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Dysregulation of RNA modification systems in clinical populations with neurocognitive disorders

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Neural Regeneration Research 2024年第6期19卷 1256-1261页

作者： Helen M.Knight Merve Demirbugen ?z Adriana PerezGrovas-Saltijeral Division of Cells Organisms and Molecular Genetics School of Life Sciences University of Notingham department of Pharmaceutical Toxicology Faculty of Pharmacy Ankara University

The study of modified RNA known as epitranscriptomics has become increasingly relevant in our understanding of disease-modifying mechanisms. Methylation of N6 adenosine(m6A) and C5 cytosine(m5C) bases occur on mRNAs, tRNA, mt-tRNA, and rRNA species as well as non-coding RNAs. With emerging knowledge of RNA binding proteins that act as writer, reader, and eraser effector proteins, comes a new understanding of physiological processes controlled by these systems. Such processes when spatiotemporally disrupted within cellular nanodomains in highly specialized tissues such as the brain, give rise to different forms of disease. In this review, we discuss accumulating evidence that changes in the m6A and m5C methylation systems contribute to neurocognitive disorders. Early studies first identified mutations within FMR1 to cause intellectual disability Fragile X syndromes several years before FMR1 was identified as an m6A RNA reader protein. Subsequently, familial mutations within the m6A writer gene METTL5, m5C writer genes NSUN2, NSUN3, NSUN5, and NSUN6, as well as THOC2 and THOC6 that form a protein complex with the m5C reader protein ALYREF, were recognized to cause intellectual development disorders. Similarly, differences in expression of the m5C writer and reader effector proteins, NSUN6, NSUN7, and ALYREF in brain tissue are indicated in individuals with Alzheimer’s disease, individuals with a high neuropathological load or have suffered traumatic brain injury. Likewise, an abundance of m6A reader and anti-reader proteins are reported to change across brain regions in Lewy bodies diseases, Alzheimer’s disease, and individuals with high cognitive reserve. m6A-modified RNAs are also reported significantly more abundant in dementia with Lewy bodies brain tissue but significantly reduced in Parkinson’s disease tissue, whilst modified RNAs are misplaced within diseased cells, particularly where synapses are located. In parahippocampal brain tissue, m6A modification is enriched in transcripts associated with psychiatri

关键词： 5-methylcytosine methylation Alzheimer's disease cognitive diseases epitranscriptomics intellectual disability Lewy body diseases N6 adenosine RNA modification

Role of renin-angiotensin system/angiotensin converting enzyme-2 mechanism and enhanced COVID-19 susceptibility in type 2 diabetes mellitus

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World Journal of Diabetes 2024年第4期15卷 606-622页

作者： Ashwin Kumar Shukla Komal Awasthi Kauser Usman Monisha Banerjee molecular and Human genetics Laboratory Department of ZoologyUniversity of LucknowLucknow 226007Uttar PradeshIndia department of Medicine King Georges’Medical UniversityLucknow 226003Uttar PradeshIndia Institute of Advanced molecular genetics and Infectious Diseases(IAMGID)University of LucknowLucknow 226007Uttar PradeshIndia

