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Neurodegenerative diseases:a hotbed for splicing defects and the potential therapies

Translational Neurodegeneration 2021年第2期10卷 195-212页

作者： Dunhui Li Craig Stewart McIntosh Frank Louis Mastaglia Steve Donald Wilton May Thandar Aung-Htut Centre for Molecular Medicine and Innovative Therapeutics Health Futures InstituteMurdoch UniversityPerthWestern AustraliaAustralia Perron Institute for Neurological and Translational Science Centre for Neuromuscular and Neurological DisordersThe University of Western AustraliaPerthWestern AustraliaAustralia

Precursor messenger RNA(pre-mRNA)splicing is a fundamental step in eukaryotic gene expression that systematically removes non-coding regions(introns)and ligates coding regions(exons)into a continuous message(mature mRNA).This process is highly regulated and can be highly flexible through a process known as alternative splicing,which allows for several transcripts to arise from a single gene,thereby greatly increasing genetic plasticity and the diversity of proteome.Alternative splicing is particularly prevalent in neuronal cells,where the splicing patterns are continuously changing to maintain cellular homeostasis and promote neurogenesis,migration and synaptic function.The continuous changes in splicing patterns and a high demand on many cis-and trans-splicing factors contribute to the susceptibility of neuronal tissues to splicing defects.The resultant neurodegenerative diseases are a large group of disorders defined by a gradual loss of neurons and a progressive impairment in neuronal function.Several of the most common neurodegenerative diseases involve some form of splicing defect(s),such as Alzheimer’s disease,Parkinson’s disease and spinal muscular atrophy.Our growing understanding of RNA splicing has led to the explosion of research in the field of splice-switching antisense oligonucleotide therapeutics.Here we review our current understanding of the effects alternative splicing has on neuronal differentiation,neuronal migration,synaptic maturation and regulation,as well as the impact on neurodegenerative diseases.We will also review the current landscape of splice-switching antisense oligonucleotides as a therapeutic strategy for a number of common neurodegenerative disorders.

关键词： Neurodegenerative diseases Parkinson’s disease Alzheimer’s disease Alternative splicing Splicing defects Antisense oligonucleotides Splice-switching Disease-modifying treatment

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The role of sequestosome 1/p62 protein in amyotrophic lateral sclerosis and frontotemporal dementia pathogenesis

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Neural Regeneration Research 2020年第12期15卷 2186-2194页

作者： Adriana Delice Foster Sarah Lyn Rea Harry Perkins Institute of Medical Research University of Western Australia Perron Institute for Neurological and Translational Science Centre for Neuromuscular and Neurological DisordersThe University of Western AustraliaNedlandsWestern AustraliaAustralia Centre for Molecular Medicine and Innovative Therapeutics Murdoch University Murdoch Western Australia Australia

Amyotrophic lateral sclerosis and frontotemporal lobar degeneration are multifaceted diseases with genotypic,pathological and clinical overlap.One such overlap is the presence of SQSTM1/p62 mutations.While traditionally mutations manifesting in the ubiquitin-associated domain of p62 were associated with Paget’s disease of bone,mutations affecting all functional domains of p62 have now been identified in amyotrophic lateral sclerosis and frontotemporal lobar degeneration patients.p62 is a multifunctional protein that facilitates protein degradation through autophagy and the ubiquitin-proteasome system,and also regulates cell survival via the Nrf2 antioxidant response pathway,the nuclear factor-kappa B signaling pathway and apoptosis.Dysfunction in these signaling and protein degradation pathways have been observed in amyotrophic lateral sclerosis and frontotemporal lobar degeneration,and mutations that affect the role of p62 in these pathways may contribute to disease pathogenesis.In this review we discuss the role of p62 in these pathways,the effects of p62 mutations and the effect of mutations in the p62 modulator TANK-binding kinase 1,in relation to amyotrophic lateral sclerosis-frontotemporal lobar degeneration pathogenesis.

