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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 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

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

Elucidating regulatory processes of intense physical activity by multi-omics analysis

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Military Medical Research 2024年第4期11卷 479-499页

作者： Ernesto S.Nakayasu Marina A.Gritsenko Young-Mo Kim Jennifer E.Kyle Kelly G.Stratton Carrie D.Nicora Nathalie Munoz Kathleen M.Navarro Daniel Claborne Yuqian Gao Karl K.Weitz Vanessa L.Paurus Kent J.Bloodsworth Kelsey A.Allen Lisa M.Bramer Fernando Montes Kathleen A.Clark Grant Tietje Justin Teeguarden Kristin E.Burnum-Johnson Biological Sciences division Pacific Northwest National LaboratoryRichlandWA 99352USA Environmental and Molecular Sciences division Pacific Northwest National LaboratoryRichlandWA 99352USA Centers for Disease Control and Prevention National Institute for Occupational Safety and HealthWestern States DivisionDenverCO 80204USA Computational Analytics division Pacific Northwest National LaboratoryRichlandWA 99352USA National Security Directorate Pacific Northwest National LaboratoryRichlandWA 99352USA Los Angeles County Fire Department Los AngelesCA 90063USA Centers for Disease Control and Prevention National Institute for Occupational Safety and HealthRespiratory Health DivisionMorgantownWV 26505USA Environmental and Molecular toxicology Oregon State UniversityCorvallisOR 97331USA

Background:Physiological and biochemical processes across tissues of the body are regulated in response to the high demands of intense physical activity in several occupations,such as firefighting,law enforcement,military,and sports.A better understanding of such processes can ultimately help improve human performance and prevent illnesses in the work ***:To study regulatory processes in intense physical activity simulating real-life conditions,we performed a multi-omics analysis of 3 biofluids(blood plasma,urine,and saliva)collected from 11 wildland firefighters before and after a 45 min,intense exercise *** profiles ***-exercise were compared by Student’s t-test followed by pathway analysis and comparison between the different omics ***:Our multi-omics analysis identified and quantified 3835 proteins,730 lipids and 182 metabolites combining the 3 different types of *** blood plasma analysis revealed signatures of tissue damage and acute repair response accompanied by enhanced carbon metabolism to meet energy *** urine analysis showed a strong,concomitant regulation of 6 out of 8 identified proteins from the renin-angiotensin system supporting increased excretion of catabolites,reabsorption of nutrients and maintenance of fluid *** saliva,we observed a decrease in 3 pro-inflammatory cytokines and an increase in 8 antimicrobial peptides.A systematic literature review identified 6 papers that support an altered susceptibility to respiratory ***:This study shows simultaneous regulatory signatures in biofluids indicative of homeostatic maintenance during intense physical activity with possible effects on increased infection susceptibility,suggesting that caution against respiratory diseases could benefit workers on highly physical demanding jobs.

关键词： Multi-omics analysis Intense exercise Human performance Biofluids Metabolism Immunity

HDPairFinder:A data processing platform for hydrogen/deuterium isotopic labeling-based nontargeted analysis of trace-level amino-containing chemicals in environmental water

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Journal of Environmental Sciences 2024年第2期136卷 583-593页

作者： Tingting Zhao Kristin Carroll Caley B.Craven Nicholas J.P.Wawryk Shipei Xing Jian Guo Xing-Fang Li Tao Huan Department of Chemistry Faculty of ScienceUniversity of British ColumbiaVancouver Campus2036 Main MallVancouverBritish ColumbiaV6T 1Z1Canada division of Analytical and Environmental toxicology Department of Laboratory Medicine and PathologyFaculty of Medicine and DentistryUniversity of AlbertaEdmontonAlberta T6G 2G3Canada

The combination of hydrogen/deuterium(H/D)formaldehyde-based isotopic methyl labeling with solid-phase extraction and high-performance liquid chromatography–high resolution mass spectrometry(HPLC-HRMS)is a powerful analytical solution for nontargeted analysis of trace-level amino-containing chemicals in water *** the huge amount of chemical information generated in HPLC-HRMS analysis,identifying all possible H/Dlabeled amino chemicals presents a significant challenge in data *** address this,we designed a streamlined data processing pipeline that can automatically extract H/D-labeled amino chemicals from the raw HPLC-HRMS data with high accuracy and ***,we developed a cross-correlation algorithm to correct the retention time shift resulting from deuterium isotopic effects,which enables reliable pairing of H-and D-labeled ***,we implemented several bioinformatic solutions to remove false chemical features generated by in-source fragmentation,salt adduction,and natural13C ***,we used a data mining strategy to construct the AMINES library that consists of over 38,000 structure-disjointed primary and secondary amines to facilitate putative compound ***,we integrated these modules into a freely available R program,*** rationale of each module was justified and its performance tested using experimental H/D-labeled chemical standards and authentic water *** further demonstrated the application of HDPairFinder to effectively extract N-containing contaminants,thus enabling the monitoring of changes of primary and secondary N-compounds in authentic water *** is a reliable bioinformatic tool for rapid processing of H/D isotopic methyl labeling-based nontargeted analysis of water samples,and will facilitate a better understanding of N-containing chemical compounds in water.

