Alpha-synuclein (α-syn) is localized in cellular organelles of most neurons, but many of its physiological functions are only partially understood. α-syn accumulation is associated with Parkinson's ...disease, dementia with Lewy bodies, and multiple system atrophy as well as other synucleinopathies; however, the exact pathomechanisms that underlie these neurodegenerative diseases remain elusive. In this review, we describe what is known about α-syn function and pathophysiological changes in different cellular structures and organelles, including what is known about its behavior as a prion-like protein. We summarize current knowledge of α-syn and its pathological forms, covering its effect on each organelle, including aggregation and toxicity in different model systems, with special interest on the mitochondria due to its relevance during the apoptotic process of dopaminergic neurons. Moreover, we explore the effect that α-syn exerts by interacting with chromatin remodeling proteins that add or remove histone marks, up-regulate its own expression, and resume the impairment that α-syn induces in vesicular traffic by interacting with the endoplasmic reticulum. We then recapitulate the events that lead to Golgi apparatus fragmentation, caused by the presence of α-syn. Finally, we report the recent findings about the accumulation of α-syn, indirectly produced by the endolysosomal system. In conclusion, many important steps into the understanding of α-syn have been made using
and
models; however, the time is right to start integrating observational studies with mechanistic models of α-syn interactions, in order to look at a more complete picture of the pathophysiological processes underlying α-synucleinopathies.
Dysfunction of cellular homeostasis can lead to misfolding of proteins thus acquiring conformations prone to polymerization into pathological aggregates. This process is associated with several ...disorders, including neurodegenerative diseases, such as Parkinson's disease (PD), and endoplasmic reticulum storage disorders (ERSDs), like alpha-1-antitrypsin deficiency (AATD) and hereditary hypofibrinogenemia with hepatic storage (HHHS). Given the shared pathophysiological mechanisms involved in such conditions, it is necessary to deepen our understanding of the basic principles of misfolding and aggregation akin to these diseases which, although heterogeneous in symptomatology, present similarities that could lead to potential mutual treatments. Here, we review: (i) the pathological bases leading to misfolding and aggregation of proteins involved in PD, AATD, and HHHS: alpha-synuclein, alpha-1-antitrypsin, and fibrinogen, respectively, (ii) the evidence linking each protein aggregation to the stress mechanisms occurring in the endoplasmic reticulum (ER) of each pathology, (iii) a comparison of the mechanisms related to dysfunction of proteostasis and regulation of homeostasis between the diseases (such as the unfolded protein response and/or autophagy), (iv) and clinical perspectives regarding possible common treatments focused on improving the defensive responses to protein aggregation for diseases as different as PD, and ERSDs.
Parkinson’s disease (PD) caused by SNCA gene triplication (3XSNCA) leads to early onset, rapid progression, and often dementia. Understanding the impact of 3XSNCA and its absence is crucial. This ...study investigates the differentiation of human induced pluripotent stem cell (hiPSC)-derived floor-plate progenitors into dopaminergic neurons. Three different genotypes were evaluated in this study: patient-derived hiPSCs with 3XSNCA, a gene-edited isogenic line with a frame-shift mutation on all SNCA alleles (SNCA 4KO), and a normal wild-type control. Our aim was to assess how the substantia nigra pars compacta (SNpc) microenvironment, damaged by 6-hydroxydopamine (6-OHDA), influences tyrosine hydroxylase-positive (Th+) neuron differentiation in these genetic variations. This study confirms successful in vitro differentiation into neuronal lineage in all cell lines. However, the SNCA 4KO line showed unusual LIM homeobox transcription factor 1 alpha (Lmx1a) extranuclear distribution. Crucially, both 3XSNCA and SNCA 4KO lines had reduced Th+ neuron expression, despite initial successful neuronal differentiation after two months post-transplantation. This indicates that while the SNpc environment supports early neuronal survival, SNCA gene alterations—either amplification or knock-out—negatively impact Th+ dopaminergic neuron maturation. These findings highlight SNCA’s critical role in PD and underscore the value of hiPSC models in studying neurodegenerative diseases.
Transplantation of immature dopaminergic neurons or neural precursors derived from embryonic stem cells (ESCs) into the substantia nigra pars compacta (SNpc) is a potential therapeutic approach for ...functional restitution of the nigrostriatal pathway in Parkinson's disease (PD). However, further studies are needed to understand the effects of the local microenvironment on the transplanted cells to improve survival and specific differentiation in situ. We have previously reported that the adult SNpc sustains a neurogenic microenvironment. Non-neuralized embryoid body cells (EBCs) from mouse ESCs (mESCs) overexpressing the dopaminergic transcription factor
gave rise to many tyrosine hydroxylase (Th
) cells in the intact and damaged adult SNpc, although only for a short-term period. Here, we extended our study by transplanting EBCs from genetically engineered naive human ESC (hESC), overexpressing the dopaminergic transcription factors
,
, and
(hESC-LFO), in the SNpc. Unexpectedly, no graft survival was observed in wild-type hESC EBCs transplants, whereas hESC-LFO EBCs showed viability in the SNpc. Interestingly, neural rosettes, a developmental hallmark of neuroepithelial tissue, emerged at 7- and 15-days post-transplantation (dpt) from the hESC-LFO EBCs. Neural rosettes expressed specification dopaminergic markers (Lmx1a, Otx2), which gave rise to several Th
cells at 30 dpt. Our results suggest that the SNpc enables the robust initiation of neural differentiation of transplanted human EBCs prompted to differentiate toward the midbrain dopaminergic phenotype.
