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Role of dipeptidyl peptidase 4 inhibitors in the new era of antidiabetic treatment

World Journal of Diabetes 2022年第2期13卷 85-96页

作者： Matilda Florentin michael s kostapanos Athanasia K Papazafiropoulou Department of Internal Medicine School of MedicineUniversity of IoanninaIoannina 45221Greece Lipid Clinic Department of General MedicineCambridge University Hospitals NHS Foundation TrustAddenbrooke's HospitalCambridge CB20QQUnited Kingdom 1st Department of Internal Medicine and Diabetes Center Tzaneio General Hospital of PiraeusAthens 18536Greece

The last few years important changes have occurred in the field of diabetes *** priority in the therapy of patients with diabetes is not glycemic control per se rather an overall management of risk factors,while individualization of glycemic target is ***,regulatory authorities now require evidence of cardiovascular(CV)safety in order to approve new antidiabetic *** most novel drug classes,i.e.,sodium-glucose transporter 2 inhibitors(sGLT2-i)and some glucagon-like peptide-1 receptor agonists(GLP-1 RA),have been demonstrated to reduce major adverse CV events and,thus,have a prominent position in the therapeutic algorithm of *** this context,the role of previously used hypoglycemic agents,including dipeptidyl peptidase 4(DPP-4)inhibitors,has been ***-4 inhibitors have a favorable safety profile,do not cause hypoglycemia or weight gain and do not require dose ***,they can be administered in patients with chronic kidney disease after dose modification and elderly patients with ***,though,they have been undermined to a third line therapeutic choice as they have not been shown to reduce CV events as is the case with sGLT2-i and GLP-1 ***,DPP-4 inhibitors appear to have a place in the management of patients with diabetes as a safe class of oral glucose lowering agents with great experience in their use.

关键词： Cardiovascular safety Dipeptidyl peptidase 4 inhibitors Glucose lowering Hypoglycemia Therapeutic algorithm Weight gain

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Is there a role of lipid-lowering therapies in the management of fatty liver disease?

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World Journal of Hepatology 2022年第1期14卷 119-139页

作者： Ismini Tzanaki Aris P Agouridis michael s kostapanos school of Medicine European University CyprusNicosiaCyprusNicosia 2404Cyprus school of Medicine European University CyprusNicosia 2404Cyprus General Medicine Addenbrooke's HospitalCambridge University HospitalsCambridge CB20QQUnited Kingdom

Atherogenic dyslipidemia is characterized by increased triglyceride-rich lipoproteins and low high-density lipoprotein cholesterol *** is highly prevalent in non-alcoholic fatty liver disease(NAFLD)and contributes to the increased cardiovascular risk associated with this *** insulin resistance it plays an important pathogenetic role in NAFLD/non-alcoholic steatohepatitis(NAsH)development and *** has been shown that cholesterol-lowering reduces cardiovascular risk more in NAFLD vs non-NAFLD high-risk *** evidence highlights the importance of effective lipid modulation in *** this narrative review the effects of the most commonly used lipid-lowering therapies on liver outcomes alongside their therapeutic implications in NAFLD/NAsH are critically *** and clinical evidence suggests that statins reduce hepatic steatosis,inflammation and fibrosis in patients with NAFLD/*** data are derived from observational and small prospective clinical studies using changes in liver enzyme activities,steatosis/fibrosis scores,and imaging evidence of steatosis as ***,relevant histologic benefits were noted in small biopsy *** and rosuvastatin showed greater benefits,whereas data for other statins are scarce and sometimes *** studies to those of statins showed efficacy of ezetimibe against hepatic ***,no significant anti-inflammatory and anti-fibrotic actions of ezetimibe have been *** studies showed that fibrates through peroxisome proliferator-activated receptor(PPAR)αactivation may have a role in NAFLD prevention and ***,no relevant benefits have been noted in human ***-related differences in PPARαexpression and its activation responsiveness may help explain this ***-3 fatty acids reduced hepatic steatosis in numerous heterogeneous studies,but their benefits on hepatic inflammation and

关键词： Non-alcoholic fatty liver Non-alcoholic steatohepatitis statin Ezetimibe Fibrates ω-3 fatty acids Bile acid resins

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sleep-based neuronal oscillations as a physiological biomarker for Alzheimer's disease:is night time the right time?

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Neural Regeneration Research 2024年第7期19卷 1417-1418页

作者： Jonathan Witton Erica s.Brady michael T.Craig Department of Clinical and Biomedical sciences Faculty of Health and Life SciencesUniversity of ExeterExeterEnglandUK Gladstone Institute for Neurological Disease San FranciscoCAUSA school of Psychology and Neuroscience College of MedicalVeterinary and Life SciencesUniversity of GlasgowGlasgowScotlandUK

Dementia is a devastating syndrome characterized by memory problems,confusion,and behavior changes that prevent people from performing everyday *** is the leading cause of dependency and disability amongst older people,resulting in a global economic cost of ~$1.3 *** 58 million people are currently afflicted by dementia worldwide,with Alzheimer s disease(AD) causing most(60-70%) of these cases.

