoforms, Aß40 and Aß42, as well as the production of toxic Aß species. Overall, we demonstrate chemical tactics for modification of amyloidogenic peptides in an effective and manageable manner utilizing the coordination capacities and photophysical properties of transition metal complexes.
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[This corrects the article DOI: 10.1039/C8SC04943B.].
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Complex amyloid aggregation of amyloid-ß (1-40) (Aß1-40) in terms of monomer structures has not been fully understood. Herein, we report the microscopic mechanism and pathways of Aß1-40 aggregation with macroscopic viewpoints through tuning its initial structure and solubility. Partial helical structures of Aß1-40 induced by low solvent polarity accelerated cytotoxic Aß1-40 amyloid fibrillation, while predominantly helical folds did not aggregate. Changes in the solvent polarity caused a rapid formation of ß-structure-rich protofibrils or oligomers via aggregation-prone helical structures. Modulation of the pH and salt concentration transformed oligomers to protofibrils, which proceeded to amyloid formation. We reveal diverse molecular mechanisms underlying Aß1-40 aggregation with conceptual energy diagrams and propose that aggregation-prone partial helical structures are key to inducing amyloidogenesis. We demonstrate that context-dependent protein aggregation is comprehensively understood using the macroscopic phase diagram, which provides general insights into differentiation of amyloid formation and phase separation from unfolded and folded structures.
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Enfermedad de Alzheimer/genética , Péptidos beta-Amiloides/ultraestructura , Fragmentos de Péptidos/ultraestructura , Agregación Patológica de Proteínas/genética , Conformación Proteica en Hélice alfa/genética , Enfermedad de Alzheimer/patología , Amiloide/química , Amiloide/genética , Péptidos beta-Amiloides/química , Humanos , Fragmentos de Péptidos/química , Conformación Proteica en Lámina beta/genética , Pliegue de Proteína/efectos de los fármacos , Estabilidad Proteica/efectos de los fármacos , Transducción de Señal/efectos de los fármacos , SolubilidadRESUMEN
We report orobol as a multifunctional isoflavone with the ability to (i) modulate the aggregation pathways of both metal-free and metal-bound amyloid-ß, (ii) interact with metal ions, (iii) scavenge free radicals, and (iv) inhibit the activity of acetylcholinesterase. Such a framework with multifunctionality could be useful for developing chemical reagents to advance our understanding of multifaceted pathologies of neurodegenerative disorders, including Alzheimer's disease.
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Enfermedad de Alzheimer , Péptidos beta-Amiloides/efectos de los fármacos , Flavonoides/farmacología , Agregación Patológica de Proteínas/tratamiento farmacológico , Acetilcolinesterasa/efectos de los fármacos , Enfermedad de Alzheimer/patología , Péptidos beta-Amiloides/química , Animales , Inhibidores Enzimáticos/farmacología , Flavonoides/química , Depuradores de Radicales Libres/farmacología , HumanosRESUMEN
Aggregation of amyloidogenic peptides could cause the onset and progression of neurodegenerative diseases, such as Alzheimer's disease and Parkinson's disease. These amyloidogenic peptides can coordinate to metal ions, including Zn(ii), which can subsequently affect the peptides' aggregation and toxicity, leading to neurodegeneration. Unfortunately, the detection of metal-amyloidogenic peptide complexation has been very challenging. Herein, we report the development and utilization of a probe (A-1) capable of monitoring metal-amyloid-ß (Aß) complexation based on Förster resonance energy transfer (FRET). Our probe, A-1, is composed of Aß1-21 grafted with a pair of FRET donor and acceptor capable of providing a FRET signal upon Zn(ii) binding even at nanomolar concentrations. The FRET intensity of A-1 increases upon Zn(ii) binding and decreases when Zn(ii)-bound A-1 aggregates. Moreover, as the FRET intensity of Zn(ii)-added A-1 is drastically changed when their interaction is disrupted, A-1 can be used for screening a chemical library to determine effective inhibitors against metal-Aß interaction. Eight natural products (out of 145 compounds; >80% inhibition) were identified as such inhibitors in vitro, and six of them could reduce Zn(ii)-Aß-induced toxicity in living cells, suggesting structural moieties useful for inhibitor design. Overall, we demonstrate the design of a FRET-based probe for investigating metal-amyloidogenic peptide complexation as well as the feasibility of screening inhibitors against metal-bound amyloidogenic peptides, providing effective and efficient methods for understanding their pathology and finding therapeutic candidates against neurodegenerative disorders.
