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Designing the new generation of intelligent biocompatible carriers for protein and peptide delivery

Acta Pharmaceutica Sinica B 2018年第2期8卷 147-164页

作者： angela m.wagner margaret P.Gran Nicholas A.Peppas mcKetta Department of Chemical Engineering The University of Texas at Austin Institute for Biomaterials Drug Delivery and Regenerative Medicine The University of Texas at Austin Department of Biomedical Engineering The University of Texas at Austin Department of Pediatrics Dell Medical School The University of Texas at Austin Department of Surgery and Perioperative Care Dell Medical School The University of Texas at Austin Division of Pharmaceutics College of Pharmacy The University of Texas at Austin

Therapeutic proteins and peptides have revolutionized treatment for a number of diseases, and the expected increase in macromolecule-based therapies brings a new set of challenges for the pharmaceutics field. Due to their poor stability, large molecular weight, and poor transport properties,therapeutic proteins and peptides are predominantly limited to parenteral administration. The short serum half-lives typically require frequent injections to maintain an effective dose, and patient compliance is a growing issue as therapeutic protein treatments become more widely available. A number of studies have underscored the relationship of subcutaneous injections with patient non-adherence, estimating that over half of insulin-dependent adults intentionally skip injections. The development of oral formulations has the potential to address some issues associated with non-adherence including the interference with daily activities, embarrassment, and injection pain. Oral delivery can also help to eliminate the adverse effects and scar tissue buildup associated with repeated injections. However, there are several major challenges associated with oral delivery of proteins and peptides, such as the instability in the gastrointestinal(GI)tract, low permeability, and a narrow absorption window in the intestine. This review provides a detailed overview of the oral delivery route and associated challenges. Recent advances in formulation and drugdelivery technologies to enhance bioavailability are discussed, including the co-administration of compounds to alter conditions in the GI tract, the modification of the macromolecule physicochemical properties, and the use of improved targeted and controlled release carriers.

关键词： Oral delivery Hydrogels Protein delivery Peptide delivery Carbohydrates mucoadhesion

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Rainfall Sensitivity to microphysics and Planetary Boundary Layer Parameterizations in Convection-Permitting Simulations over Northwestern South America

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Journal of meteorological Research 2024年第4期38卷 805-825页

作者： K.Santiago HERNANDEZ Sebastian GOmEZ-RIOS Juan J.HENAO Vanessa ROBLEDO Alvaro RAmiREZ-CARDONA angela m.RENDON Geolimna Escuela AmbientalFacultad de IngenieriaUniversidad de AntioquiaMedellin 050010Colombia Grupo de Ingenieria y Gestion Ambiental(GIGA) Escuela AmbientalFacultad de IngenieriaUniversidad de AntioquiaMedellin 050010Colombia Division of Atmospheric Sciences Desert Research InstituteRenoNV 89512USA

Convection-permitting modeling allows us to understand mechanisms that influence rainfall in specific ***,microphysics parameterization(mP) and planetary boundary layer(PBL) schemes remain an important source of uncertainty,affecting rainfall intensity,occurrence,duration,and ***,we study the sensitivity of rainfall to three mP [Weather Research and Forecasting(WRF) Single-moment 6-class(WSm6),Thompson,and morrison] and two PBL [the Yonsei University(YSU) and mellor–Yamada Nakanishi Niino(mYNN)] schemes with a convection-permitting resolution(4 km) over northwestern South America(NWSA).Simulations were performed by using the WRF model and the results were evaluated against soundings,rain gauges,and satellite data,considering the spatio-temporal variability of rainfall over diverse regions prone to deep convection in *** and PBL schemes largely influenced simulated rainfall,with better results for the less computationally expensive WSm6 mP and YSU PBL *** rain gauges and satellite estimates,simulations with morrison mP overestimated rainfall,especially westward of the Andes,whereas the mYNN PBL underestimated precipitation in the Amazon–Savannas *** found that the uncertainty in the rainfall representation is highly dependent on the region,with a higher influence of mP in the Colombian Pacific and PBL in the Amazon–Savannas *** analyzing rainfall-related processes,the selection of both mP and PBL parameterizations exerted a large influence on the simulated lower tropospheric moisture flux and moisture *** schemes significantly influenced the downward shortwave radiation,with mYNN simulating a greater amount of low clouds,which decreased the radiation ***,latent heat fluxes were greater for YSU,favoring moist convection and *** schemes had a marked impact on vertical ***,morrison mP showed stronger convection and higher precipitation rates,which is assoc