Human embryonic stem cell (hESC) and human-induced pluripotent stem cell (hiPSC) technologies have a critical role in regenerative strategies for personalized medicine. Both share the ability to ...differentiate into almost any cell type of the human body. The study of their properties and clinical applications requires the development of robust and reproducible cell culture paradigms that direct cell differentiation toward a specific phenotype in vitro and in vivo. Our group evaluated the potential of mouse ESCs (mESCs), hESCs, and hiPSCs (collectively named pluripotent stem cells, PSCs) to analyze brain microenvironments through the use of embryoid body (EB)-derived cells from these cell sources. EB are cell aggregates in 3D culture conditions that recapitulate embryonic development. Our approach focuses on studying the midbrain dopaminergic phenotype and transplanting EB into the substantia nigra pars compacta (SNpc) in a Parkinson's disease rodent model. Here, we describe cell culture protocols for EB generation from PSCs that show significant in vivo differentiation toward dopaminergic neurons.
Resumen Introducción: El estudio de las anormalidades de la placentación es primordial en Anestesiología Obstétrica.Dirigir el manejocon metas hemodinámicas en las pacientes con bloqueo epidural ...ofrece seguridad a la paciente en un procedimiento de alto riesgo. Objetivo: Evaluar la hemodinamia en pacientescon diagnóstico de placenta ácreta o pércreta programadas a histerectomía obstétrica. Diseño: Estudio prospectivo, causas e incidencias, analítico comparativo, longitudinal con 21 pacientes. Métodos:Pacientes mayores de 18 años, programadas por el departamento de Perinatología. En quirófano se instaló línea arterial radial y catéter venoso central en yugular izquierda guiado con ultrasonido, se conectaron a monitor EV1000 usando Flotrac.Posteriormente se colocó bloqueo epidural lumbar. Resultados: Se estudiaron 12 (57.14%) diagnósticos de placentas ácretas y nueve (42.86%) placentas pércretas. Con131.11, ±26.07 min de cirugía, y sangrado de 3177.78, ±733.33 ml. En las fases de tiempo no encontramos diferencias en resistencias vasculares sistémicas (P=0.589), la presión arterial media se encontró estable y sin variación (P=0.989). EnÍndice Cardiaco (P=0.039) observamos diferencias por descenso gradual,en parámetros normales, con cambios observados a los 90 min (Phoc=0.336), y 130 min de la cirugía (Phoc=0.288); en frecuencia cardiaca (P=0.006) encontramos diferencias con frecuencias aumentadas al bloqueo epidural (15 min, Phoc=0.059) y un gradual descenso de la misma a lo largo del procedimiento. Conclusiones: Los parámetros se observaron en rangos normales durante el transoperatorio, con cambios del Índice Cardiaco al final del procedimiento por el cierre del cortocircuito uterino.
The main aim of this international consensus document on obstructive sleep apnea is to provide guidelines based on a critical analysis of the latest literature to help health professionals make the ...best decisions in the care of adult patients with this disease. The expert working group was formed primarily of 17 scientific societies and 56 specialists from a wide geographical area (including the participation of 4 international societies), an expert in methodology, and a documentalist from the Iberoamerican Cochrane Center. The document consists of a main section containing the most significant innovations from the ICD and a series of online manuscripts that report the systematic literature searches performed for each section of the ICD. This document does not discuss pediatric patients or the management of patients receiving chronic non-invasive mechanical ventilation (these topics will be addressed in separate consensus documents).
El objetivo principal de este documento internacional de consenso sobre apnea obstructiva del sueño es proporcionar unas directrices que permitan a los profesionales sanitarios tomar las mejores decisiones en la asistencia de los pacientes adultos con esta enfermedad según un resumen crítico de la literatura más actualizada. El grupo de trabajo de expertos se ha constituido principalmente por 17 sociedades científicas y 56 especialistas con amplia representación geográfica (con la participación de 4 sociedades internacionales), además de un metodólogo experto y un documentalista del Centro Cochrane Iberoamericano. El documento consta de un manuscrito principal, con las novedades más relevantes del DIC, y una serie de manuscritos online que recogen las búsquedas bibliográficas sistemáticas de cada uno de los apartados del DIC. Este documento no cubre la edad pediátrica ni el manejo del paciente en ventilación mecánica crónica no invasiva (que se publicarán en sendos documentos de consenso aparte).