Coronavirus disease 2019(COVID-19)is a disease that caused a global pandemic and is caused by infection of severe acute respiratory syndrome coronavirus 2 virus.It has affected over 768 million people worldwide,resulting in approx-imately 6900000 deaths.High-risk groups,identified by the Centers for Disease Control and Prevention,include individuals with conditions like type 2 diabetes mellitus(T2DM),obesity,chronic lung disease,serious heart conditions,and chronic kidney disease.Research indicates that those with T2DM face a hei-ghtened susceptibility to COVID-19 and increased mortality compared to non-diabetic individuals.Examining the renin-angiotensin system(RAS),a vital regulator of blood pressure and pulmonary stability,reveals the significance of the angiotensin-converting enzyme(ACE)and ACE2 enzymes.ACE converts angiotensin-I to the vasoconstrictor angiotensin-II,while ACE2 counters this by converting angiotensin-II to angiotensin 1-7,a vasodilator.Reduced ACE2 exp-ression,common in diabetes,intensifies RAS activity,contributing to conditions like inflammation and fibrosis.Although ACE inhibitors and angiotensin receptor blockers can be therapeutically beneficial by increasing ACE2 levels,concerns arise regarding the potential elevation of ACE2 receptors on cell membranes,potentially facilitating COVID-19 entry.This review explored the role of the RAS/ACE2 mechanism in amplifying severe acute respiratory syndrome cor-onavirus 2 infection and associated complications in T2DM.Potential treatment strategies,including recombinant human ACE2 therapy,broad-spectrum antiviral drugs,and epigenetic signature detection,are discussed as promising avenues in the battle against this pandemic.

关键词： Angiotensin-converting enzyme 2 Angiotensin-converting enzyme inhibitors Angiotensin-II receptor blockers Complex diseases COVID-19 Type 2 diabetes

Drosophila X virus-like particles as delivery carriers for improved oral insecticidal efficacy of scorpion Androctonus australis peptide against the invasive fruit fly,Drosophila suzukii

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Insect Science 2024年第3期31卷 847-858页

作者： Qi Xue Luc Swevers Clauvis Nji Tizi Taning Faculty of Bioscience Engineering Department of Plants and CropsGhent UniversityGhentBelgium Insect molecular genetics and Biotechnology Institute of Biosciences and ApplicationsNational Centre for Scientific Research"Demokritos"AthensGreece

Insect-specific neurotoxic peptides derived from the venoms of scorpions and spiders can cause acute paralysis and death when injected into insects,offering a promising insecticidal component for insect pest control.However,effective delivery systems are required to help neurotoxic peptides pass through the gut barrier into the hemolymph,where they can act.Here,we investigated the potential of a novel nanocarrier,Drosophila X virus-like particle(DXV-VLP),for delivering a neurotoxin from the scorpion Androctonus australis Hector(AaIT)against the invasive pest fruit fly,Drosophila suzuki.Our results show that the fusion proteins of DXV polyproteins with AalT peptide at their Ctermini could be sufficiently produced in Lepidoptera Hi5 cells in a soluble form using the recombinant baculovirus expression system,and could self-assemble into VLPs with similar particle morphology and size to authentic DXV virions.In addition,the AalT peptides displayed on DXV-VLPs retained their toxicity,as demonstrated in injection bioassays that resulted in severe mortality(72%)in adults after 72 h.When fed to adults,mild mortality was observed in the group treated with DXV-AalT(38%),while no mortality occurred in the group treated with AaIT peptide,thus indicating the significant role of DXV-VLPs in delivering AalT peptides.Overall,this proof-of-concept study demonstrates for the first time that VLPs can be exploited to enhance oral delivery of insect-specific neurotoxic peptides in the context of pest control.Moreover,it provides insights for further improvements and potentially the development of neurotoxin-based bioinsecticides and/or transgenic crops for insect pest control.

关键词： AalT Drosophila suzuki nanocarrier neurotoxic peptides pest control virus-like particle(VLP)

Mathematical Modeling of Cell Polarity Establishment of Budding Yeast

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Communications on Applied Mathematics and Computation 2024年第1期6卷 218-235页

作者： Yue Liu Jun Xie Hay-Oak Park Wing-Cheong Lo department of Mathematics City University of Hong KongTat Chee AvenueKowloonHong KongChina department of molecular genetics The Ohio State UniversityColumbusOHUSA

The budding yeast Saccharomyces cerevisiae is a powerful model system for studying the cell polarity establishment.The cell polarization process is regulated by signaling molecules,which are initially distributed in the cytoplasm and then recruited to a proper location on the cell membrane in response to spatial cues or spontaneously.Polarization of these signaling molecules involves complex regulation,so the mathematical models become a useful tool to investigate the mechanism behind the process.In this review,we discuss how mathematical modeling has shed light on different regulations in the cell polarization.We also propose future applications for the mathematical modeling of cell polarization and morphogenesis.

