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Preclinical models of idiosyncratic drug-induced liver injury(iDILI):Moving towards prediction

Acta Pharmaceutica Sinica B 2021年第12期11卷 3685-3726页

作者： Antonio Segovia-Zafra Daniel e.Di Zeo-Sanchez Carlos Lopez-Gomez Zeus Perez-Valdes eduardo Garcıa-Fuentes Raul J.Andrade M.Isabel Lucena Marina Villanueva-Paz unidad de Gestio´n clı´nica de Gastroenterologı´a Servicio de Farmacologıa ClınicaInstituto de Investigacio´n Biomedica de Malaga-IBIMAHospital Universitario Virgen de la VictoriaUniversidad de MalagaMalaga 29071Spain Centro de Investigacion Biomedica en Red en el Area Tematica de enfermedades Hepaticas y Digestivas(CIBeRehd) Madrid 28029Spain Platform ISCIII de ensayos clınicos UICEC-IBIMAMalaga 29071Spain unidad de Gestion clınica de Aparato Digestivo Instituto de Investigacion Biomedica de Malaga(IBIMA)Hospital Universitario Virgen de la VictoriaMalaga 29010Spai

Idiosyncratic drug-induced liver injury(iDILI) encompasses the unexpected harms that prescription and non-prescription drugs,herbal and dietary supplements can cause to the *** remains a major public health problem and a major cause of drug *** the lack of biomarkers for iDILI prediction,diagnosis and prognosis,searching new models to predict and study mechanisms of iDILI is *** of the major limitations of iDILI preclinical assessment has been the lack of correlation between the markers of hepatotoxicity in animal toxicological studies and clinically significant ***,major advances in the understanding of iDILI susceptibility and pathogenesis have come from the study of well-phenotyped iDILI ***,there are many gaps for explaining all the complexity of iDILI susceptibility and ***,there is a need to optimize preclinical human in vitro models to reduce the risk of iDILI during drug ***,the current experimental models and the future directions in iDILI modelling are thoroughly discussed,focusing on the human cellular models available to study the pathophysiological mechanisms of the disease and the most used in vivo animal iDILI *** also comment about in silico approaches and the increasing relevance of patient-derived cellular models.

关键词： Drug-induced liver injury Preclinical models Mechanisms Oxidative stress Mitochondrial damage Immune response Personalized medicine

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Chronic Urticaria Due to Allergy to Wheat Alpha-Amylase Inhibitor Proteins

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Case Reports in clinical Medicine 2016年第4期5卷 130-133页

作者： Nagore Arruti Oyarzabal Olga Villarreal Balza de Vallejo Nagore Bernedo Belar Maria Teresa Audicana Berasategui Natividad Longo Areso Borja Bartolomé Servicio de alergia e inmunología clínica Hospital Universitario Araba Vitoria-Gasteiz Spain Bial-Aristegui Laboratories Bilbao Spain

Chronic spontaneous urticaria (CSU) is defined as the spontaneous appearance of wheals, angioedema, or both, for at least 6 weeks, due to known or unknown causes [1]. In some patients who present a CSU with daily or almost daily symptoms a type I allergy could be the underlying cause. We present one adult patient with chronic urticaria who was finally diagnosed as a non-occupational case of Ige-mediated wheat allergy manifested following exposure by 3 different routes: inhalation (rhinitis and bronchial asthma), dermal absorption (contact urticaria) and ingestion (systemic chronic urticaria). We were able to detect the culprit proteins by immunoblotting. Serum Ige binds mainly to alpha-amylase/trypsin inhibitors and, to a lesser extent, to other proteins associated with food allergy to grains (e.g. beta-glucanase, serpin, peroxidase). In our opinion, skin prick tests with a food standard battery could help in the etiological diagnosis of chronic urticaria. The identification of responsible allergens could be difficult because only a few complex in vitro techniques allow detecting the allergy to several proteins.

