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Site-directed deuteration of dronedarone preserves cytochrome P4502J2 activity and mitigates its cardiac adverse effects in canine arrhythmic hearts

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Acta Pharmaceutica Sinica B 2022年第10期12卷 3905-3923页

作者： Aneesh V.Karkhanis Gopalakrishnan Venkatesan Ryuichi Kambayashi Jacqueline Wen Hui Leow Marcus Qingrui Han Hiroko Izumi-Nakaseko Ai Goto Jeremy Kah Sheng Pang Boon Seng Soh Pipin Kojodjojo Atsushi Sugiyama Eric Chun Yong Chan Department of Pharmacy Faculty of ScienceNational University of SingaporeSingapore 117543Singapore Department of Pharmacology Faculty of MedicineToho UniversityTokyo 143-8540Japan Institute of Molecular and Cell Biology Agency for ScienceTechnology and ResearchSingapore 138673Singapore Department of Biological Sciences Faculty of ScienceNational University of SingaporeSingapore 117558Singapore Department of Medicine Yong Loo Lin School of MedicineNational University of SingaporeSingapore 119228Singapore

Cytochrome P4502J2(CYP2J2)metabolizes arachidonic acid(AA)to cardioprotective epoxyeicosatrienoic acids(EETs).Dronedarone,an antiarrhythmic drug prescribed for treatment of atrial fibrillation(AF)induces cardiac adverse effects(AEs)with poorly understood mechanisms.We previously demonstrated that dronedarone inactivates CYP2J2 potently and irreversibly,disrupts AA-EET pathway leading to cardiac mitochondrial toxicity rescuable via EET enrichment.In this study,we investigated if mitigation of CYP2J2 inhibition prevents dronedarone-induced cardiac AEs.We first synthesized a deuterated analogue of dronedarone(termed poyendarone)and demonstrated that it neither inactivates CYP2J2,disrupts AA-EETs metabolism nor causes cardiac mitochondrial toxicity in vitro.Our patch-clamp experiments demonstrated that pharmacoelectrophysiology of dronedarone is unaffected by deuteration.Next,we show that dronedarone treatment or CYP2J2 knockdown in spontaneously beating cardiomyocytes indicative of depleted CYP2J2 activity exacerbates beat-to-beat(BTB)variability reflective of proarrhythmic phenotype.In contrast,poyendarone treatment yields significantly lower BTB variability compared to dronedarone in cardiomyocytes indicative of preserved CYP2J2 activity.Importantly,poyendarone and dronedarone display similar antiarrhythmic properties in the canine model of persistent AF,while poyendarone substantially reduces beat-to-beat variability of repolarization duration suggestive of diminished proarrhythmic risk.Our findings prove that deuteration of dronedarone prevents CYP2J2 inactivation and mitigates dronedarone-induced cardiac AEs.

关键词： Arachidonic acid Atrial fibrillation CYP2J2 Drug-induced proarrhythmia Epoxyeicosatrienoic acids Mechanism-based inactivation Dronedarone

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Behavior,toxicity and diffusive flux of metals in a sediment core and pore-water from Anzali wetland

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Acta Geochimica 2023年第2期42卷 309-331页

作者： Y.Mehdizadeh A.R.Karbassi T.Nasrabadi A.Sarang Graduate faculty of Environment University of TehranP.O.Box 14155-6135TehranIran

Concentrations of metals along with pH,potential redox(Eh),total dissolved solid(TDS),electrical conductivity(EC)and salinity were measured for sediments of different layers,pore and surface water in the Anzali wetland.Also,the diffusive flux of metals was calculated ad compared with the values in other aquatic bodies.The abundance of metals in sediments was Al>Fe>Ca>Ti>Mn>Zn>V>Cr>Ni>Cu>Pb>Co>As>Mo>Ag>Cd,while the pore-water results indicated a different concentration profile:Ca>Mn>Fe>Al>V>Mo>As>Ni>Cu>Co.Anzali wetland is classified within a high ecological risk.Pore-water toxicity test showed it is in non-polluted condition.Eh–pH diagrams showed that all species of elements are in a stable state in surface and pore-waters.However,Mn and Co(in some layers)are in soluble form and free ions and thus are bioavailable to the organisms.V and As are also present in the form of hydrogen compounds and Ni in the form of hydroxides,therefore,they are toxic to aquatic animals due to their solubility and ionic forms.Diffusive fluxes for As,Al,Fe,Ca,Cu,Mn,Mo,Ni and V are 0.43,1.80,48.52,43,147.50,0.12,1.47,0.15,1.28,0.21μg/m^(2)/day,respectively.Cluster analysis showed that in a solid phase of sediments,elements such as Cr,As and Ti are of petroleum and terrestrial origin.In pore-waters,Cu is of petroleum and biological origin,and Mo,As,Cu and Co are controlled by p H.