关键词： aggregate/inclusion body formation amyotrophic lateral sclerosis-frontotemporal lobar degeneration autophagy cell signaling mitophagy p62/SQSTM1 protein degradation

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New perspectives on cytoskeletal dysregulation and mitochondrial mislocalization in amyotrophic lateral sclerosis

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Translational Neurodegeneration 2021年第4期10卷 595-610页

作者： Frances Theunissen Phillip K.West Samuel Brennan Bojan Petrovic Kosar Hooshmand P.Anthony Akkari Matt Keon Boris Guennewig Perron Institute for Neurological and Translational Science NedlandsWAAustralia Centre for Molecular Medicine and Innovative Therapeutics Murdoch UniversityMurdochWAAustralia GenieUs Genomics Pty Ltd SydneyNSWAustralia Brain and Mind centre and Central Clinical School Faculty of Medicine and Healththe University of SydneyamperdownNSWAustralia Division of Neurology Duke University Medical CentreDuke UniversityDurhamNCUSA

Amyotrophic lateral sclerosis(ALS)is a progressive neurodegenerative disease characterized by selective,early degeneration of motor neurons in the brain and spinal cord.Motor neurons have long axonal projections,which rely on the integrity of neuronal cytoskeleton and mitochondria to regulate energy requirements for maintaining axonal stability,anterograde and retrograde transport,and signaling between neurons.The formation of protein aggregates which contain cytoskeletal proteins,and mitochondrial dysfunction both have devastating effects on the function of neurons and are shared pathological features across several neurodegenerative conditions,including ALS,Alzheimer's disease,Parkinson's disease,Huntington's disease and Charcot-Marie-Tooth disease.Furthermore,it is becoming increasingly clear that cytoskeletal integrity and mitochondrial function are intricately linked.Therefore,dysregulations of the cytoskeletal network and mitochondrial homeostasis and localization,may be common pathways in the initial steps of neurodegeneration.Here we review and discuss known contributors,including variants in genetic loci and aberrant protein activities,which modify cytoskeletal integrity,axonal transport and mitochondrial localization in ALS and have overlapping features with other neurodegenerative diseases.Additionally,we explore some emerging pathways that may contribute to this disruption in ALS.

关键词： Cytoskeleton Neurofilament Mitochondria Amyotrophic lateral sclerosis Neurodegeneration Axonal transport Gut microbiome

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Self-Healing MXene-and Graphene-Based Composites:Properties and Applications

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Nano-Micro Letters 2023年第7期15卷 165-192页

作者： Atefeh Zarepour Sepideh Ahmadi Navid Rabiee Ali Zarrabi Siavash Iravani Department of Biomedical Engineering Faculty of Engineering and Natural SciencesIstinye University34396 IstanbulTürkiye Department of Medical Biotechnology School of Advanced Technologies in MedicineShahid Beheshti University of Medical SciencesTehran 19857-17443Iran Cellular and molecular Biology Research Center Shahid Beheshti University of Medical SciencesTehran 19857-17443Iran Centre for Molecular Medicine and Innovative Therapeutics Murdoch UniversityPerthWA 6150Australia School of Engineering Macquarie UniversitySydneyNSW 2109Australia Faculty of Pharmacy and Pharmaceutical Sciences Isfahan University of Medical SciencesEsfahān 81746-73461Iran

Today,self-healing graphene-and MXene-based composites have attracted researchers due to the increase in durability as well as the cost reduction in long-time applications.Different studies have focused on designing novel self-healing graphene-and MXenebased composites with enhanced sensitivity,stretchability,and flexibility as well as improved electrical conductivity,healing efficacy,mechanical properties,and energy conversion efficacy.These composites with self-healing properties can be employed in the field of wearable sensors,supercapacitors,anticorrosive coatings,electromagnetic interference shielding,electronic-skin,soft robotics,etc.However,it appears that more explorations are still needed to achieve composites with excellent arbitrary shape adaptability,suitable adhesiveness,ideal durability,high stretchability,immediate self-healing responsibility,and outstanding electromagnetic features.Besides,optimizing reaction/synthesis conditions and finding suitable strategies for functionalization/modification are crucial aspects that should be comprehensively investigated.MXenes and graphene exhibited superior electrochemical properties with abundant surface terminations and great surface area,which are important to evolve biomedical and sensing applications.However,flexibility and stretchability are important criteria that need to be improved for their future applications.Herein,the most recent advancements pertaining to the applications and properties of self-healing graphene-and MXene-based composites are deliberated,focusing on crucial challenges and future perspectives.