关键词： Alzheimer everyday performing

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High density lipoproteins and type 2 diabetes:Emerging concepts in their relationship

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World Journal of Experimental Medicine 2014年第1期4卷 1-6页

作者： michael s kostapanos Moses s Elisaf Department of Internal Medicine School of Medicine University of Ioannina45110 IoanninaGreece

Patients with type 2 diabetes mellitus(T2DM) frequently exhibit macrovascular complications of atherosclerotic cardiovascular(CV) disease. High density lipoproteins(HDL) are protective against atherosclerosis. Low levels of HDL cholesterol(HDL-C) independently contribute to CV risk. Patients with T2 DM not only exhibit low HDL-C, but also dysfunctional HDL. Furthermore, low concentration of HDL may increase the risk for the development of T2 DM through a decreased β cell survival and secretory function. In this paper, we discuss emerging concepts in the relationship of T2 DM with HDL.

关键词： Type 2 diabetes High density lipoproteins Insulin secretion βcells Paraoxonase-1

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Emerging structures and dynamic mechanisms ofγ-secretase for Alzheimer’s disease

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Neural Regeneration Research 2025年第1期20卷 174-180页

作者： Yinglong Miao michael s.Wolfe Computational Medicine Program and Department of Pharmacology University of North Carolina–Chapel HillChapel HillNCUSA Department of Medicinal Chemistry University of KansasLawrenceKSUSA

γ-secretase,called“the proteasome of the membrane,”is a membrane-embedded protease complex that cleaves 150+peptide substrates with central roles in biology and medicine,including amyloid precursor protein and the Notch family of cell-surface *** inγ-secretase and amyloid precursor protein lead to early-onset familial Alzheimer’s disease.γ-secretase has thus served as a critical drug target for treating familial Alzheimer’s disease and the more common late-onset Alzheimer’s disease as ***,critical gaps remain in understanding the mechanisms of processive proteolysis of substrates,the effects of familial Alzheimer’s disease mutations,and allosteric modulation of substrate cleavage byγ-*** this review,we focus on recent studies of structural dynamic mechanisms ofγ-*** mechanisms,including the“Fit-stay-Trim,”“sliding-Unwinding,”and“Tilting-Unwinding,”have been proposed for substrate proteolysis of amyloid precursor protein byγ-secretase based on all-atom molecular dynamics *** an incorrect registry of the Notch1 substrate was identified in the cryo-electron microscopy structure of Notch1-boundγ-secretase,molecular dynamics simulations on a resolved model of Notch1-boundγ-secretase that was reconstructed using the amyloid precursor protein-boundγ-secretase as a template successfully capturedγ-secretase activation for proper cleavages of both wildtype and mutant Notch,being consistent with biochemical experimental *** approach could be potentially applied to decipher the processing mechanisms of various substrates byγ-*** addition,controversy over the effects of familial Alzheimer’s disease mutations,particularly the issue of whether they stabilize or destabilizeγ-secretase-substrate complexes,is ***,an outlook is provided for future studies ofγ-secretase,including pathways of substrate binding and product release,effects of modulators on familial Alzheimer’s disease mutations

关键词： Alzheimer’s disease amyloid precursor protein cryo-EM structures drug design intramembrane proteolysis molecular dynamics Notch

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Rationale,design and baseline patient characteristics of the optimal type 2 diabetes management including benchmarking and standard treatment study in Greece

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World Journal of Diabetes 2014年第1期5卷 76-83页

作者： michael s kostapanos Vasilis Tsimihodimos Moses s Elisaf Emmanouil Tzouvelekis Nikos Nikas Department of Internal Medicine School of MedicineUniversity of Ioannina Medical Department