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Aggregation of amyloid-ß (Aß) peptides is implicated in the development of Alzheimer's disease (AD), the most common type of dementia. Thus, numerous efforts to identify chemical tactics to control the aggregation pathways of Aß peptides have been made. Among them, transition metal complexes as a class of chemical modulators against Aß aggregation have been designed and utilized. Transition metal complexes are able to carry out a variety of chemistry with Aß peptides (e.g., coordination chemistry and oxidative and proteolytic reactions for peptide modifications) based on their tunable characteristics, including the oxidation state of and coordination geometry around the metal center. This Viewpoint illustrates three strategies employing transition metal complexes toward modulation of Aß aggregation pathways (i.e., oxidation and hydrolysis of Aß as well as coordination to Aß), along with some examples of such transition metal complexes. In addition, proposed mechanisms for three reactivities of transition metal complexes with Aß peptides are discussed. Our greater understanding of how transition metal complexes have been engineered and used for alteration of Aß aggregation could provide insight into the new discovery of chemical reagents against Aß peptides found in AD.
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Péptidos beta-Amiloides/metabolismo , Complejos de Coordinación/farmacología , Fragmentos de Péptidos/metabolismo , Multimerización de Proteína/efectos de los fármacos , Péptidos beta-Amiloides/química , Línea Celular Tumoral , Complejos de Coordinación/química , Complejos de Coordinación/metabolismo , Complejos de Coordinación/efectos de la radiación , Humanos , Luz , Metales Pesados/química , Oxidación-Reducción , Fragmentos de Péptidos/química , Unión Proteica , ProteolisisRESUMEN
Neurodegenerative diseases pose a substantial socioeconomic burden on society. Unfortunately, the aging world population and lack of effective cures foreshadow a negative outlook. Although a large amount of research has been dedicated to elucidating the pathologies of neurodegenerative diseases, their principal causes remain elusive. Metal ion dyshomeostasis, proteopathy, oxidative stress, and neurotransmitter deficiencies are pathological features shared across multiple neurodegenerative disorders. In addition, these factors are proposed to be interrelated upon disease progression. Thus, the development of multifunctional compounds capable of simultaneously interacting with several pathological components has been suggested as a solution to undertake the complex pathologies of neurodegenerative diseases. In this review, we outline and discuss possible therapeutic targets in Alzheimer's disease, Parkinson's disease, and amyotrophic lateral sclerosis and molecules, previously designed or discovered as potential drug candidates for these disorders with emphasis on multifunctionality. In addition, underrepresented areas of research are discussed to indicate new directions.
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Enfermedad de Alzheimer/tratamiento farmacológico , Esclerosis Amiotrófica Lateral/tratamiento farmacológico , Enfermedad de Parkinson/tratamiento farmacológico , Profármacos/uso terapéutico , Enfermedad de Alzheimer/patología , Esclerosis Amiotrófica Lateral/patología , Productos Biológicos/química , Productos Biológicos/uso terapéutico , Descubrimiento de Drogas , Humanos , Metales/química , Metales/metabolismo , Proteínas del Tejido Nervioso/química , Proteínas del Tejido Nervioso/metabolismo , Estrés Oxidativo , Enfermedad de Parkinson/patología , Profármacos/químicaRESUMEN
Proteins from the S100 family perform numerous functions and may contribute to Alzheimer's disease (AD). Herein, we report the effects of S100A8/S100A9 heterooligomer calprotectin (CP) and the S100B homodimer on metal-free and metal-bound amyloid-ß (Aß; Aß40 and Aß42) aggregation in vitro. Studies performed with CP-Ser [S100A8(C42S)/S100A9(C3S) oligomer] indicate that the protein influences the aggregation profile for Aß40 in both the absence and presence of metal ions [i.e., Zn(ii) and Cu(ii)]. Moreover, the detection of Aß40-CP-Ser complexes by mass spectrometry suggests a direct interaction as a possible mechanism for the involvement of CP in Aß40 aggregation. Although the interaction of CP-Ser with Aß40 impacts Aß40 aggregation in vitro, the protein does not attenuate Aß-induced toxicity in SH-SY5Y cells. In contrast, S100B has a slight effect on the aggregation of Aß. Overall, this work supports a potential association of CP with Aß in the absence and presence of metal ions in AD.