关键词： Budding yeast Cdc42 Morphogenesis Septin Mathematical models

Therapeutic potential and pharmacological mechanism of visnagin

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Journal of Integrative Medicine 2024年第4期22卷 399-412页

作者： Poonam Yadav Sumeet Kumar Singh Sayantap Datta Saloni Verma Aarti Verma Arnab Rakshit Anjana Bali Jasvinder Singh Bhatti Amit Khurana Umashanker Navik department of Pharmacology School of Health SciencesCentral University of Punjab department of Pharmacological and Pharmaceutical Sciences College of PharmacyUniversity of Houston department of Human genetics and molecular Medicine School of Health SciencesCentral University of Punjab

Visnagin is a furanochromone and one of the most important compound in the Ammi visnaga (L.) Lam (a synonym of Visnaga daucoides Gaertn.) plant,which is used to cure various ailments.Many investigations into the bioactive properties of visnagin have been studied to date.The literature on visnagin demonstrates its biological properties,including anti-inflammatory,anti-diabetic,and beneficial effects in cardiovascular and renal diseases.Moreover,visnagin improves sperm quality parameters,stimulates steroidogenesis,and increases serum gonadotropins and testosterone levels,while decreasing proinflammatory cytokines,oxidative damage,genomic instability,and it modulates apoptosis.Thus,visnagin has emerged as an exciting lead for further research,owing to its potential in various unmet clinical needs.The current review summarized its basic structure,pharmacokinetics,and pharmacological effects,focusing on its mechanisms of action.The review will help to understand the potential of visnagin as an alternative treatment strategy for several diseases and provide insight into research topics that need further exploration for visnagin’s safe clinical use.

关键词： Ammi visnaga L. Anti-inflammatory Cancer Phytochemical Visnaga daucoides Gaertn Visnagin

Apoer2/Lrp8:the undercover cop of synaptic homeostasis

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Neural Regeneration Research 2024年第12期19卷 2563-2564页

作者： Gordon C.Werthmann Joachim Herz department of molecular genetics and Center for Translational Neurodegeneration Research University of Texas Southwestern Medical Center at DallasDallasTXUSA department of Neuroscience department of Neurology University of Texas Southwestern Medical Center at Dallas DallasTXUSA

Apolipoprotein E receptor 2(ApoER2)is a receptor for the protein ApoE,the most common genetic risk factor for late-onset Alzheimer's disease(AD).It is also a key modulator of syna ptic homeostasis,in part through its effect on the expression of neuronal genes including those implicated in AD and other neuropsychiatric disorders.In this perspective,we highlight several genes affected by ApoER2 and its alternatively spliced forms and how aberrant expression can be rescued by the reintroduction of the ApoER2 intracellular domain in the mouse hippocampus.

关键词： homeostasis ApoE Alzheimer

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Photo-activated microtubule targeting drugs: Advancing therapies for colorectal cancer

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World Journal of Gastroenterology 2024年第26期30卷 3257-3260页

作者： Naresh Singh Samantha Sharma department of Medical and molecular genetics Indiana University School of MedicineIndianapolisIN 46202United States

Over the years immunotherapy has demonstrably improved the field of cancer treatment.However,achieving long-term survival for colorectal cancer(CRC)patients remains a significant unmet need.Combination immunotherapies incor-porating targeted drugs like MEK or multi-kinase inhibitors have offered some palliative benefit.Nevertheless,substantial gaps remain in the current therapeutic armamentarium for CRC.In recent years,there has been a surge of interest in exploring novel treatment strategies,including the application of light-activated drugs in conjunction with optical devices.This approach holds promise for achie-ving localized and targeted delivery of cytotoxic agents,such as microtubule-targeting drugs,directly to cancerous cells within the colon.