关键词： MXenes Graphene Self-healing materials Electromagnetic interference shielding Wearable sensors

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Localization and role of metabotropic glutamate receptors subtype 5 in the gastrointestinal tract

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World Journal of Gastroenterology 2017年第25期23卷 4500-4507页

作者： Andrea Ferrigno Clarissa Berardo Laura G Di Pasqua Veronica Siciliano Plinio Richelmi Mariapia Vairetti Department of Internal medicine and therapeutics (Cellular and molecular Pharmacology and Toxicology) University of Pavia

Metabotropic glutamate receptor subtype 5(mGluR5) is a Group I mGlu subfamily of receptors coupled to the inositol trisphosphate/diacylglycerol pathway. Like other m Glu R subtypes, mGluR5 s contain a phylogenetically conserved, extracellular orthosteric binding site and a more variable allosteric binding site, located on the heptahelical transmembrane domain. The mGluR5 receptor has proved to be a key pharmacological target in conditions affecting the central nervous system(CNS) but its presence outside the CNS underscores its potential role in pathologies affecting peripheral organs such as the gastrointestinal(GI) tract and accessory digestive organs such as the tongue, liver and pancreas. Following identification of mGluR5s in the mouth, various studies have subsequently demonstrated its involvement in mechanical allodynia, inflammation, pain and oral cancer. mGluR5 expression has also been identified in gastroesophageal vagal pathways. Indeed, experimental and human studies have demonstrated that mGluR5 blockade reduces transient lower sphincter relaxation and reflux episodes. In the intestine, mGluR5s have been shown to be involved in the control of intestinal inflammation, visceral pain and the epithelial barrier function. In the liver, mGluR5s have a permissive role in the onset of ischemic injury in rat and mice hepatocytes. Conversely, livers from mice treated with selective negative allosteric modulators and mGluR5 knockout mice are protected against ischemic injury. Similar results have been observed in experimental models of free-radical injury and in vivo mouse models of acetaminophen intoxication. Finally, mGluR5s in the pancreas are associated with insulin secretion control. The picture is, however, far from complete as the review attempts to establish in particular as regards identifying specific targets and innovative therapeutic approaches for the treatment of GI disorders.

关键词： Metabotropic glutamate 受体子类型 5 食管肠肝胰

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Humanized mice are susceptible to Salmonella typhi infection

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Cellular & molecular Immunology 2011年第1期8卷 83-87页

作者： M Firoz Mian Elisabeth A Pek Meghan J Chenoweth Ali A Ashkar Institute for Infectious Disease Research Centre for Gene TherapeuticsDepartment of Pathology and Molecular MedicineMcMaster UniversityHamiltonOntarioCanada

Salmonella enterica serovar Typhi is a pathogen that only infects humans.Currently,there is no animal model for studying this pathogen.Recently,alymphoid RAG2^(-/-)/γc^(-/-) mice engrafted with human leukocytes,known as humanized mice,have been successfully utilized to develop experimental models for several human-specific viral infections,including HIV,human-like dengue fever and hepatitis C virus.Little is known about the usefulness and feasibility of the humanized mouse model for the study of human-specific bacterial pathogens,such as S.typhi.The aim of this study was to determine if Salmonella enterica serovar Typhi could establish productive infection in humanized mice.Here we report that intravenous inoculation of S.typhi into humanized mice,but not controls,established S.typhi infections.High bacterial loads were found in the liver,spleen,blood and bone marrow of mice reconstituted with human leukocytes,but not in the unreconstituted control mice.Importantly,S.typhi-infected humanized mice lost significant body weight,and some of the infected mice displayed neurological symptoms.Our data suggest,for the first time,that humanized mice are susceptible to S.typhi challenge and that this model can be utilized to study the pathogenesis of S.typhito develop novel therapeutic strategies.

