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SIRT2 as a potential new therapeutic target for Alzheimer's disease

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Neural Regeneration Research 2024年第1期19卷 124-131页

作者： Noemi Sola-Sevilla Elena Puerta department of Pharmacology and toxicology Faculty of PharmacyUniversity of NavarraNavarra Institute for Health Research(IdiSNA)PamplonaSpain

Alzheimer's disease is the most common cause of dementia globally with an increasing incidence over the years,bringing a heavy burden to individuals and society due to the lack of an effective *** this context,sirtuin 2,the sirtuin with the highest expression in the brain,has emerged as a potential therapeutic target for neurodegenerative *** review summarizes and discusses the complex roles of sirtuin 2 in different molecular mechanisms involved in Alzheimer's disease such as amyloid and tau pathology,microtubule stability,neuroinflammation,myelin formation,autophagy,and oxidative *** role of sirtuin 2 in all these processes highlights its potential implication in the etiology and development of Alzheimer's ***,its presence in different cell types and its enormous variety of substrates leads to apparently contra dictory conclusions when it comes to understanding its specific *** studies in sirtuin 2 research with selective sirtuin2 modulators targeting specific sirtuin 2 substrates are necessary to clarify its specific functions under different conditions and to validate it as a novel pharmacological *** will contribute to the development of new treatment strategies,not only for Alzheimer's disease but also for other neurodegenerative diseases.

关键词： Alzheimer's disease amyloid autophagy memory neurodegenerative diseases neuroinflammation sirtuin 2 tau

Severe aconite poisoning successfully treated with veno-arterial extracorporeal membrane oxygenation:A case report

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World Journal of Clinical Cases 2024年第2期12卷 399-404页

作者： Saeko Kohara Yoshito Kamijo Ryoko Kyan Ichiro Okada Eiju Hasegawa Soichiro Yamada Koichi Imai Asuka Kaizaki-Mitsumoto Satoshi Numazawa department of Critical Care Medicine and Trauma National Hospital Organization Disaster Medical CenterTokyo 1900014Japan department of Clinical toxicology Saitama Medical UniversitySaitama 3500495Japan Saitama Prefectural Institute of Public Health Saitama Prefectural Institute of Public HealthSaitama 3550133Japan Division of toxicology Department of PharmacologyToxicology and TherapeuticsShowa University School of PharmacyTokyo 1428555Japan

BACKGROUND Most species of aconite contain highly toxic aconitines,the oral ingestion of which can be fatal,primarily because they cause ventricular *** describe a case of severe aconite poisoning that was successfully treated through venoarterial extracorporeal membrane oxygenation(VA-ECMO)and in which detailed toxicological analyses of the aconite roots and biological samples were performed using liquid chromatography-tandem mass spectrometry(LC-MS/MS).CASE SUMMARY A 23-year-old male presented to the emergency room with circulatory collapse and ventricular arrhythmia after ingesting approximately half of a root labeled,“Aconitum japonicum Thunb”.Two hours after arrival,VA-ECMO was initiated as circulatory collapse became refractory to antiarrhythmics and *** hours after arrival,an electrocardiogram revealed a return to sinus *** patient was weaned off VA-ECMO and the ventilator on hospital days 3 and 5,*** hospital day 15,he was transferred to a psychiatric *** other half of the root and his biological samples were toxicologically analyzed using LC-MS/MS,revealing 244.3 mg/kg of aconitine and 24.7 mg/kg of mesaconitine in the *** on admission contained 1.50 ng/mL of *** hospital day 2,neither were *** on admission showed 149.09 ng/mL of aconitine and 3.59 ng/mL of mesaconitine,but these rapidly decreased after hospital day *** The key to saving the life of a patient with severe aconite poisoning is to introduce VA-ECMO as soon as possible.