关键词： Isotope labeling Nontargeted analysis Reactive N-compounds HPLC-HRMS Source water

A Comprehensive Review on Preclinical Safety and Toxicity of Medicinal Plants

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Clinical Complementary Medicine and Pharmacology 2024年第1期4卷 95-111页

作者： Madhav Nilakanth Mugale Kapil Dev Bhumika S.More Vaishali Sunil Mishra Kaveri R.Washimkar Kishan Singh Rakesh Maurya Srikanta Kumar Rath Debprasad Chattopadhyay Naibedya Chattopadhyay division of toxicology and Experimental Medicine CSIR-Central Drug Research Institute(CSIR-CDRI)Lucknow 226031India division of Phytochemistry CSIR-Central Institute of Medicinal and Aromatic Plants(CSIR-CIMAP)Lucknow 226015India Medicinal and Process Chemistry division CSIR-CDRI Lucknow 226031India division of Endocrinology CSIR-CDRI Lucknow 226031India division of Ethnomedicine ICMR-National Institute of Traditional MedicineNehru NagarBelagavi 590010and ICMR-Virus UnitKolkata 700010India Department of Health Research NSHM Knowledge CampusKolkata 700051India

Background:Globally,80%people use plant-derived products for treating or preventing *** prevalent perception about medicinal plants is that they are safe and devoid of adverse ***,approximately 1,50,000 plants contain toxic ***:The present review focuses on medicinal plant extracts/fractions toxicity assessments made in preclin-ical models by oral ***:Detail studies were searched from databases including PubMed and Google Scholar.A manual reference screening of the selected studies was done to identify relevant articles,with no language restriction being imposed at the time of ***:The studies included were performed in rodents,and the test substances were administered *** search revealed 33 widely used plants or products with significant toxicity,and phytochemicals from these plants have been *** a systematic review,we identified a plethora of medicinal plant extracts reporting safety and toxicity ***:In the future,preclinical toxicokinetic studies of herbs and the determination of their no-observed-adverse-effect levels are required for a complete safety ***,the interaction of herbs with com-monly used/over-the-counter drugs in terms of the latter’s metabolic profile should be undertaken.

关键词： Extract Herbal medicine Toxicity Rodent Secondary metabolite

SARS-CoV-2 aberrantly elevates mitochondrial bioenergetics to induce robust virus propagation

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Signal Transduction and Targeted Therapy 2024年第6期9卷 2702-2715页

作者： Hye Jin Shin Wooseong Lee Keun Bon Ku Gun Young Yoon Hyun-Woo Moon Chonsaeng Kim Mi-Hwa Kim Yoon-Sun Yi Sangmi Jun Bum-Tae Kim Jong-Won Oh Aleem Siddiqui Seong-Jun Kim Department of Convergent Research of Emerging Virus Infection Korea Research Institute of Chemical TechnologyDaejeon 34114Republic of Korea Gyeongnam Biohealth Research Center Gyeongnam Branch InstituteKorea Institute of ToxicologyJinju 52834Republic of Korea Center for Research Equipment Korea Basic Science InstituteCheongjuChungcheongbuk-do 28119Republic of Korea Department of Biotechnology Yonsei UniversitySeoul 03722Republic of Korea division of Infectious Diseases School of MedicineUniversity of CaliforniaSan DiegoLa JollaCA 92093USA Present address:Department of Microbiology Chungnam National University School of MedicineDaejeon 35015Republic of Korea