AIM:To describe baseline data of the optimal type2 diabetes management including benchmarking and standard treatment(OPTIMIsE)study in ***:"Benchmarking"is the process of receiving feedback comparing one’s performance with that of *** OPTIMIsE(NCT00681850)study is a multinational,multicenter study assessing,at a primary care level,whether using"benchmarking"can help to improve the quality of patient care,compared with a set of guideline-based reference values("non-benchmarking").In the Greek region,797 outpatients(457men,mean age 63.8 years)with type 2 diabetes were enrolled by 84 office-based *** characteristics of this population are ***:Hypertension was the most prevalent concomitant disorder(77.3%)and coronary heart disease was the most frequent macrovascular complication of diabetes(23.8%).Most patients were overweight or obese(body mass index 29.6±5 kg/m2),exhibiting mostly abdominal obesity(waist circumference102.6±13.6 cm).Biguanides were the most prevalent prescribed drugs for the management of diabetes(70.1%of all prescriptions),whereas statins(93.5%of all prescriptions)and angiotensin receptor blockers(55.8%of all prescriptions)were the most prevalent prescribed drugs for hyperlipidemia and hypertension,*** 37.4%of patients were on *** treatment,pre-defined targets for fasting plasma glucose(systolic blood pressure(s with proteinuria)and low density lipoprotein cholesterol levels(s with coronary heart disease)were reached in a relatively small proportion of patients(29%,53%,27%and 31%,respectively).In a Greek population with type 2 diabetes,the control of glycemia or concomitant disorders which increase cardiovascular risk remains ***:Despite relevant treatment,there is a poor control of diabetes,hypertension and hyperlipidemia in Greek outpatients with type 2 diabetes

关键词： Diabetes Benchmarking Treatment tar-get Glycemic control Dyslipidemia Blood pressure

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Current role of fenofibrate in the prevention and management of non-alcoholic fatty liver disease

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World Journal of Hepatology 2013年第9期5卷 470-478页

作者： michael s kostapanos Anastazia Kei Moses s Elisaf Department of Internal Medicine School of MedicineUniversity of Ioannina45110 IoanninaGreece

Non-alcoholic fatty liver disease(NAFLD) is a common health problem with a high mortality burden due to its liver- and vascular-specific complications. It is associated with obesity, high-fat diet as well as with type 2 diabetes mellitus(T2DM) and metabolic syndrome(Mets).Impaired hepatic fatty acid(FA) turnover together with insulin resistance are key players in NAFLD pathogenesis. Peroxisome proliferator-activated receptors(PPARs)are involved in lipid and glucose metabolic *** novel concept is that the activation of the PPARαsubunit may protect from liver steatosis. Fenofibrate, by activating PPARα, effectively improves the atherogenic lipid profile associated with T2DM and Mets. Experimental evidence suggested various protective effects of the drug against liver steatosis. Namely, fenofibraterelated PPARα activation may enhance the expression of genes promoting hepatic FA β-oxidation. Furthermore, fenofibrate reduces hepatic insulin resistance. It also inhibits the expression of inflammatory mediators involved in non-alcoholic steatohepatitis *** include tumor necrosis factor-α, intercellular cell adhesion molecule-1, vascular cell adhesion molecule-1and monocyte chemoattractant protein-1. Consequently, fenofibrate can limit hepatic macrophage infiltration. Other liver-protective effects include decreased oxidative stress and improved liver microvasculature function. Experimental studies showed that fenofibrate can limit liver steatosis associated with high-fat diet,T2DM and obesity-related insulin resistance. Few studies showed that these benefits are also relevant even in the clinical setting. However, these have certain limitations. Namely, these were uncontrolled, their sample size was small, fenofibrate was used as a part of multifactorial approach, while histological data were *** this context, there is a need for large prospective studies, including proper control groups and full assessment of liver histology.

关键词： Fenofibrate Non-alcoholic fatty liver disease steatohepatitis Peroxisome proliferator-activated receptors

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Application of a simplified ADM1 for full-scale anaerobic co-digestion of cattle slurry and grass silage:assessment of input variability

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Frontiers of Environmental science & Engineering 2024年第4期18卷 125-139页

作者： sofia Tisocco sören Weinrich Gary Lyons michael Wills Xinmin Zhan Paul Crosson Civil Engineering College of Science and EngineeringUniversity of GalwayGalwayH91 TK33Ireland Teagasc Animal and Bioscience Research Department Animal and Grassland Research and Innovation CentreDunsanyC15 PW93Ireland Biochemical Conversion Department Deutsches Biomasseforschungszentrum gemeinnützige GmbHLeipzig 04347Germany Faculty of Energy·Building services·Environmental Engineering Münster University of Applied SciencesSteinfurt 48565Germany Agri-Food and Biosciences Institute HillsboroughBT266DRUK Ryan Institute University of GalwayGalwayH91 TK33Ireland MaREI Research Centre for Energy Climate and MarineRyan InstituteUniversity of GalwayGalwayH91 TK33Ireland