关键词： Aquatic Environment Pollution Aerobic Geochemistry Elements

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Lowering fasting blood glucose with non-dialyzable material of cranberry extract is dependent on host genetic background,sex and diet

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Animal Models and Experimental Medicine 2023年第3期6卷 196-210页

作者： Fatima Amer-Sarsour Rana Tarabeih Itzhak Ofek Fuad A.Iraqi Department of Clinical Microbiology and Immunology Sackler Faculty of MedicineTel-Aviv UniversityTel-AvivIsrael

Background:Type 2 diabetes(T2D)is a polygenic metabolic disease,character-ized by high fasting blood glucose(FBG).The ability of cranberry(CRN)fruit to regulate glycemia in T2D patients is well known.Here,a cohort of 13 lines of the genetically diverse Collaborative Cross(CC)mouse model was assessed for the effect of non-dialyzable material(NDM)of cranberry extract in lowering fasting blood glucose.Methods:Eight-week-old mice were maintained on either a standard chow diet(con-trol group)or a high-fat diet(HFD)for 12 weeks,followed by injections of intraperi-toneal(IP)NDM(50 mg/kg)per mouse,three times a week for the next 6 weeks.Absolute FBG(mg/dl)was measured bi-weekly and percentage changes in FBG(%FBG)between weeks 0 and 12 were calculated.Results:Statistical analysis showed a significant decrease in FBG between weeks 0 and 12 in male and female mice maintained on CHD.However,a non-significant in-crease in FBG values was observed in male and female mice maintained on HFD dur-ing the same period.Following administration of NDM during the following 6 weeks,the results show a variation in significant levels of FBG lowering between lines,male and female mice and under the different diets.Conclusion:The results suggest that the efficacy of NDM treatment in lowering FGB depends on host genetic background(pharmacogenetics),sex of the mouse(phar-macosex),and diet(pharmacodiet).All these results support the need for follow-up research to better understand and implement a personalized medicine approach/uti-lization of NDM for reducing FBG.

关键词： chow diet(CHD) collaborative cross(CC)mouse model fasting blood glucose(FBG) high-fat diet(HFD) non-dialyzable material(NDM)of cranberry extract type 2 diabetes(T2D)

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Ligand-free monophasic CuPd alloys endow boosted reaction kinetics toward energy-efficient hydrogen fuel production paired with hydrazine oxidation

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Journal of Materials Science & Technology 2023年第12期143卷 20-29页

作者： Yujeong Jeong Shreyanka Shankar Naik Yiseul Yu Jayaraman Theerthagiri Seung Jun Lee Pau Loke Show Hyun Chul Choi Myong Yong Choi Department of Chemistry(BK21 FOUR) Research Institute of Natural SciencesGyeongsang National UniversityJinju 52828Republic of Korea core-Facility Center for Photochemistry&Nanomaterials Gyeongsang National UniversityJinju 52828Republic of Korea Zhejiang Provincial Key Laboratory for Subtropical Water Environment and Marine Biological Resources Protection Wenzhou UniversityWenzhou 325035China Department of Chemical and Environmental Engineering Faculty of Science and EngineeringUniversity of Nottingham MalaysiaJalan Broga43500 SemenyihSelangor Darul EhsanMalaysia Department of Chemistry Chonnam National UniversityGwangju 61186Republic of Korea

Optimizing the structure and components is a prevalent strategy for increasing electrocatalytic energy-saving H 2 fuel production.One of the sustainable and efficient techniques is electrocatalytic water split-ting for H 2 generation,but it is still restricted by the kinetically sluggish OER.Due to the lower standard oxidation potential of−0.33 V,replacing the OER with anodic hydrazine oxidation reaction(HzOR)is an effective way to extensively reduce the use of electricity in water electrolysis.Through alloying,the semiconductor and adsorption characteristics of Cu,interlaced by Pd 2+solution on the Pd surface by pulsed laser ablation(PLA)in methanol,are selectively altered to maximize cathodic HER and anodic HzOR performance.The optimal Cu1Pd3/C ratio demonstrates outstanding HER performance with a low overpotential of 0.315 V at 10 mA cm^(−2),as well as an ultralow overpotential of 0.560 V for HzOR in 0.5 M N_(2) H_(4)/1.0 M KOH.Furthermore,the constructed HzOR-assisted electrolyzer cell with Cu1Pd3/C||Cu1Pd3/C as anode and cathode exhibits a cell voltage of 0.505 V at 10 mA cm^(−2) with exceptional en-durance over 5 h.The current study advances competent CuPd alloys as multifunctional electrocatalysts for H 2 fuel production using a HzOR-assisted energy-efficient electrolyzer.