Severe acute respiratory syndrome coronavirus 2(SARS-CoV-2)is a‘highly transmissible respiratory pathogen,leading to severe multiorgan ***,knowledge regarding SARS-CoV-2-induced cellular alterations is *** this study,we report that SARSCoV-2 aberrantly elevates mitochondrial bioenergetics and activates the EGFR-mediated cell survival signal cascade during the early stage of viral ***-CoV-2 causes an increase in mitochondrial transmembrane potential via the SARS-CoV-2 RNAnucleocapsid cluster,thereby abnormally promoting mitochondrial elongation and the OXPHOS process,followed by enhancing ATP ***,SARS-CoV-2 activates the EGFR signal cascade and subsequently induces mitochondrial EGFR trafficking,contributing to abnormal OXPHOS process and viral *** EGFR inhibitors remarkably reduce SARS-CoV-2 propagation,among which vandetanib exhibits the highest antiviral *** of SARS-CoV-2-infected cells with vandetanib decreases SARS-CoV-2-induced EGFR trafficking to the mitochondria and restores SARS-CoV-2-induced aberrant elevation in OXPHOS process and ATP generation,thereby resulting in the reduction of SARS-CoV-2 ***,oral administration of vandetanib to SARS-CoV-2-infected hACE2 transgenic mice reduces SARS-CoV-2 propagation in lung tissue and mitigates SARS-CoV-2-induced lung *** also exhibits potent antiviral activity against various SARS-CoV-2 variants of concern,including alpha,beta,delta and omicron,in in vitro cell culture *** together,our findings provide novel insight into SARS-CoV-2-induced alterations in mitochondrial dynamics and EGFR trafficking during the early stage of viral infection and their roles in robust SARS-CoV-2 propagation,suggesting that EGFR is an attractive host target for combating COVID-19.

关键词： alterations aberrant thereby

Residential energy transition and chronic respiratory diseases

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The Innovation 2024年第3期5卷 33-43页

作者： Hongcheng Wei Qiurun Yu Danrong Chen Mingzhi Zhang Quanquan Guan Bo Hang Antoine M.Snijders Adrian Covaci Yankai Xia State Key Laboratory of Reproductive Medicine and Offspring Health Center for Global HealthSchool of Public HealthNanjing Medical UniversityNanjing 211166China Key Laboratory of Modern toxicology of Ministry of Education School of Public HealthNanjing Medical UniversityNanjing 211166China The Affiliated Wuxi People’s Hospital of Nanjing Medical University Wuxi People’s HospitalWuxi Medical CenterNanjing Medical UniversityWuxi 214023China Biological Systems and Engineering division Lawrence Berkeley National LaboratoryBerkeleyCA 94720USA Toxicological Centre University of Antwerp2610 WilrijkBelgium

Obtaining clean energy is of prime importance for planetary health and sustainable *** aimed to assess the association between residential energy transition and the risk of chronic respiratory *** data from the Global Health Observatory and Global Burden of Diseases,Injuries,and Risk Factors Study,we delineated the spatial distribution and temporal trends of the population using clean fuels for cooking at a global *** the China Health and Retirement Longitudinal Study,we performed rigorous and well-structured multistage analyses incorporating both cross-sectional and prospective data analyses to examine the associations between solid fuel use,residential energy transition,duration of solid fuel use,and the risk of chronic respiratory *** great progress,huge disparities in access to clean energy persist *** energy transition was associated with a lower risk of chronic respiratory *** the period of 2011–2013,compared with persistent solid fuel users,both participants who switched from solid to clean fuels(adjusted risk ratio[RR]0.78,95%confidence interval[CI]0.62–0.98)and persistent clean fuel users(adjusted RR 0.71,95%CI 0.57–0.89)had significantly lower risk of chronic respiratory diseases(p<0.001 for trend).Consistent associations were observed in the period of 2011–2015 and 2011–*** energy transition from solid to clean fuels could reduce the risk of chronic respiratory *** is a valuable lesson for policy-makers and the general public to accelerate energy switching to alleviate the burden of chronic respiratory diseases and achieve health benefits,particularly in low-and middle-income countries.

关键词： cooking income globally

Diabetic cardiomyopathy:Importance of direct evidence to support the roles of NOD-like receptor protein 3 inflammasome and pyroptosis

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World Journal of Diabetes 2024年第8期15卷 1659-1662页

作者： Lu Cai Yi Tan Md Shahidul Islam Michael Horowitz Kupper A Wintergerst Pediatric Research Institute Departments of PediatricsRadiation OncologyPharmacology and ToxicologyUniversity of LouisvilleWendy Novak Diabetes InstituteNorton Children’s HospitalLouisvilleKY 40202United States Department of Biochemistry School of Life SciencesUniversity of KwaZulu-NatalDurban 4000KwaZulu-NatalSouth Africa Department of Medicine University of AdelaideAdelaide 5005Australia Pediatric Research Institute Division of EndocrinologyDepartment of PediatricsWendy Novak Diabetes InstituteNorton Children’s HospitalUniversity of LouisvilleLouisvilleKY 40202United States