关键词： Alpha-Amylase Inhibitor Wheat Chronic Urticaria Allergy

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Management of nonalcoholic fatty liver disease:An evidence-based clinical practice review

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World Journal of Gastroenterology 2014年第34期20卷 12182-12201页

作者： Juan P Arab Roberto Candia Rodrigo Zapata Cristián Mu?oz Juan P Arancibia Jaime Poniachik Alejandro Soza Francisco Fuster Javier Brahm edgar Sanhueza Jorge Contreras M Carolina Cuellar Marco Arrese Arnoldo Riquelme departamento de Gastroenterología Escuela de MedicinaPontificia Universidad Católica de Chile8330024 SantiagoChile Sección de Gastroenterología Hospital del SalvadorEscuela de MedicinaUniversidad de Chile7500922 SantiagoChile unidad de Gastroenterología Universidad del DesarrolloClínica Alemana7650568 SantiagoChile unidad de Trasplante Hepático Hospital del SalvadorUnidad de GastroenterologíaClínica Las Lilas7510524 SantiagoChile Sección de Gastroenterología Departamento de MedicinaHospital Clínico Universidad de ChileChile8380456 SantiagoChile Sección de Gastroenterología Hospital Clínico Universidad de ChileEscuela de MedicinaUniversidad de Chile8380456 SantiagoChile Digestive Diseases Unit Clínica Re?aca2540364 Vi?a del MarChile Gastroenterology department Clínica Las Condes6770128 SantiagoChile Centre for Medical education Escuela de MedicinaPontificia Universidad Católica de Chile8330024 SantiagoChile

AIM: To build a consensus among Chilean specialists on the appropriate management of patients with nonalcoholic fatty liver disease (NAFLD) in clinical practice.

关键词： Nonalcoholic fatty liver disease Steatosis Consensus evidence-based medicine Treatment

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Presenilin mutations and their impact on neuronal differentiation in Alzheimer’s disease

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Neural Regeneration Research 2022年第1期17卷 31-37页

作者： Mercedes A.Hernández-Sapiéns edwin e.Reza-Zaldívar Ana L.Márquez-Aguirre Ulises Gómez-Pinedo Jorge Matias-Guiu Ricardo R.Cevallos Juan C.Mateos-Díaz Víctor J.Sánchez-González Alejandro A.Canales-Aguirre unidad de evaluación Preclínica Unidad de Biotecnología Médica y FarmacéuticaCentro de Investigación y Asistencia en Tecnología y Diseño del Estado de JaliscoGuadalajaraMéxico Instituto de Neurociencias IdISSCHospital Clínico San CarlosMadridEspaña Biochemistry and Molecular Genetics department University of AlabamaBirminghamAlabama unidad de Biotecnología Industrial Centro de Investigación y Asistencia en Tecnología y Diseño del Estado de JaliscoGuadalajaraMéxico Centro Universitario de los Altos Universidad de GuadalajaraGuadalajaraMéxico

The presenilin genes(PSeN1 and PSeN2)are mainly responsible for causing early-onset familial Alzheimer’s disease,harboring~300 causative mutations,and representing~90%of all mutations associated with a very aggressive disease *** 1 is the catalytic core of theγ-secretase complex that conducts the intramembranous proteolytic excision of multiple transmembrane proteins like the amyloid precursor protein,Notch-1,N-and e-cadherin,LRP,Syndecan,delta,Jagged,CD44,erbB4,and *** 1 plays an essential role in neural progenitor maintenance,neurogenesis,neurite outgrowth,synaptic function,neuronal function,myelination,and ***,an imbalance caused by mutations in presenilin 1/γ-secretase might cause aberrant signaling,synaptic dysfunction,memory impairment,and increased Aβ42/Aβ40 ratio,contributing to neurodegeneration during the initial stages of Alzheimer’s disease *** review focuses on the neuronal differentiation dysregulation mediated by PSeN1 mutations in Alzheimer’s ***,we emphasize the importance of Alzheimer’s disease-induced pluripotent stem cells models in analyzing PSeN1 mutations implication over the early stages of the Alzheimer’s disease pathogenesis throughout neuronal differentiation impairment.