Gut microbiota-dependent phenylacetylglutamine in cardiovascular disease:current knowledge and new insights

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Frontiers of Medicine 2024年第1期18卷 31-45页

作者： Yaonan Song Haoran Wei Zhitong Zhou Huiqing Wang Weijian Hang Junfang Wu Dao Wen Wang Division of Cardiology Department of Internal MedicineTongji HospitalTongji Medical CollegeHuazhong University of Science and TechnologyWuhan430030China Hubei Key Laboratory of genetics and molecular Mechanisms of Cardiological Disorders Wuhan430030China

Phenylacetylglutamine(PAGln)is an amino acid derivate that comes from the amino acid phenylalanine.There are increasing studies showing that the level of PAGln is associated with the risk of different cardiovascular diseases.In this review,we discussed the metabolic pathway of PAGln production and the quantitative measurement methods of PAGln.We summarized the epidemiological evidence to show the role of PAGln in diagnostic and prognostic value in several cardiovascular diseases,such as heart failure,coronary heart disease/atherosclerosis,and cardiac arrhythmia.The underlying mechanism of PAGln is now considered to be related to the thrombotic potential of platelets via adrenergic receptors.Besides,other possible mechanisms such as inflammatory response and oxidative stress could also be induced by PAGln.Moreover,since PAGln is produced across different organs including the intestine,liver,and kidney,the cross-talk among multiple organs focused on the function of this uremic toxic metabolite.Finally,the prognostic value of PAGln compared to the classical biomarker was discussed and we also highlighted important gaps in knowledge and areas requiring future investigation of PAGln in cardiovascular diseases.

关键词： PAGln cardiovascular disease gut microbiota uremic metabolite biomarker

lncRNA ZNF593-AS inhibits cardiac hypertrophy and myocardial remodeling by upregulating Mfn2 expression

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Frontiers of Medicine 2024年第3期18卷 484-498页

作者： Xiang Nie Jiahui Fan Yanwen Wang Rong Xie Chen Chen Huaping Li Dao Wen Wang Division of Cardiology Department of Internal MedicineTongji HospitalTongji Medical CollegeHuazhong University of Science and TechnologyWuhan430030China Hubei Key Laboratory of genetics and molecular Mechanisms of Cardiological Disorders Wuhan430030China

lncRNA ZNF593 antisense(ZNF593-AS)transcripts have been implicated in heart failure through the regulation of myocardial contractility.The decreased transcriptional activity of ZNF593-AS has also been detected in cardiac hypertrophy.However,the function of ZNF593-AS in cardiac hypertrophy remains unclear.Herein,we report that the expression of ZNF593-AS reduced in a mouse model of left ventricular hypertrophy and cardiomyocytes in response to treatment with the hypertrophic agonist phenylephrine(PE).In vivo,ZNF593-AS aggravated pressure overload–induced cardiac hypertrophy in knockout mice.By contrast,cardiomyocyte-specific transgenic mice(ZNF593-AS MHC-Tg)exhibited attenuated TAC-induced cardiac hypertrophy.In vitro,vector-based overexpression using murine or human ZNF593-AS alleviated PE-induced myocyte hypertrophy,whereas GapmeR-induced inhibition aggravated hypertrophic phenotypes.By using RNA-seq and gene set enrichment analyses,we identified a link between ZNF593-AS and oxidative phosphorylation and found that mitofusin 2(Mfn2)is a direct target of ZNF593-AS.ZNF593-AS exerts an antihypertrophic effect by upregulating Mfn2 expression and improving mitochondrial function.Therefore,it represents a promising therapeutic target for combating pathological cardiac remodeling.

关键词： lncRNA ZNF593-AS cardiac hypertrophy Mfn2 oxidative phosphorylation