关键词： sensitivity microphysics planetary boundary layer(PBL) Weather Research and Forecasting(WRF) processes

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Calcium-sensitive protein mLC1 as a possible modulator of the astrocyte functional state

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Neural Regeneration Research 2025年第7期20卷 2008-2010页

作者： Elena Ambrosini angela Lanciotti maria Stefania Brignone Department of Neuroscience Istituto Superiore di SanitàRomeItaly

Astrocytes,the main population of glial cells in the central nervous system(CNS),exert essential tasks for the control of brain tissue homeostasis,supporting neuron and other glial cell activity from the developmental stage to adult *** maintain the optimal functionality of the brain,astroglial cells are particularly committed to reacting to every change in tissue homeostatic conditions,from mild modifications of the physiological environment,a process called astrocyte activation,to the more severe alterations occurring in pathological situations causing astrocyte reactivity or reactive astrogliosis(Escartin et al.,2021).During these reactive states,astrocytes mount an active,progressive response encompassing morphological,molecular,and interactional remodeling,leading to the acquisition of new functions and the loss of others,whose intensity,duration,and reversibility are dependent on the nature of the stimulus and regulated in a context-specific manner.

关键词： alterations modulator maintain

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A Golden Touch in the Design of multifunctional Porphyrin metallacages:Host-Guest Chemistry for Drug-Target Interactions

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CCS Chemistry 2024年第7期6卷 1662-1671页

作者： Tamara Rodríguez-Prieto Darren Wragg Nicole Heiduk mihyun Park Nicole Strittmatter Roland A.Fischer angela Casini Guillermo moreno-Alcántar Chair of medicinal and Bioinorganic Chemistry Department of ChemistrySchool of Natural SciencesTechnical University of Munich85748 Garching b.München Professorship for Analytical Chemistry Department of ChemistrySchool of Natural SciencesTechnical University of Munich85748 Garching b.München Chair of Inorganic and metalOrganic Chemistry Department of ChemistrySchool of Natural SciencesTechnical University of Munich85748 Garching b.München munich Data Science Institute(mDSI) Technical University of Munich85748 Garching b.München

The use of three-dimensional self-assembled metallacages(mCgs)as multimodal drug platforms holds great ***,the synthesis of mCgs with increased complexity and functionality is a great challenge since understanding of the interaction of mCgs with biological targets is still *** this context,this work reports on the integration of a gold(III)porphyrin scaffold into a prismatic mCg structure and explores its application for multimodal therapy of cancer in vitro,namely enabling both photodynamic therapy and *** experimental approaches with a state-of-the-art metadynamics theoretical study,we discovered that the gold cage shows unprecedented host-guest interaction-driven selective stabilization of guanine-quadruplex(G4)structures-validated anticancer drug targets-disclosing a new mechanism to pursue in the design of supramolecular drugs.

关键词： gold metallacages porphyrins G4stabili-zation host-guestchemistry anticanceragents

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Prehospital transdermal glyceryl trinitrate for ultra- acute ischaemic stroke: data from the RIGHT- 2 randomised sham- controlled ambulance trial

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Stroke & Vascular Neurology 2024年第1期9卷 38-49,I0035-I0046页