关键词： animal model humanized mice RAG2-/-γc-/- Salmonella typhi

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Exploring behavioral traits over different contexts in four species of Australian funnel-web spiders

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Current Zoology 2023年第6期69卷 766-774页

作者： Linda Hernandez Duran David Thomas Wilson Tasmin Lee Rymer College of Science and Engineering James Cook UniversityP.O.Box 6811CairnsQLD 4870Australia centre for Tropical Environmental and Sustainability Sciences James Cook UniversityCairnsQLD 4870Australia centre for molecular therapeutics Austr alian Institute for Tropical Health and MedicineJames Cook UniversityCairnsQLD 4878Australia

Australian funnel-web spiders are arguably the most venomous spiders in the world,with much research focusing on this aspect of their biology.However,other aspects related to their life history,ecology and behaviour have been overlooked.For the first time,we assessed repeatability.namely risk-taking behaviour,aggressiveness and activity in the contexts of predation,conspecific tolerance and exploration of a new territory in four species of Australian funnel-web spiders:two are closely related,Hadronyche valida and H.infensa,and two have overlapping distributions but occupy different habitats,H.cerberea and Atrax robustus.We also compared behaviors between species.At the species level,we found that H.valida showed consistency in risk-taking behavior when exposed to a predator stimulus,aggressiveness against conspecifics,and exploration of a new territory.In contrast,in the other species,only A.robustus showed repeatability in the context of exploration of a new territory.These results suggest that some behavioral traits are likely more flexible than others,and that the repeatability of behaviors may be species-specific in funnel-webs.When we compared species,we found differences in risk-taking behavior and defensiveness.This study provides novel insights to understanding variation in behavioral traits within and between species of funnel-web spiders,suggesting that some behavioral traits are likely context and/or species dependent,as a result of their evolutionary history.These findings provide key insights for understanding the ecological role of behavior and venom deployment in venomous animals,and a greater understanding of behavior in these medically significant and iconic spiders thatareof conservation concern.

关键词： arachnids behavior ecological contexts flexibility mygalomorphae repeatability

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Bioengineered materials with selective antimicrobial toxicity in biomedicine

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Military Medical Research 2023年第6期10卷 798-817页

作者： Pooyan Makvandi Hao Song Cynthia K.Y.Yiu Rossella Sartorius Ehsan Nazarzadeh Zare Navid Rabiee Wei-Xi Wu Ana Cláudia Paiva-Santos Xiang-Dong Wang Cheng-Zhong Yu Franklin R.Tay The Quzhou Affiliated Hospital of Wenzhou Medical University Quzhou People’s HospitalQuzhou 324000ZhejiangChina Istituto Italiano di Tecnologia Centre for Materials InterfacesPontedera 56025Italy Australian Institute for Bioengineering and Nanotechnology The University of QueenslandBrisbaneQLD 4072Australia Paediatric Dentistry and Orthodontics Faculty of DentistryThe University of Hong KongPrince Philip Dental HospitalHong Kong SARChina Institute of Biochemistry and Cell Biology(IBBC) National Research Council(CNR)80131 NaplesItaly School of Chemistry Damghan UniversityDamghan 36716‑45667Iran School of Engineering Macquarie UniversitySydneyNSW 2109Australia Centre for Molecular Medicine and Innovative Therapeutics Murdoch UniversityPerthWA 6150Australia Department of Pharmaceutical Technology Faculty of Pharmacy of the University of CoimbraUniversity of Coimbra3000‑548 CoimbraPortugal REQUIMTE/LAQV Group of Pharmaceutical TechnologyFaculty of Pharmacy of the University of CoimbraUniversity of Coimbra3000‑548 CoimbraPortugal Department of Pulmonary and Critical Care medicine Zhongshan HospitalFudan University Shanghai Medical CollegeShanghai 200032China School of Chemistry and molecular Engineering East China Normal UniversityShanghai 200241China The Graduate School Augusta UniversityAugustaGA 30912USA

Fungi and bacteria afflict humans with innumerous pathogen-related infections and ailments.Most of the commonly employed microbicidal agents target commensal and pathogenic microorganisms without discrimination.To distinguish and fight the pathogenic species out of the microflora,novel antimicrobials have been developed that selectively target specific bacteria and fungi.The cell wall features and antimicrobial mechanisms that these microorganisms involved in are highlighted in the present review.This is followed by reviewing the design of antimicrobials that selectively combat a specific community of microbes including Gram-positive and Gram-negative bacterial strains as well as fungi.Finally,recent advances in the antimicrobial immunomodulation strategy that enables treating microorganism infections with high specificity are reviewed.These basic tenets will enable the avid reader to design novel approaches and compounds for antibacterial and antifungal applications.