关键词： PLA CuPd alloy Sonochemical process HzOR Hydrazine evolution reaction Hydrazine splitting Water splitting

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Physical exercises for preventing injuries among adult male football players:A systematic review

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Journal of Sport and Health Science 2022年第1期11卷 115-122页

作者： Jorge Pérez-Gómez JoséCarmelo Adsuar Pedro EAlcaraz Jorge Carlos-Vivas Health EconomyMotricity and Education(HEME)Research GroupFaculty of Sports SciencesUniversity of ExtremaduraCaceres 10003Spain UCAM Research Center for High Performance Sport Catholic University of MurciaMurcia 30107Spain faculty of Sport Sciences Catholic University of MurciaMurcia 30107Spain

Background:Football is the most practised sport in the world and is associated with the risk of injuries in the players.Some studies have been published that identify injury prevention programs,but there is no review of the full body of evidence on injury prevention programs for use by football coaches.The aim of this article was to carry out a systematic review of published studies on injury prevention programs for adult male footballers,identify points of common understanding and establish recommendations that should be considered in the design of injury prevention strategies.Methods:PubMed and EMBASE databases were used to identify relevant published articles using the following keywords:"soccer"AND"injury"AND"prevention".Results:A total of 2512 studies were identified initially,but only 11 studies met the inclusion criteria,and their outcomes are presented.Results revealed that injury prevention programs in football have focused on strength training,proprioceptive training,multicomponent programs(balance,core stability,and functional strength and mobility),and warm-up programs.Conclusion:Based on results from the studies analyzed,football players can lower the incidence of match and training injuries by participating in dynamic warm-up programs that include preventive exercises before games or during training sessions,and by adding strength,balance,and mobility training to the training sessions.

关键词： Balance core stability Injury prevention programs Soccer Warm-up

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Towards system genetics analysis of head and neck squamous cell carcinoma using the mouse model,cellular platform,and clinical human data

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Animal Models and Experimental Medicine 2023年第6期6卷 537-558页

作者： Osayd Zohud Iqbal M.Lone Aysar Nashef Fuad A.Iraqi Department of Clinical Microbiology and Immunology Sackler Faculty of MedicineTel-Aviv UniversityTel AvivIsrael Department of Oral and Maxillofacial Surgery Baruch Padeh Medical CenterPoriyaIsrael Azrieli faculty of Medicine Bar-Ilan UniversityRamat GanIsrael

Head and neck squamous cell cancer(HNSCC)is a leading global malignancy.Every year,More than 830000 people are diagnosed with HNSCC globally,with more than 430000 fatalities.HNSCC is a deadly diverse malignancy with many tumor locations and biological characteristics.It originates from the squamous epithelium of the oral cavity,oropharynx,nasopharynx,larynx,and hypopharynx.The most frequently impacted regions are the tongue and larynx.Previous investigations have demonstrated the critical role of host genetic susceptibility in the progression of HNSCC.Despite the advances in our knowledge,the improved survival rate of HNSCC patients over the last 40 years has been limited.Failure to identify the molecular origins of development of HNSCC and the genetic basis of the disease and its biological heterogeneity impedes the development of new therapeutic methods.These results indicate a need to identify more genetic factors underlying this complex disease,which can be better used in early detection and prevention strategies.The lack of reliable animal models to investigate the underlying molecular processes is one of the most significant barriers to understanding HNSCC tumors.In this report,we explore and discuss potential research prospects utilizing the Collaborative Cross mouse model and crossing it to mice carrying single or double knockout genes(e.g.Smad 4 and P53 genes)to identify genetic factors affecting the development of this complex disease using genome-wide association studies,epigenetics,micro RNA,long noncoding RNA,lnc RNA,histone modifications,methylation,phosphorylation,and proteomics.