关键词： familial Alzheimer’s disease familial Alzheimer’s disease-induced pluripotent stem cells models induced pluripotent stem cells neurogenesis neuronal differentiation Notch presenilin 1 PSeN1 mutations γ-secretase complex

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Physiological effects of amyloid precursor protein and its derivatives on neural stem cell biology and signaling pathways involved

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Neural Regeneration Research 2019年第10期14卷 1661-1671页

作者： Raquel Coronel Charlotte Palmer Adela Bernabeu-Zornoza María Monteagudo Andreea Rosca Alberto Zambrano Isabel Liste unidad de Regeneración Neural Unidad Funcional de Investigación de Enfermedades Crónicas Instituto de Salud Carlos Ⅲ (ISCⅢ)

The pathological implication of amyloid precursor protein(APP)in Alzheimer’s disease has been widely documented due to its involvement in the generation of amyloid-β ***,the physiological functions of APP are still poorly *** is considered a multimodal protein due to its role in a wide variety of processes,both in the embryo and in the adult ***,APP seems to play a key role in the proliferation,differentiation and maturation of neural stem *** addition,APP can be processed through two canonical processing pathways,generating different functionally active fragments:soluble APP-α,soluble APP-β,amyloid-β peptide and the APP intracellular C-terminal *** fragments also appear to modulate various functions in neural stem cells,including the processes of proliferation,neurogenesis,gliogenesis or cell ***,the molecular mechanisms involved in these effects are still *** this review,we summarize the physiological functions of APP and its main proteolytic derivatives in neural stem cells,as well as the possible signaling pathways that could be implicated in these *** knowledge of these functions and signaling pathways involved in the onset or during the development of Alzheimer’s disease is essential to advance the understanding of the pathogenesis of Alzheimer’s disease,and in the search for potential therapeutic targets.

关键词： amyloid precursor protein APP soluble APP alpha soluble APP beta amyloid beta peptide APP intracellular domain neural stem cells neural progenitor cells neurogenesis signaling pathways

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Proteomics for discovery of candidate colorectal cancer biomarkers

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World Journal of Gastroenterology 2014年第14期20卷 3804-3824页

作者： Paula lvarez-Chaver Olalla Otero-estévez María Páez de la Cadena Francisco J Rodríguez-Berrocal Vicenta S Martínez-Zorzano unidad de Proteómica Servicio de Determinación EstructuralProteómica y GenómicaCentro de Apoyo Científico y Tecnológico a la InvestigaciónUniversidad de VigoCampus As Lagoas-Marcosende área de Bioquímica y Biología Molecular Departamento de BioquímicaGenética e InmunologíaFacultad de BiologíaUniversidad de VigoCampus As Lagoas-Marcosende

Colorectal cancer(CRC)is the second most common cause of cancer-related deaths in europe and other Western countries,mainly due to the lack of wellvalidated clinically useful biomarkers with enough sensitivity and specificity to detect this disease at early *** it is well known that the pathogenesis of CRC is a progressive accumulation of mutations in multiple genes,much less is known at the proteome ***,in the last years many proteomic studies have been conducted to find new candidate protein biomarkers for diagnosis,prognosis and as therapeutic targets for this malignancy,as well as to elucidate the molecular mechanisms of colorectal *** important advantage of the proteomic approaches is the capacity to look for multiple differentially expressed proteins in a single *** review provides an overview of the recent reports describing the different proteomic tools used for the discovery of new protein markers for CRC such as two-dimensional electrophoresis methods,quantitative mass spectrometry-based techniques or protein ***,we will also focus on the diverse biological samples used for CRC biomarker discovery such as tissue,serum and faeces,besides cell lines and murine models,discussing their advantages and disadvantages,and summarize the most frequently identified candidate CRC markers.