关键词： Aconite poisoning Fatal arrhythmia Veno-arterial extracorporeal membrane oxygenation Aconitine Mesaconitine Case report

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 DemirbugenÖz Adriana PerezGrovas-Saltijeral Division of Cells Organisms and Molecular GeneticsSchool of Life SciencesUniversity of NottinghamNottinghamUK department of Pharmaceutical toxicology Faculty of PharmacyAnkara UniversityAnkaraTurkey

The study of modified RNA known as epitranscriptomics has become increasingly relevant in our understanding of disease-modifying *** of N6 adenosine(m^(6)A)and C5 cytosine(m^(5)C)bases occur on mRNAs,tRNA,mt-tRNA,and rRNA species as well as non-coding *** 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 *** processes when spatiotemporally disrupted within cellular nanodomains in highly specialized tissues such as the brain,give rise to different forms of *** this review,we discuss accumulating evidence that changes in the m^(6)A and m^(5)C methylation systems contribute to neurocognitive *** studies first identified mutations within FMR1 to cause intellectual disability Fragile X syndromes several years before FMR1 was identified as an m^(6)A RNA reader ***,familial mutations within the m^(6)A writer gene METTL5,m^(5)C writer genes NSUN2,NSUN3,NSUN5,and NSUN6,as well as THOC2 and THOC6 that form a protein complex with the m^(5)C reader protein ALYREF,were recognized to cause intellectual development ***,differences in expression of the m^(5)C 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 ***,an abundance of m^(6)A 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.m^(6)A-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 *** parahippocampal brain tissue,m^(6)A modification is enri

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

Dual activities of a silencing information regulator complex in yeast transcriptional regulation and DNA-damage response

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mLife 2024年第2期3卷 207-218页

作者： Josephine Rybchuk Wei Xiao department of Biochemistry Microbiology and ImmunologyUniversity of SaskatchewanSaskatoonSaskatchewanCanada toxicology Program University of SaskatchewanSaskatoonSaskatchewanCanada

The Saccharomyces cerevisiae silencing information regulator(SIR)complex contains up to four proteins,namely Sir1,Sir2,Sir3,and *** Sir2 encodes a NAD-dependent histone deacetylase,other SIR proteins mainly function as structural and scaffold components through physical interaction with various *** SIR complex displays different conformation and composition,including Sir2 homotrimer,Sir1-4 heterotetramer,Sir2-4 heterotrimer,and their derivatives,which recycle and relocate to different chromosomal *** activities of the SIR complex are transcriptional silencing through chromosomal remodeling and modulation of DNA double-strand-break repair *** activities allow the SIR complex to be involved in mating-type maintenance and switching,telomere and subtelomere gene silencing,promotion of nonhomologous end joining,and inhibition of homologous recombination,as well as control of cell *** review explores the potential link between epigenetic regulation and DNA damage response conferred by the SIR complex under various conditions aiming at understanding its roles in balancing cell survival and genomic stability in response to internal and environmental *** core activities of the SIR complex are highly conserved in eukaryotes from yeast to humans,knowledge obtained in the yeast may apply to mammalian Sirtuin homologs and related diseases.

关键词： chromatin remodeling DNA-damage response SiR complex transcriptional silencing yeast

Fasn involved in the nephrotoxicity induced by polystyrene nanoplastics and the intervention of melatonin through intestinal microbiota-mediated lipid metabolism disorder

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Nano Research 2024年第8期17卷 7365-7375页

作者： Huiwen Kang Danyang Huang Jiaru Jing Wei Zhang Lei Zhang Jingyu Wang Ziyan Liu Lin Han Ziyan Wang Lefeng Zhang Ai Gao department of Occupational Health and Environmental Health School of Public HealthCapital Medical UniversityBeijing 100069China Beijing Key Laboratory of Environmental toxicology Capital Medical UniversityBeijing 100069China

Nanoplastics(NPs)can accumulate in the kidney and cause kidney injury,but the multi-organ interaction mechanism and preventive measures of kidney injury are still *** this study,in vivo(60μg/day,42 days)and in vitro(0.4μg/μL,24 h)exposure models of polystyrene nanoplastics(PS-NPs,80 nm)in mice and human kidney cortex proximal tubule epithelial cells(HK-2 cells)were established,*** study revealed that PS-NPs caused obvious pathological changes and impaired renal function in mice,which were related to lipid metabolism disorders mediated by intestinal ***-fatty acid synthase(Fasn)-docosahexaenoic acid(DHA)pathway may be one of the mechanisms of kidney injury in ***,we also found that melatonin attenuates PS-NPs-induced nephrotoxicity by modulating lipid metabolism disorders(represented by DHA)and affects Fasn *** conclusion,our study revealed the important role of intestinal flora-mediated lipid metabolism in PS-NPs-induced nephrotoxicity and preliminarily provided potential key gene targets and effective preventive measures for PS-NPs-induced nephrotoxicity.