The main aim of this international consensus document on obstructive sleep apnea is to provide guidelines based on a critical analysis of the latest literature to help health professionals make the ...best decisions in the care of adult patients with this disease. The expert working group was formed primarily of 17 scientific societies and 56 specialists from a wide geographical area (including the participation of 4 international societies), an expert in methodology, and a documentalist from the Iberoamerican Cochrane Center. The document consists of a main section containing the most significant innovations and a series of online manuscripts that report the systematic literature searches performed for each section of the international consensus document. This document does not discuss pediatric patients or the management of patients receiving chronic non-invasive mechanical ventilation (these topics will be addressed in separate consensus documents).
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•New cholesteryl dithio-phosphonates of As(III) and Sb(III)•Metallolanes y metallocanes of As(III) and Sb(III) involved in a dithiophosphonate ligand.•Biological activity and DFT ...correlations of dithiophosphonate complexes of As(III) and Sb(III)•Crystal structure of Arsenic and Antimony dithiophosphonates into metalloheterocycles.
The synthesis and characterization of six new O-cholesteryl-dithiophosphonates containing thio-metalloheterocycles of As(III) and Sb(III); (CH2S)2AsS2P(cholesteryl)(4-MeOC6H5) (2), (CH2S)2SbS2P(cholesteryl)(4-MeOC6H5) (3), O(CH2CH2S)2AsS2P(cholesteryl)(4-MeOC6H5) (4), O(CH2CH2S)2SbS2P(cholesteryl)(4-MeOC6H5) (5), S(CH2CH2S)2As S2P(cholesteryl)(4-MeOC6H5) (6), and S(CH2CH2S)2SbS2P(cholesteryl)(4-MeOC6H5) (7) are reported. 2–7 have been prepared from the reaction between the triethylammonium salt of O-3β-cholest-5-en-3-yl (4-methoxyphenyl) dithiophosphonate (1) and five and eight membered chloro-metalloheterocycles of As(III) and Sb(III). The obtained compounds have been characterized by elemental analyses, IR and NMR (1H, 13C, and 31P) spectroscopy. The 31P NMR data suggest that the dithiophosphonate ligand presents, in solution, a bidentate coordination. The structures of 3 and 4 were determined by X-ray single crystal analysis, that correspond to the first examples of such determinations in Group 15 dithiophosphonates, showing an anisobidentate coordination mode of the dithiophosphonate moiety. Sb(III) and As(III) in compounds 3 and 4 present tetracoordination and pentacoordination, respectively. The pentacoordination in 4 is achieved through a 1,5 transannular As⋯O interaction. Antibacterial assays were performed and the activity was correlated with the electronic distribution and molecular shape, employing their geometrical structures, Mulliken partial charges, dipole moments and Molecular Electrostatic Potential maps from DFT calculations.
This work present the synthesis and characterization of essential metals coordination compounds with ligand N4-donor 2,9-di(ethylaminomethyl)-1,10-phenanthroline. Complexes with diverse geometry and ...coordination number were obtained. Cyclic voltammetry studies showed different redox behavior for the compounds. Ligand amoebicide activity is increased by the metal. The moderate antitumor and amoebicide activity is linked to redox behavior this suggest an imbalance redox cell damage action mechanism.
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•The essential metals complexes with a N4-donor ligand derivative of Necouproine were synthetized and characterized.•The pH conditions and the rigidity of the ligand L impose the denticity either three or four coordinated.•The redox potencial values found for these complexes are a direct consequence of the π-acceptor nature of the ligand.•The antitumor and amoebicidal activity are linked with redox behavior of the complexes.•A redox imbalance promoted by the coordination compounds is proposed as the mechanism of cellular damage.
The work shows the synthesis and characterization of N4-donor L: 2,9-di(ethylaminomethyl)-1,10-phenanthroline and its coordination compounds with some divalent essential metals (Mn, Fe, Co, Ni Cu and Zn). L was obtained as the hydrochloride derivative H3LCl3. The complexes were synthesized by two routes: 1) using L as hydrochloride for Mn, Fe, Co and Zn complexes and 2) from L as a free base for Cu and Ni ones. Co(HL)Cl2NO3 and Zn(HL)Cl2Cl were crystallized and reveal that L is bound to metallic nuclei by only three nitrogen atoms. Cyclic voltammetry studies showed that L alone is capable of being reduced and in complexes, the potential of the coordinated compound process is lower. DFT calculations explain the observable redox behavior regarding HOMO-LUMO orbital energies. Also, the modeling of protonated species of the ligand L suggests that the tetradentate behavior depends on pH conditions of the synthesis. The antiproliferative activity observed on Entamoeba Histolytica and HeLa human tumor cell cultures confirmed that even if complexes are less active than the first choice drugs (metronidazole and cisplatin respectively), it exists a correlation between the observed cytotoxicity and the compounds redox potential.
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![[Translated article] Intern...](http://api.summon.serialssolutions.com/2.0.0/image/issn/XR4PS5YY4K/0300-2896/small "[Translated article] International consensus document on obstructive sleep apnea")