关键词： Colorectal cancer Serum Tissue Proteins Biomarkers Proteomics Protein identification Mass spectrometry

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Role of hypoxia preconditioning in therapeutic potential of mesenchymal stem-cell-derived extracellular vesicles

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World Journal of Stem Cells 2022年第7期14卷 453-472页

作者： Victoria Pulido-escribano Bárbara Torrecillas-Baena Marta Camacho-Cardenosa Gabriel Dorado MaríaÁngeles Gálvez-Moreno Antonio Casado-Díaz unidad de Gestión clínica de endocrinología y Nutrición-GC17 Instituto Maimónides de Investigación Biomédica de CórdobaHospital Universitario Reina SofíaCórdoba 14004Spain dep.Bioquímica y Biología Molecular Campus Rabanales C6-1-E17Campus de Excelencia Internacional Agroalimentario(ceiA3)Universidad de CórdobaCIBERFESCórdoba 14071Spain

The use of mesenchymal stem-cells(MSC)in cell therapy has received considerable attention because of their *** properties include high expansion and differentiation in vitro,low immunogenicity,and modulation of biological processes,such as inflammation,angiogenesis and ***,the regenerative effect of MSC is partly due to their paracrine *** has prompted numerous studies,to investigate the therapeutic potential of their secretome in general,and specifically their extracellular vesicles(eV).The latter contain proteins,lipids,nucleic acids,and other metabolites,which can cause physiological changes when released into recipient ***,contents of eV can be modulated by preconditioning MSC under different culture *** them,exposure to hypoxia stands out;these cells respond by activating hypoxia-inducible factor(HIF)at low O_(2) *** has direct and indirect pleiotropic effects,modulating expression of hundreds of genes involved in processes such as inflammation,migration,proliferation,differentiation,angiogenesis,metabolism,and cell *** of these genes is reflected in the contents of secreted ***,numerous studies show that MSC-derived eV conditioned under hypoxia have a higher regenerative capacity than those obtained under *** this review,we show the implications of hypoxia responses in relation to tissue *** addition,hypoxia preconditioning of MSC is being evaluated as a very attractive strategy for isolation of eV,with a high potential for clinical use in regenerative medicine that can be applied to different pathologies.

关键词： Cell priming extracellular vesicles Hypoxia Hypoxia-inducible factor Mesenchymal stemcells Regenerative medicine

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Preparation and Characterization of Flexible, Transparent and Thermally Stable Aromatic Co-polyamides

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Chinese Journal of Polymer Science 2019年第2期37卷 136-141页

作者： José Antonio Tec-Sánchez Andrés Iván Oliva Arias Manuel Aguilar-Vega Juan Valerio Cauich-Rodríguez José Luis Santiago-García unidad de Materiales Centro de Investigación Científica de Yucatán A. C. Centro de Investigación y de estudios Avanzados del IPN Unidad Mérida Departamento de Física Aplicada

Two aromatic co-polyamides were synthesized combining two diacid monomers containing bulky pendant groups, 5-(9,10-dihydro-9,10-ethanoanthracene-11,12-dicarboximido)isophthalic acid(deAIA) and 5-tert-butylisophthalic acid(TeRT), with 4,4′-(hexafluoroisopropylidene)dianiline(HFA) or 2,3,5,6-tetramethyl-1,4-phenylenediamine(Durene) by direct polycondensation. The structures of the obtained aromatic co-polyamides were confirmed by FTIR, Raman and 1 H-NMR. The co-copolyamide films, DHTH and DDTD, exhibited rms-roughness values between 0.94 and 1.60 nm, respectively. Moreover, they presented good thermal stability up to300 °C. Young's moduli of the co-polyamide films were between 4.1 and 4.3 GPa. X-ray diffraction results showed that the co-polyamide films were amorphous due to the incorporation of both bulky pendant groups, tert-butyl and dibenzobarrelene. The combination of bulky pendant groups provided intrinsically transparent co-polyamide films with a transmittance higher than 88% in the range of 400-780 *** to these outstanding film and optical properties, they are suggested to be flexible substrates in applications for solar cell and other portable electronic devices.