关键词： nanoplastics nephrotoxicity lipid metabolism fatty acid synthase(Fasn) melatonin

Decabromodiphenyl ether induces the chromosome association disorders of spermatocytes and deformation failures of spermatids in mice

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Journal of Environmental Sciences 2024年第4期138卷 531-542页

作者： Jinglong Xue Xiangyang Li Yafei Chi Leqiang Gao Yue Zhang Yan Wang Moxuan Zhao Jialiu Wei Zhixiong Shi Xianqing Zhou department of toxicology and Hygienic Chemistry School of Public HealthCapital Medical UniversityBeijing 100069China Beijing Key Laboratory of Environmental toxicology Capital Medical UniversityBeijing 100069China Laboratory Animal Center Capital Medical UniversityBeijing 100069China Key Laboratory of Cardiovascular Epidemiology&department of Epidemiology Fuwai HospitalNational Center for Cardiovascular DiseasesChinese Academy of Medical Sciences and Peking Union Medical CollegeBeijing 100037China

The environmental presence of decabromodiphenyl ether(BDE-209),which is toxic to the male reproductive system,is *** current study investigated its mechanism of toxicity in *** results showed,that BDE-209 induced DNA damage,decreased the expression of the promoter of meiosis spermatogenesis-and oogenesis-specific basic helix-loop-helix 1(Sohlh1),meiosis related-factors Lethal(3)malignant brain tumor like 2(L3MBTL2),PIWI-like protein 2(MILI),Cyclin-dependent kinase 2(CDK2),Cyclin A,synaptonemal complex protein 1(SYCP1)and synaptonemal complex protein 3(SYCP3),and caused spermatogenic cell apoptosis,resulting in a decrease in sperm quantity and ***,BDE-209 downregulated the levels of anaphase-promoting complex/cyclosome(APC/C),increased the expression of PIWI-like protein 1(MIWI)in the cytoplasm of elongating spermatids,and decreased the nuclear levels of RING finger protein 8(RNF8),ubiquitinated(ub)-H2A/ub-H2B,and Protamine 1(PRM1)/Protamine 2(PRM2),while increasing H2A/H2B nuclear levels in *** reproductive toxicity was persistent for 50 days following the withdrawal of BDE-209 *** results suggested that BDE-209 inhibits the initiation of meiosis by decreasing the expression of ***,the reduced expression of L3MBTL2 inhibited the formation of chromosomal synaptonemal complexes by depressing the expression of meiosis regulators affecting the meiotic progression and also inhibited histone ubiquitination preventing the replacement of histones by protamines,by preventing RNF8 from entering nuclei,which affected the evolution of spermatids into mature sperm.

关键词： BDE-209 Meiosis L3MBTL2 Sperm RNF8 Histone ubiquitination

Identification of Key Blood Biomarkers Linking Di(2-ethylhexyl)Phthalate and Autoimmune Diseases in Adolescents Mice

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Biomedical and Environmental Sciences 2024年第5期37卷 521-525页

作者： XU Xiao Mei LI Xiao Lu HU Die CAI Xiao Yue LI Qi Meng ZHENG Yuan Zhuo CAI Yang QI Yin Yin XU Tao ZHAO Ling Li NING Xia department of Infectious Diseases Anhui Provincial Children’s HospitalHefei 231000AnhuiChina department of toxicology School of Public HealthKey Laboratory of Environmental Toxicology of Anhui Higher Education InstitutesAnhui Medical UniversityHefei 231000AnhuiChina School of Biology Food and EnvironmentHefei UniversityHefei 230601AnhuiChina

Di(2-ethylhexyl)phthalate(DEHP)is a widely used plasticizer known for its reproductive developmental and immune system toxicity,mainly through esophagal,dermal,and respiratory exposure^([1-3]).Maternal exposure to DEHP during pregnancy can lead to adverse birth outcomes in offspring,including impacts on the thyroid system of adolescent offspring^([2-4]).