作者： Jason Philip Appleton Lisa J Woodhouse Craig S Anderson Sandeep Ankolekar Lesley Cala mark Dixon Timothy J England Kailash Krishnan Grant mair Keith W muir John Potter Christopher I Price marc Randall Thompson G Robinson Christine Roffe Else C Sandset Jeffrey L Saver angela Shone Aloysius Niroshan Siriwardena Joanna m Wardlaw Nikola Sprigg Philip m Bath Stroke University Hospitals Birmingham NHS Foundation TrustBirminghamUK Institute of Applied HealthResearch University of Birmingham College of Medical and Dental SciencesBirminghamUK Stroke Trials Unit Mental Health and Clinical NeurosciencesUniversity of NottinghamNottinghamUK Faculty of medicine The George Institute for Global HealthSydneyNew South WalesAustralia The George Institute China at Peking University Health Science Center BeijingChina Neurology Royal Prince Alfred HospitalSydney Health PartnersSydneyNew South WalesAustralia Department of Neurology King's College Hospital NHS Foundation TrustLondonUK Faculty of Health and medical Sciences University of Western AustraliaCrawleyWestern AustraliaAustralia East midlands Ambulance Service NHS Trust NottinghamUK Stroke Queen's Medical CentreNottingham University Hospitals NHS TrustNottinghamUK Centre for Clinical Brain Sciences Dementia Research InstituteUniveristy of EdinburghEdinburghUK Institute of Neurology and Psychology University of GlasgowGlasgowUK Bob Champion Research and Education Building University of East AngliaNorwichUK Institute of Neuroscience Newcastle UniversityNewcastle upon TyneUK Department of Neurology Leeds Teaching Hospitals NHS TrustLeedsUK Department of Cardiovascular Sciences and NIHR Leicester Biomedical Research Centre University of LeicesterLeicesterUK Stroke Research in Stoke Institute for Science and Technology in MedicineKeele UniversityStoke-on TrentUK Department of Neurology Oslo University HospitalOsloNorway Research and Development Norwegian Air Ambulance FoundationOsloNorway Department of Neurology and Comprehensive Stroke Center David Geffen School of MedicineUCLALos AngelesCaliforniaUSA Research and Graduate Services University of NottinghamNottinghamUK Community and Health Research Unit University of LincolnLincolnUK

Background The effect of transdermal glyceryl trinitrate(GTN,a nitrovasodilator)on clinical outcome when administered before hospital admission in suspected stroke patients is ***,we assess the safety and efficacy of GTN in the prespecified subgroup of patients who had an ischaemic stroke within the Rapid Intervention with Glyceryl trinitrate in Hypertensive stroke Trial-2(RIGHT-2).methods RIGHT-2 was an ambulance-based multicentre sham-controlled blinded-endpoint study with patients randomised within 4hours of *** primary outcome was a shift in scores on the modified Rankin scale(mRS)at day *** outcomes included death;a global analysis(Wei-Lachin test)containing Barthel Index,EuroQol-5D,mRS,telephone interview for cognitive status-modified and Zung depression scale;and neuroimaging-determined‘brain frailty’*** were reported as n(%),mean(SD),median[IQR],adjusted common OR(acOR),mean difference or mann-Whitney difference(mWD)with 95%*** 597 of 1149(52%)patients had a final diagnosis of ischaemic stroke;age 75(12)years,premorbid mRS>2107(18%),Glasgow Coma Scale 14(2)and time from onset to randomisation 67[45,108]***‘brain frailty’was common:median score 2[2,3](range 0–3).At day 90,GTN did not influence the primary outcome(acOR for increased disability 1.15,95%CI 0.85 to 1.54),death or global analysis(mWD 0.00,95%CI-0.10 to 0.09).In subgroup analyses,there were non-significant interactions suggesting GTN may be associated with more death and dependency in participants randomised within 1hour of symptom onset and in those with more severe *** In patients who had an ischaemic stroke,ultra-acute administration of transdermal GTN in the ambulance did not improve clinical outcomes in a population with more clinical and radiological frailty than seen in previous in-hospital *** IS ALREADY KNOWN ON THIS TOPIC⇒Transdermal glyceryl trinitrate(GTN)was associat-ed with less death and dependency in those w

关键词： Glasgow nitrate random

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Small is beautiful–a glycolytic metabolite signals mTORC1 activation in cancer cell metabolism

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Signal Transduction and Targeted Therapy 2020年第1期5卷 299-300页

作者： angela m.Otto munich Institute of BioEngineering Technical University of Munich85748 GarchingGermany

Even though the mTOR complex has been known for decades as a nutrient sensor,being thus in focus for drug targeting in metabolic disease and cancer metabolism,it has remained puzzling how it is able to get a sense of glucose availability in ***,a small metabolite of the glycolytic pathway,dihydroxyacetone phosphate,has been identified by Sabatini and his coworkers,who show how mTORC1-activity is regulated in glucose-starved and replenished cancer cells.