Mathematical modeling of anaerobic digestion is a powerful tool to predict gas yields and optimize the *** Anaerobic Digestion Model No.1(ADM1)is a widely implemented model for this ***,modeling full-scale biogas plants is challenging due to the extensive substrate and parameter characterization *** study describes the modification of the ADM1 through a simplification of individual process phases,characteristic components and required ***,the ability of the simplified model to simulate the co-digestion of grass silage and cattle slurry was evaluated using data from a full-scale biogas *** impacts of substrate composition(crude carbohydrate,protein and lipid concentration)and variability of carbohydrate degradability on simulation results were assessed to identify the most influential *** indicated that the simplified version was able to depict biogas and biomethane production with average model efficiencies,according to the Nash-sutcliffe efficiency(NsE)coefficient,of 0.70 and 0.67,respectively,and was comparable to the original ADM1(average model efficiencies of 0.71 and 0.63,respectively).The variability of crude carbohydrate,protein and lipid concentration did not significantly impact biogas and biomethane output for the data sets *** contrast,carbohydrate degradability seemed to explain much more of the variability in the biogas and methane ***,the application of simplified models provides a reliable basis for the process simulation and optimization of full-scale agricultural biogas plants.

关键词： ADM1 Agricultural feedstocks Biogas technology Input variability Parameter estimation

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A review of control strategies used for morphing aircraft applications

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Chinese Journal of Aeronautics 2024年第4期37卷 436-463页

作者： Muhammed s.PARANCHEERIVILAKKATHIL Jafar s.PILAKKADAN Rafic M.AJAJ Mohammadreza AMOOZGAR Davood AsADI Yahya ZWEIRI michael I.FRIsWELL Department of Aerospace Engineering Khalifa University of Science and TechnologyAbu DhabiUnited Arab Emirates Department of Aerospace Engineering Advanced Research and Innovation Center(ARIC)Khalifa University of Science and TechnologyAbu DhabiUnited Arab Emirates Department of Mechanical Materials&Manufacturing EngineeringUniversity of NottinghamNottingham NG72RDUK Department of Aerospace Engineering Adana Alparslan Turkes Science and Technology UniversityTurkey College of Engineering Swansea UniversitySwansea SA18ENUK

This paper reviews the various control algorithms and strategies used for fixed-wing morphing aircraft applications. It is evident from the literature that the development of control algorithms for morphing aircraft technologies focused on three main areas. The first area is related to precise control of the shape of morphing concepts for various flight conditions. The second area is mainly related to the flight dynamics, stability, and control aspects of morphing aircraft. The third area deals mainly with aeroelastic control using morphing concepts either for load alleviation purposes and/or to control the instability boundaries. The design of controllers for morphing aircraft/wings is very challenging due to the large changes that can occur in the structural, aerodynamic, and inertial characteristics. In addition, the type of actuation system and actuation rate/speed can have a significant effect on the design of such controllers. The aerospace community is in strong need of such a critical review especially as morphing aircraft technologies move from fundamental research at a low Technology Readiness Level(TRL) to real-life applications. This critical review aims to identify research gaps and propose future directions. In this paper, research activities/papers are categorized according to the control strategy used. This ranges from simple Proportional Integral Derivative(PID) controllers at one end to complex robust adaptive controllers and deep learning algorithms at the other end. This includes analytical, computational, and experimental studies. In addition, the various dynamic models used and their fidelities are highlighted and discussed.

关键词： Control strategies Morphing aircraft shape morphing Flight dynamics Aeroelasticity

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The energetics of cellular life transitions

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Life Metabolism 2024年第3期3卷 12-20页

作者： Anna s.Monzel michael Levin Martin Picard Department of Psychiatry Division of Behavioral MedicineCollege of Physicians and SurgeonsColumbia University Irving Medical CenterNew YorkNY 10032United States Department of Biology Tufts UniversityMedfordMA 02155United States Allen Discovery Center at Tufts University MedfordMA 02155United States Wyss Institute for Biologically Inspired Engineering Harvard UniversityBostonMA 02115United States Department of Neurology H.Houston Merritt CenterColumbia Translational Neuroscience InitiativeCollege of Physicians and SurgeonsColumbia University Irving Medical CenterNew YorkNY 10032United States New York state Psychiatric Institute New YorkNY 10032United States Robert N Butler Columbia Aging Center Columbia University Mailman School of Public HealthNew YorkNY 10032United States

Major life transitions are always difficult because change costs *** findings have demonstrated how mitochondrial oxidative phosphorylation(OxPhos)defects increase the energetic cost of living and that excessive integrated stress response(IsR)signaling may prevent cellular identity transitions during *** this perspective,we discuss general bioenergetic principles of life transitions and the costly molecular processes involved in reprograming the cellular hardware/software as cells shift *** energetic cost of cellular differentiation has not been directly quantified,representing a gap in *** propose that the IsR is an energetic checkpoint evolved to(i)prevent OxPhos-deficient cells from engaging in excessively costly transitions and(ii)allow IsR-positive cells to recruit systemic energetic resources by signaling via GDF15 and the brain.

关键词： energy mitochondria signaling pathway growth differentiation factor 15 energy balance development

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