关键词： Blood respiratory pregnancy

The link between intracellular calcium signaling and exosomal PD-L1 in cancer progression and immunotherapy

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Genes & Diseases 2024年第1期11卷 321-334页

作者： Md Rakibul Alam Md Mizanur Rahman Zhiguo Li department of toxicology and Cancer Biology College of MedicineUniversity of KentuckyLexingtonKY 40506USA department of Medicine(Nephrology) Faculty of Medicine and DentistryUniversity of AlbertaEdmontonAlberta T6E2H7Canada

Exosomes are small membrane vesicles containing microRNA,RNA,DNA fragments,and proteins that are transferred from donor cells to recipient *** cells release exo-somes to reprogram the factors associated with the tumor microenvironment(TME)causing tu-mor metastasis and immune *** evidence revealed that cancer cell-derived exosomes carry immune inhibitory molecule program death ligand 1(PD-L1)that binds with re-ceptor program death protein 1(PD-1)and promote tumor progression by escaping immune ***,some FDA-approved monoclonal antibodies are clinicallyused for cancer treatment by blocking PD-1/PD-L1 *** notable treatment outcomes,some pa-tients show poor drug *** PD-L1 plays a vital role in lowering the treatment response,showing resistance to PD-1/PD-L1 blockage therapy through recapitulating the ef-fect of cell surface *** enhance therapeutic response,inhibition of exosomal PD-L1 is *** signaling is the central regulator of tumorigenesis and can regulate exosome biogenesis and secretion by modulating Rab GTPase family and membrane fusion ***-mune checkpoints are also connected with calcium signaling and calcium channel blockers like amlodipine,nifedipine,lercanidipine,diltiazem,and verapamil were also reported to suppress cellular PD-L1 ***,to enhance the PD-1/PD-L1 blockage therapy response,the reduction of exosomal PD-L1 secretion from cancer cells is in our therapeutic *** this review,we proposed a therapeutic strategy by targeting calcium signaling to inhibit the expression of PD-L1-containing exosome levels that could reduce the anti-PD-1/PD-L1 therapy resistance and increase the patient's drug response rate.

关键词： Calcium signaling CD8^(+)T cells Exosomal PD-L1 Exosomes biogenesis Immunosuppression Immunotherapy

TransCell:In Silico Characterization of Genomic Landscape and Cellular Responses by Deep Transfer Learning

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Genomics, Proteomics & Bioinformatics 2024年第2期22卷 157-170页

作者： Shan-Ju Yeh Shreya Paithankar Ruoqiao Chen Jing Xing Mengying Sun Ke Liu Jiayu Zhou Bin Chen department of Pediatrics and Human Development Michigan State UniversityGrand RapidsMI 49503USA department of Pharmacology and toxicology Michigan State UniversityGrand RapidsMI 49503USA department of Computer Science and Engineering Michigan State UniversityEast LansingMI 48824USA

Gene expression profiling of new or modified cell lines becomes routine today;however,obtaining comprehensive molecular characterization and cellular responses for a variety of cell lines,including those derived from underrepresented groups,is not trivial when resources are *** gene expression to predict other measurements has been actively explored;however,systematic investigation of its predictive power in various measurements has not been well ***,we evaluated commonly used machine learning methods and presented TransCell,a two-step deep transfer learning framework that utilized the knowledge derived from pan-cancer tumor samples to predict molecular features and *** these models,TransCell had the best performance in predicting metabolite,gene effect score(or genetic dependency),and drug sensitivity,and had comparable performance in predicting mutation,copy number variation,and protein ***,TransCell improved the performance by over 50%in drug sensitivity prediction and achieved a correlation of 0.7 in gene effect score ***,predicted drug sensitivities revealed potential repurposing candidates for new 100 pediatric cancer cell lines,and predicted gene effect scores reflected BRAF resistance in melanoma cell ***,we investigated the predictive power of gene expression in six molecular measurement types and developed a web portal(http://***/transcell/)that enables the prediction of 352,000 genomic and cellular response features solely from gene expression profiles.

关键词： Genomics Transcriptomics Cancer dependency Drug repurposing Transfer learning