关键词： metabolism cancer mTORC1

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Dysfunction of the adhesion G protein-coupled receptor latrophilin 1(ADGRL1/LPHN1)increases the risk of obesity

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Signal Transduction and Targeted Therapy 2024年第5期9卷 2298-2311页

作者： Heba ZabriTorsten Schöneberg AndréNguyen Dietzsch Hadi Al-Hasani Joachim Altschmied Katharina Bottermann Jana Brendler Judith Haendeler Susanne Horn Isabell Kaczmarek Antje Körner Kerstin Krause Kathrin Landgraf Diana Le Duc Laura Lehmann Stefan Lehr Stephanie Pick Albert Ricken Rene Schnorr angela Schulz martina Strnadová Akhil Velluva Heba Zabri Torsten Schöneberg Doreen Thor Simone Prömel Rudolf Schönheimer Institute of Biochemistry Medical FacultyLeipzig UniversityLeipzigGermany Institute for Clinical Biochemistry and Pathobiochemistry Medical FacultyGerman Diabetes CenterLeibniz Center for Diabetes Research at Heinrich Heine University DüsseldorfDüsseldorfGermany German Center for Diabetes Research(DZD e.V.) Munich-NeuherbergGermany Cardiovascular Degeneration Clinical Chemistry and Laboratory DiagnosticsMedical FacultyUniversity Hospital and Heinrich Heine University DüsseldorfDüsseldorfGermany Cardiovascular Research Institute(CARID) Medical FacultyUniversity Hospital and Heinrich Heine University DüsseldorfDüsseldorfGermany Institute of Pharmacology Medical FacultyUniversity Hospital and Heinrich Heine University DüsseldorfDüsseldorfGermany Institute of Anatomy Medical FacultyLeipzig UniversityLeipzigGermany Center for Pediatric Research Hospital for Children and AdolescentsMedical FacultyLeipzig UniversityLeipzigGermany Helmholtz Institute for metabolic Obesity and Vascular Research(HI-MAG)of the Helmholtz Zentrum München at the University of Leipzig and University Hospital LeipzigLeipzigGermany Department of Endocrinology NephrologyRheumatologyLeipzig University Medical CenterLeipzigGermany Institute of Human Genetics Leipzig University Medical CenterLeipzigGermany Institute of Cell Biology Department of BiologyHeinrich Heine University DüsseldorfDüsseldorfGermany School of medicine University of Global Health EquityKigaliRwanda

Obesity is one of the diseases with severe health consequences and rapidly increasing worldwide *** the complex network of food intake and energy balance regulation is an essential prerequisite for pharmacological intervention with obesity.G protein-coupled receptors(GPCRs)are among the main modulators of metabolism and energy ***,for instance,regulate appetite and satiety in certain hypothalamic neurons,as well as glucose and lipid metabolism and hormone secretion from *** in some GPCRs,such as the melanocortin receptor type 4(mC4R),have been associated with early-onset ***,we identified the adhesion GPCR latrophilin 1(ADGRL1/LPHN1)as a member of the regulating network governing food intake and the maintenance of energy *** of the highly conserved receptor in mice results in increased food consumption and severe obesity,accompanied by dysregulation of glucose ***,we identified a partially inactivating mutation in human ADGRL1/LPHN1 in a patient suffering from ***,we propose that LPHN1 dysfunction is a risk factor for obesity development.