关键词： Co-polyamides Flexible films Transmittance Thermal stability Polycondensation

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Frequency and severity of OSAHS in Mexican adolescents. The role of BMI and neck circumference

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Health 2013年第8期5卷 1-8页

作者： Armando Partida-Gaytán Arturo Berber Blanca estela del Río-Navarro Reyes Haro-Valencia Chief of Sleep Breathing Disorders clinic Universidad Nacional Autónoma de México Hospital General de México Secretaria de Salud Distrito Federal México departamento de alergia e inmunología clínica Pediátrica Hospital Infantil de México Federico Gómez Instituto Nacional de Salud Secretaria de Salud Distrito Federal México

Background: Overweight and obesity are major public-health issues in Mexico. Sleep breathing disorders directly impact the health of affected subjects. The aim of this study was to describe the frequency and severity of obstructive sleep apnea/hypopnea syndrome (OSAHS) in Mexican adolescents grouped by weight status. Secondary objectives were to describe the influence of body mass index (BMI) and neck circumference (NC) as predictive factors of OSAH. Method: Somatometric, demographic data and full-night polysomnography were done. Linear and logistic regression models described the relationship between BMI and NC with OSAHS presence and severity. Receiver-Operating-Characteristics (ROC) curves showed different sensitivity and specificity performances of BMI and NC cutoff-values. Results: OSAHS frequency and severity were significantly greater in obese and extremely-obese adolescents (8% vs 22% vs 67%;p ear regression showed an AHI increase of 0.940 events/hour for every centimeter-increase in NC and 0.696 events/hour for every1 kg/m2-increase in BMI. Logistic-regression showed extreme-obesity as the main risk factor (OR 9.9) for diagnosis of OSAHS. ROC curves showed an area under the curve (AUC) of 0.83 for BMI defined cutoff-values, and of 0.80 for BMI percentile-for-age cutoff-values. The AUC of NC ROC curve was 0.8043. Conclusion: This is the largest study made on Latin-American population evaluating the frequency and severity of OSAHS with full-night polysomnography. We showed that obese and extremely-obese Mexican-adolescents are at highest risk for OSAHS. Increasing BMI and NC showed positive correlation with AHI. Different BMI cut-off values showed similar diagnostic performance. extreme-obesity increases 8 times the risk association for OSAHS.

关键词： Obesity Obstructive Sleep Apnea Hyopopnea Syndrome (OSAHS) Obstructive Sleep Apnea Sleep Apnea Syndromes Polysomnography Body Mass Index (BMI) Neck Circumference Adolescents

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enantioselective Synthesis,(Chir)optical Properties,and Postsynthetic Functionalization of Furan-Containing Oxa[5]-,Oxa[6]-,and Dioxa[6]helicenes

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CCS Chemistry 2024年第10期6卷 2439-2451页

作者： Wei Fu Valentina Pelliccioli Raquel Casares-López Juan M.Cuerva Martin Simon Christopher Golz Manuel Alcarazo Institut für Organische und Biomolekulare Chemie Georg-August-Universität Göttingen37077 Göttingen departamento de Química Orgánica Universidad de GranadaUnidad de Excelencia Química Aplicada a Biomedicina y MedioambienteE-18071 Granada

An expedient synthesis of a series of configurationally stable oxa[5]helicenes,oxa[6]helicenes,and dioxa[6]helicenes has been developed using an intramolecular,highly enantioselective,Au-catalyzed,alkyne hydroarylation *** absolute configuration of the newly prepared structures has been established by crystallography,their inversion barriers have been determined theoretically and experimentally,and their chiroptical properties have been *** of these data with those reported for thia-or carbohelicenes sharing an otherwise identical helical framework enables the establishment of comprehensive correlations between the nature of the embedded(hetero)atom(s)and the magnitude of these *** studies on the postsynthetic functionalization of the oxahelicenes obtained are also ***,siteselective bromination at the 15-position in oxa[5]helicene 5d allows its subsequent manipulation into pyridine-containing aza-oxa[7]helicene 13d;while the two termini of oxa[6]helicene 7d have been intramolecularly cyclised into the pleiadeno[1,12,11-bcde]benzofuran derivative 15d by acidic *** transformations take place without erosion of the enantiopurity.

关键词： Au-catalysis enantioselective synthesis oxa[n]helicenes racemization dynamics postsynthetic functionalization

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