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Péptidos beta-Amiloides/metabolismo , Complejo de Antígeno L1 de Leucocito/metabolismo , Metales/metabolismo , Agregado de Proteínas , Subunidad beta de la Proteína de Unión al Calcio S100/metabolismo , Humanos , Neuroblastoma/metabolismo , Neuroblastoma/patología , Células Tumorales CultivadasRESUMEN
A catecholamine neurotransmitter, dopamine (DA), is suggested to be linked to the pathology of dementia; however, the involvement of DA and its structural analogues in the pathogenesis of Alzheimer's disease (AD), the most common form of dementia, composed of multiple pathogenic factors has not been clear. Herein, we report that DA and its rationally designed structural derivatives (1-6) based on DA's oxidative transformation are able to modulate multiple pathological elements found in AD [i.e., metal ions, metal-free amyloid-ß (Aß), metal-bound Aß (metal-Aß), and reactive oxygen species (ROS)], with demonstration of detailed molecular-level mechanisms. Our multidisciplinary studies validate that the protective effects of DA and its derivatives on Aß aggregation and Aß-mediated toxicity are induced by their oxidative transformation with concomitant ROS generation under aerobic conditions. In particular, DA and the derivatives (i.e., 3 and 4) show their noticeable anti-amyloidogenic ability toward metal-free Aß and/or metal-Aß, verified to occur via their oxidative transformation that facilitates Aß oxidation. Moreover, in primary pan-microglial marker (CD11b)-positive cells, the major producers of inflammatory mediators in the brain, DA and its derivatives significantly diminish inflammation and oxidative stress triggered by lipopolysaccharides and Aß through the reduced induction of inflammatory mediators as well as upregulated expression of heme oxygenase-1, the enzyme responsible for production of antioxidants. Collectively, we illuminate how DA and its derivatives could prevent multiple pathological features found in AD. The overall studies could advance our understanding regarding distinct roles of neurotransmitters in AD and identify key interactions for alleviation of AD pathology.
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Enfermedad de Alzheimer/metabolismo , Péptidos beta-Amiloides/metabolismo , Dopamina/metabolismo , Fragmentos de Péptidos/metabolismo , Agregación Patológica de Proteínas/metabolismo , Cobre/metabolismo , Dopamina/análogos & derivados , Humanos , Inflamación , Metales , Microglía/metabolismo , Estrés Oxidativo , Especies Reactivas de Oxígeno/metabolismo , Zinc/metabolismoRESUMEN
An amyloidogenic peptide, amyloid-ß (Aß), has been implicated as a contributor to the neurotoxicity of Alzheimer's disease (AD) that continues to present a major socioeconomic burden for our society. Recently, the use of metal complexes capable of cleaving peptides has arisen as an efficient tactic for amyloid management; unfortunately, little has been reported to pursue this strategy. Herein, we report a novel approach to validate the hydrolytic cleavage of divalent metal complexes toward two major isoforms of Aß (Aß40 and Aß42) and tune their proteolytic activity based on the choice of metal centers (M = Co, Ni, Cu, and Zn) which could be correlated to their anti-amyloidogenic properties. Such metal-dependent tunability was facilitated employing a tetra-N-methylated cyclam (TMC) ligand that imparts unique geometric and stereochemical control, which has not been available in previous systems. Co(II)(TMC) was identified to noticeably cleave Aß peptides and control their aggregation, reporting the first Co(II) complex for such reactivities to the best of our knowledge. Through detailed mechanistic investigations by biochemical, spectroscopic, mass spectrometric, and computational studies, the critical importance of the coordination environment and acidity of the aqua-bound complexes in promoting amide hydrolysis was verified. The biological applicability of Co(II)(TMC) was also illustrated via its potential blood-brain barrier permeability, relatively low cytotoxicity, regulatory capability against toxicity induced by both Aß40 and Aß42 in living cells, proteolytic activity with Aß peptides under biologically relevant conditions, and inertness toward cleavage of structured proteins. Overall, our approaches and findings on reactivities of divalent metal complexes toward Aß, along with the mechanistic insights, demonstrate the feasibility of utilizing such metal complexes for amyloid control.
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Péptidos beta-Amiloides/antagonistas & inhibidores , Compuestos Heterocíclicos/farmacología , Metales Pesados/farmacología , Compuestos Organometálicos/farmacología , Péptidos beta-Amiloides/química , Línea Celular Tumoral , Supervivencia Celular/efectos de los fármacos , Compuestos Heterocíclicos/química , Humanos , Hidrólisis , Metales Pesados/química , Estructura Molecular , Compuestos Organometálicos/químicaRESUMEN
Aggregates of amyloidogenic peptides are involved in the pathogenesis of several degenerative disorders. Herein, an iridium(III) complex, Ir-1, is reported as a chemical tool for oxidizing amyloidogenic peptides upon photoactivation and subsequently modulating their aggregation pathways. Ir-1 was rationally designed based on multiple characteristics, including 1)â photoproperties leading to excitation by low-energy radiation; 2)â generation of reactive oxygen species responsible for peptide oxidation upon photoactivation under mild conditions; and 3)â relatively easy incorporation of a ligand on the IrIII center for specific interactions with amyloidogenic peptides. Biochemical and biophysical investigations illuminate that the oxidation of representative amyloidogenic peptides (i.e., amyloid-ß, α-synuclein, and human islet amyloid polypeptide) is promoted by light-activated Ir-1, which alters the conformations and aggregation pathways of the peptides. Additionally, their potential oxidation sites are identified as methionine, histidine, or tyrosine residues. Overall, our studies on Ir-1 demonstrate the feasibility of devising metal complexes as chemical tools suitable for elucidating the nature of amyloidogenic peptides at the molecular level, as well as controlling their aggregation.