关键词： obesity metabolism intake

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mitochondrial transcription factor A （TFAm）： one actor for different roles

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Frontiers in Biology 2012年第1期7卷 30-39页

作者： angela m. S. LEZZA Department of Biochemistry and molecular Biology ＇E. Quagliariello University of Bari Aldo Moro Bari Italy

mitochondrial Transcription Factor A （TFAm） is a nuclear-encoded factor present in mitochondria from allkinds of animals, even with a homologous form in yeast, which has strongly and progressively gained an eminent relevance in the regulation of mitochondrial DNA （mtDNA） functions. This is due to the various functions performed by the protein, which cover a very wide scenario including： replication, transcription, maintenance and eventually repair of mtDNA molecules. In consideration of so many different roles it plays, it can be understood there is a deep interest in its regulation of expression and activity as well as its eventual involvement in pathologies related to a decreased functionality/presence of the mitochondrial genome and the consequences of TFAm induced overexpression.

关键词： TFAm mtDNA transcription replication and maintenance

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Smoking increases the risk of extraintestinal manifestations in Crohn's disease

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World Journal of Gastroenterology 2014年第34期20卷 12269-12276页

作者： Claudia Ott angela Takses Florian Obermeier Elisabeth Schnoy martina müller Department of Internal medicine I University of Regensburg93042 RegensburgGermany

AIm:To demonstrate a high prevalence of extraintestinal manifestations(EIms)in a prospective populationbased cohort of inflammatory bowel disease(IBD)patients at first diagnosis as well as during the early course of the ***:EIms are common in patients with *** on the frequency of EIms have mostly been assessed in patients from tertiary centers;however,data about the prevalence of EIms at first diagnosis as well as factors influencing their incidence during the early course of disease from prospective population-based cohorts are *** present data of patients of our population-based"Oberpfalz cohort"(Bavaria,Germany)from first diagnosis(up to 3 mo after first diagnosis)as well as during the early course of the *** risk factors were assessed by calculating the relative risk(RR)as well as using logistic regression ***:In total,data of 257 newly diagnosed patients with IBD were evaluated[161 Crohn’s disease(CD),96 ulcerative colitis(UC)].median duration of follow-up was 50 mo after first *** 63.4%of all patients(n=163),an EIm was diagnosed at any point during the observation *** first diagnosis,patients with CD had a significantly increased risk of an EIm[n=69(42.9%)]compared with UC patients[n=21(21.9%);Pmoking increased the risk of CD patients developing an EIm during the early course of the disease,but notably not of UC patients(P=0.046;RR=1.96;95%CI:1.01-3.79).In addition,using logistic regression analysis,the need for IBD-related surgery and a young age at first diagnosis were identified as risk factors for the development of an EIm in CD *** association with EIms was found for the factors sex,localization of the disease and positive family history of *** contrast,no key factors which increased the risk of development of an EIm could be identified in UC ***:We found a high prevalence of EIm in this cohort at first diagnosis and during th

关键词： Extraintestinal manifestations Crohn's disease Ulcerative colitis Smoking Surgery Age at onset

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Pancreatic biomarkers:Could they be the answer?

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World Journal of Gastroenterology 2014年第24期20卷 7819-7829页

作者： angela Lamarca Jaime Feliu Department of medical Oncology The Christie NHS Foundation TrustManchester M20 4BXUnited Kingdom Department of medical Oncology La Paz University Hospital28046 MadridSpain

Pancreatic ductal adenocarcinoma(PDA)is known for its poor *** of the patients are diagnosed with advanced stages,when no curative treatment is ***,despite extensive clinical research on PDA,the median overall survival remains *** delay and primary chemo-resistance due to its intrinsic biological nature may explain the challenges to improve our *** knowledge about the molecular biology of PDA has exponentially increased during the last decades and its use for the development of biomarkers could help to reach better results in the clinical *** biomarkers could be the clue for the improvement in PDA clinical research by earlier detection strategies with diagnostic biomarkers,and by an individualization of treatment approach with prognostic and predictive *** review summarizes the current knowledge about the molecular biology of PDA and the status of the most important prognostic and predictive biomarkers.

关键词： Pancreatic adenocarcinoma Biomarkers Diagnosis Prognostic Predictive Treatment

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