关键词： Antimicrobial nanotechnology Immumodualtion Selective toxicity Smart nanomaterials Targeting microorganism

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Effect of different intensities of physical activity on cardiometabolic markers and vascular and cardiac function in adult rats fed with a high-fat high-carbohydrate diet

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Journal of Sport and Health Science 2018年第1期7卷 109-119页

作者： Romeo B.Batacan Jr Mitch J.Duncan Vincent J.Dalbo Geraldine L.Buitrago Andrew S.Fenning School of Medical and Applied Sciences Central Queensland University centre for Physical Activity Studies Central Queensland University School of medicine & Public Health Priority Research Centre for Physical Activity and Nutrition Faculty of Health and MedicineThe University of Newcastle University Drive Clinical Biochemistry Laboratory Central Queensland University centre for Biodiscovery and molecular Development of therapeutics Australian Institute of Tropical Health and MedicineJames Cook University

Background: Physical activity(PA) and diet are 2 lifestyle factors that affect cardiometabolic risk. However, data on how a high-fat highcarbohydrate(HFHC) diet influences the effect of different intensities of PA on cardiometabolic health and cardiovascular function in a controlled setting are yet to be fully established. This study investigated the effect of sedentary behavior, light-intensity training(LIT), and high-intensity interval training(HIIT) on cardiometabolic markers and vascular and cardiac function in HFHC-fed adult rats.Methods: Twelve-week-old Wistar rats were randomly allocated to 4 groups(12 rats/group): control(CTL), sedentary(SED), LIT, and HIIT.Biometric indices, glucose and lipid control, inflammatory and oxidative stress markers, vascular reactivity, and cardiac electrophysiology of the experimental groups were examined after 12 weeks of HFHC-diet feeding and PA interventions.Results: The SED group had slower cardiac conduction(p = 0.0426) and greater thoracic aortic contractile responses(p < 0.05) compared with the CTL group. The LIT group showed improved cardiac conduction compared with the SED group(p = 0.0003), and the HIIT group showed decreased mesenteric artery contractile responses compared with all other groups and improved endothelium-dependent mesenteric artery relaxation compared with the LIT group(both p < 0.05). The LIT and HIIT groups had lower visceral(p = 0.0057 for LIT, p = 0.0120 for HIIT)and epididymal fat(p < 0.0001 for LIT, p = 0.0002 for HIIT) compared with the CTL group.Conclusion: LIT induced positive adaptations on fat accumulation and cardiac conduction, and HIIT induced a positive effect on fat accumulation,mesenteric artery contraction, and endothelium-dependent relaxation. No other differences were observed between groups. These findings suggest that few positive health effects can be achieved through LIT and HIIT when consuming a chronic and sustained HFHC diet.

关键词：高脂肪心脏老鼠食谱脉管标记成年物理

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Improved Specificity for Breast Cancer Screening Using an Oncogenic(miRNA-21)and a Gene Suppressor(miRNA-195)miRNA in the Serum for a Point of Care(POC)Screening Solution

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Biomedical and Environmental Sciences 2023年第6期36卷 549-552页

作者： Krishnamoorthy Kokilavani Ancy Terryna Chanayiltharayil John Bindu Salim Madhulika Vijayakumar Sankar Ganesh Jeyaraj PSG Institute of Advanced Studies Avinashi RoadPeelameduCoimbatore641004 PSG Institute of Medical Science and Research Avinashi Road PeelameduCoimbatore641004 PSG Center for molecular medicine and therapeutics PSG Institute of Medical Sciences and ResearchCoimbatoreTamil Nadu641004India PSG centre for Genetics and molecular Biology Off Avinashi RoadPeelameduCoimbatoreTamil Nadu641004India

The overall incidence and burden caused by breast cancer is increasing,affecting the global socio-economic development and life expectancy[1].According to“WHO Global Breast Cancer Initiative(GBCI)reports”,if the mortality rate due to breast cancer can be reduced by 2.4%annually,we may prevent 2.5 million breast cancer deaths between2020-2040.

关键词： Breast Cancer Serum

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