Recently,the roles of pyroptosis,a form of cell death induced by activated NODlike receptor protein 3(NLRP3)inflammasome,in the pathogenesis of diabetic cardiomyopathy(DCM)have been extensively ***,most studies have focused mainly on whether diabetes increases the NLRP3 inflammasome and associated pyroptosis in the heart of type 1 or type 2 diabetic rodent models,and whether various medications and natural products prevent the development of DCM,associated with decreased levels of cardiac NLRP3 inflammasome and *** direct link of NLRP3 inflammasome and associated pyroptosis to the pathogenesis of DCM remains unclear based on the limited evidence derived from the available studies,with the approaches of NLRP3 gene silencing or pharmaceutical application of NLRP3 specific *** thus emphasize the requirement for more systematic studies that are designed to provide direct evidence to support the link,given that several studies have provided both direct and indirect evidence under specific *** editorial emphasizes that the current investigation should be circumspect in its conclusion,i.e.,not overemphasizing its role in the pathogenesis of DCM with the fact of only significantly increased expression or activation of NLRP3 inflammasome and pyroptosis in the heart of diabetic rodent *** clear-cut evidence-based causative roles of NLRP3 inflammasome and pyroptosis in the pathogenesis of DCM can help to develop effective and safe medications for the clinical management of DCM,targeting these biomarkers.

关键词： Diabetic cardiomyopathy Nucleotide oligomerization domain NOD-like receptor protein 3 inflammasome Cardiac cell death Pyroptosis

Analysis of the combined effect of rs699 and rs5051 on angiotensinogen expression and hypertension

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Chronic Diseases and Translational Medicine 2024年第2期10卷 102-117页

作者： Nicholas R.Powell Tyler Shugg Jacob Leighty Matthew Martin Rolf P.Kreutz Michael T.Eadon Dongbing Lai Tao Lu Todd C.Skaar division of Clinical Pharmacology Department of MedicineSchool of MedicineIndiana UniversityIndianapolisIndianaUSA Department of Pharmacology and toxicology School of MedicineIndiana UniversityIndianapolisIndianaUSA Department of Cardiology School of MedicineKrannert Institute of CardiologyIndiana UniversityIndianapolisIndianaUSA division of Nephrology Department of MedicineSchool of MedicineIndiana UniversityIndianapolisIndianaUSA Department of Medical and Molecular Genetics School of MedicineIndiana UniversityIndianapolisIndianaUSA

Background Hypertension(HTN)involves genetic variability in the renin-angiotensin system and influences antihypertensive *** previously reported that angiotensinogen(AGT)messenger RNA(mRNA)is endogenously bound by miR-122-5p and rs699 A>G decreases reporter mRNA in the microRNA functional-assay *** AGT promoter variant rs5051 C>T is in linkage disequilibrium(LD)with rs699 A>G and increases AGT *** independent effect of these variants is understudied due to their LD therefore we aimed to test the hypothesis that increased AGT by rs5051 C>T counterbalances AGT decreased by rs699 A>G,and when these variants occur independently,it translates to HTN-related *** We used in silico,in vitro,in vivo,and retrospective models to test this *** In silico,rs699 A>G is predicted to increase miR-122-5p binding affinity by 3%.Mir-eCLIP results show rs699 is 40–45 nucleotides from the strongest microRNA-binding site in the AGT ***,rs699 A>G increases AGT mRNA in an AGT-plasmid-cDNA HepG2 expression ***-Tissue Expression(GTEx)and UK Biobank analyses demonstrate liver AGT expression and HTN phenotypes are not different when rs699 A>G occurs independently from rs5051 C>***,GTEx and the in vitro experiments suggest rs699 A>G confers cell-type-specific effects on AGT mRNA abundance,and suggest paracrine renal renin-angiotensin-system perturbations could mediate the rs699 A>G associations with *** We found that rs5051 C>T and rs699 A>G significantly associate with systolic blood pressure in Black participants in the UK Biobank,demonstrating a fourfold larger effect than in White *** studies are warranted to determine if altered antihypertensive response in Black individuals might be due to rs5051 C>T or rs699 A>*** like this will help clinicians move beyond the use of race as a surrogate for genotype.

关键词： angiotensinogen genetic and genomic medicine hypertension rs699