关键词： animal models Collaborative Cross mice genomics head and neck squamous cell cancinoma host genetic susceptibility

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Factors affecting populations of the endemic Iberian hare(Lepus granatensis)after the first myxomatosis outbreaks in Central Spain

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Integrative Zoology 2023年第6期18卷 981-993页

作者： Carlos LÁZARO JoséLuis GUZMÁN Fabián CASAS Carlos SÁNCHEZ-GARCÍA Department of Research Fundación ArtemisanCiudad RealSpain Department of Zoology Faculty of SciencesUniversity of GranadaGranadaSpain

The Iberian hare(Lepus granatensis)is an endemic species distributed in Spain and Portugal.Myxomatosis outbreaks affecting this species were detected in 2018 in Central and Southern Spain,spreading afterward.Aiming to evaluate factors affecting the status of hare population after the arrival of myxomatosis,we conducted 108 nocturnal hare counts in Central Spain during two study periods(winter/spring and summer/autumn)in 54 different hunting grounds,covering 1071 km and observing 884 individuals.The mean density in winter/spring was 7.66 hares/100 ha,(range 6.14-9.54/100 ha),while in summer/autumn,it was 3.4 hares/100 ha(range 2.6-4.4/100 ha).Densities of hares were not affected by the dominant habitat and the presence/absence of myxomatosis outbreaks.Hares were more abundant at hunting grounds at a higher altitude and in those conducting targeted management,while detection of myxomatosis was related to lower altitude and higher levels of game management.A MaxEnt model used to generate a risk map for myxomatosis occurrence showed that the temperature annual range was the most important predictor,which suggests that environmental factors affecting myxomatosis vectors(mosquitoes,fleas,and ticks)could play a key role in disease transmission.As myxomatosis in hares is becoming endemic,hare densities may be improved by game management and the monitoring and surveillance of this emerging disease.These surveillance programs could be the basis of effective collaborations between hunters,researchers,and environmental managers.

关键词： game management habitat Iberian hare MaxEnt monitoring myxomatosis

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Hepatitis B and circadian rhythm of the liver

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World Journal of Gastroenterology 2022年第27期28卷 3282-3296页

作者： Ivana Skrlec Jasminka Talapko Department of Biophysics Biologyand ChemistryFaculty of Dental Medicine and HealthJ.J.Strossmayer University of OsijekOsijek 31000Croatia Department of Anatomy Histology EmbryologyPathology Anatomy and Pathology HistologyFaculty of Dental Medicine and HealthOsijek 31000Croatia

The circadian rhythm in humans is determined by the central clock located in the hypothalamus’s suprachiasmatic nucleus,and it synchronizes the peripheral clocks in other tissues.Circadian clock genes and clock-controlled genes exist in almost all cell types.They have an essential role in many physiological processes,including lipid metabolism in the liver,regulation of the immune system,and the severity of infections.In addition,circadian rhythm genes can stimulate the immune response of host cells to virus infection.Hepatitis B virus(HBV)infection is the leading cause of liver disease and liver cancer globally.HBV infection depends on the host cell,and hepatocyte circadian rhythm genes are associated with HBV replication,survival,and spread.The core circadian rhythm proteins,REV-ERB and brain and muscle ARNTL-like protein 1,have a crucial role in HBV replication in hepatocytes.In addition to influencing the virus’s life cycle,the circadian rhythm also affects the pharmacokinetics and efficacy of antiviral vaccines.Therefore,it is vital to apply antiviral therapy at the appropriate time of day to reduce toxicity and improve the effectiveness of antiviral treatment.For these reasons,understanding the role of the circadian rhythm in the regulation of HBV infection and host responses to the virus provides us with a new perspective of the interplay of the circadian rhythm and anti-HBV therapy.Therefore,this review emphasizes the importance of the circadian rhythm in HBV infection and the optimization of antiviral treatment based on the circadian rhythm-dependent immune response.

关键词： Circadian rhythm Clock genes Hepatitis B virus Immune system Liver

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Heparin/Growth Factors‑Immobilized Aligned Electrospun Nanofibers Promote Nerve Regeneration in Polycaprolactone/Gelatin‑Based Nerve Guidance Conduits

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Advanced Fiber Materials 2023年第2期5卷 554-573页

作者： Yasuhiro Ikegami Muhammad Shafiq Shinichi Aishima Hiroyuki Ijima Department of Chemical Engineering Faculty of EngineeringGraduate SchoolKyushu University744 MotookaNishi‑KuFukuoka 819‑0395Japan Department of Biotechnology Faculty of Science and TechnologyUniversity of Central Punjab(UCP)Lahore 54000Pakistan Department of Pathology and Microbiology Faculty of MedicineSaga UniversityNabeshima 5‑1‑1Saga 849‑8501Japan

Injuries to the nervous system account for the widespread morbidity,mortality,and discomfort worldwide.Artificial nerve guidance conduits(NGCs)offer a promising platform for nerve reconstruction,however,they require extracellular matrix(ECM)-like features to better mimic the in vivo microenvironment.Consequently,this research was aimed to fabricate heparin/growth factors(GFs)-immobilized artificial NGCs.Heparin was covalently immobilized onto aligned electrospun polycapro-lactone/gelatin(PCL/Gel)nanofibers.Thereafter,basic fibroblast growth factor(bFGF)and nerve growth factor(NGF)were preferentially immobilized on heparinized nanofibers;the immobilization efficiency of GFs was found to be 50%with respect to(w.r.t.)their initial loaded amounts.The in vivo implantation of NGCs in a sciatic nerve defect model revealed the successful retention(~10%w.r.t the initial loaded amount)and bioactivity of NGF for up to 5 days.The permeability of bovine serum albumin(BSA)from nanofibrous membranes was further assessed and found to be comparable with the commercialized cel-lulose acetate membranes.The bioactivity of NGCs was assessed in a sciatic nerve defect model in rats for short-term(1 week)and long-term(1-month).The NGCs displayed good structural stability and biocompatibility in vivo.The in vivo evaluation revealed the accumulation of host cells into the transplanted NGCs.Taken together;these heparin/GFs-immobilized artificial NGCs may have broad implications for nerve regeneration and related tissue engineering disciplines.

关键词： Heparin Growth factor-immobilized scaffolds Aligned nanofibers core/shell nanofibers Nerve tissue engineering Scaffolds Co-axial electrospinning

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The host-targeting compound peruvoside has a broad-spectrum antiviral activity against positive-sense RNA viruses

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Acta Pharmaceutica Sinica B 2023年第5期13卷 2039-2055页

作者： Kan Xing Wu Thinesshwary Yogarajah Marcus Wing Choy Loe Parveen Kaur Regina Ching Hua Lee Chee Keng Mok Yi Hao Wong Patchara Phuektes Li Sze Yeo Vincent T.K.Chow Yong Wah Tan Justin Jang Hann Chu Department of Microbiology and Immunology Yong Loo Lin School of MedicineNational University Health SystemNational University of SingaporeSingapore 117597Singapore Department of Pathobiology Faculty of Veterinary MedicineKhonkaen UniversityKhonkaen 40002Thailand Infectious Disease Programme Yong Loo Lin School of MedicineNational University of SingaporeSingapore 117597Singapore Institute of Molecular and Cell Biology Agency for ScienceTechnology and Research(A∗STAR)Singapore 138648Singapore Lee Kong Chian School of Medicine Nanyang Technological UniversitySingapore 308232Singapore NUSMed Biosafety Level 3 core Facility Yong Loo Lin School of MedicineNational University of SingaporeSingapore 117599Singapore

Positive-sense RNA viruses modify intracellular calcium stores,endoplasmic reticulum and Golgi apparatus(Golgi)to generate membranous replication organelles known as viral factories.Viral factories provide a conducive and substantial enclave for essential virus replication via concentrating necessary cellular factors and viral proteins in proximity.Here,we identified the vital role of a broadspectrum antiviral,peruvoside in limiting the formation of viral factories.Mechanistically,we revealed the pleiotropic cellular effect of Src and PLC kinase signaling via cyclin-dependent kinase 1 signaling leads to Golgi-specific brefeldin A-resistance guanine nucleotide exchange factor 1(GBF1)phosphorylation and Golgi vesiculation by peruvoside treatment.The ramification of GBF1 phosphorylation fosters GBF1 deprivation consequentially activating downstream antiviral signaling by dampening viral factories formation.Further investigation showed signaling of ERK1/2 pathway via cyclin-dependent kinase 1 activation leading to GBF1 phosphorylation at Threonine 1337(T1337).We also showed 100%of protection in peruvoside-treated mouse model with a significant reduction in viral titre and without measurable cytotoxicity in serum.These findings highlight the importance of dissecting the broad-spectrum antiviral therapeutics mechanism and pave the way for consideration of peruvoside,host-directed antivirals for positive-sense RNA virus-mediated disease,in the interim where no vaccine is available.

关键词： Positive-sense RNA viruses Peruvoside Antiviral CDKI signaling Viral factories Calcium efflux Broad-spectrum Golgi apparatus

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