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Adenosine triphosphate-binding pocket inhibitor for mixed lineage kinase domain-like protein attenuated alcoholic liver disease via necroptosis-independent pathway

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World Journal of Gastroenterology 2025年第6期31卷 44-61页

作者： Han-Ning Xuan Yuan Hyun Sung Kim Gye Ryeol Park Jae Eun Ryu Ji Eun Kim In Young Kang Hye Young Kim Seung Min Lee Ju Hee Oh Eileen L Yoon Dae Won Jun department of internal medicine Hanyang University School of MedicineSeoul 04763South Korea department of Pathology Hanyang University School of MedicineSeoul 04763South Korea department of Translational medicine Graduate School of Biomedical Science and EngineeringHanyang UniversitySeoul 04763South Korea department of Obstetrics and Gynecology Institute of Women’s Medical Life ScienceYonsei Cancer CenterSeverance HospitalYonsei University College of MedicineSeoul 04763South Korea department of internal medicine Sanggye Paik HospitalInje University College of MedicineSeoul 01757South Korea

BACKGROUND Mixed lineage kinase domain-like protein(MLKL)serves as a critical mediator in necroptosis,a form of regulated cell death linked to various liver *** study aims to specifically investigate the role of MLKL’s adenosine triphosphate(ATP)-binding pocket in facilitating necroptosis-independent pathways that may contribute to liver disease *** focusing on this mechanism,we seek to identify potential therapeutic targets that can modulate MLKL activity,offering new strategies for the prevention and treatment of liver-related *** To investigate the possibility of using the ATP-binding pocket-associated,necro-ptosis-independent MLKL pathway as a target for liver *** Cell death following necroptosis stimuli was evaluated using cell proliferation assays,flow cytometry,and electron microscopy in various *** human liver organoid system was used to evaluate whether the MLKL ATP pocket-binding inhibitor could attenuate ***,alcoholic and non-alcoholic fatty liver diseases animal models were used to determine whether MLKL ATP pocket inhibitors could attenuate liver *** While an MLKL ATP pocket-binding inhibitor did not prevent necroptosis-induced cell death in RAW 264.7 cells,it did reduce the necroptosis-led expression of CXCL2,ICAM,and ***,MLKL ATP pocket inhibitor diminishes the expression of CXCL2,ICAM,and VCAM by inhibiting the IκB kinase and nuclear factor kappa-B pathways without inducing necroptosis-induced cell death in two-dimensional cell culture as well as the human-derived liver organoid *** MLKL ATP-binding inhibitor was ineffective in non-alcoholic fatty liver disease animal models,MLKL ATP-binding inhibitor attenuated hepatic inflammation in the alcoholic liver disease *** MLKL ATP pocket-binding inhibitor exerted anti-inflammatory effects through the necroptosis-independent MLKL pathway in an animal model of alcoholic liver disease.

关键词： RAW 264.7 cell Cell death Necroptosis Mixed lineage kinase domain-like protein Non-alcoholic fatty liver disease Mixed lineage kinase domain-like protein adenosine triphosphate binding inhibitor Alcoholic liver disease

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Cryptic exon inclusion in TDP-43 proteinopathies:opportunities and challenges

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Neural Regeneration Research 2025年第7期20卷 2003-2004页

作者： Lorena Decker Sonja Menge Axel Freischmidt department of neurology Ulm UniversityUlmGermany

TDP-43 proteinopathies and cryptic exons:Transactive response DNA binding protein of 43 kDa(TDP-43)is a ubiquitously expressed RNA/DNA binding protein crucial for coding and non-coding RNA metabolism including transcription,splicing,transport,translation,and ***-43 shuttles between the nucleus and cytoplasm,but is predominantly localized in the *** diseases(NDs)may be accompanied by nuclear loss and possible cytoplasmic accumulation and aggregation of TDP-43 in vulnerable neurons and *** neuropathology is the hallmark of most individuals suffering from amyotrophic lateral sclerosis(ALS),frontotemporal dementia(FTD)with TDP-43-immunoreactive pathology(FTD-TDP),limbic-predominant age-related TDP-43 encephalopathy(LATE)and Perry syndrome,but also coexists with the primary pathology in subsets of patients suffering from other NDs,such as Alzheimer’s disease,Lewy body dementias,or Huntington’s *** in the gene encoding TDP-43(TARDBP)are the cause of ALS and/or FTD in some rare cases substantiating the importance of this protein in aging *** is still controversial if loss of nuclear,or increased cytoplasmic and/or aggregating TDP-43 is more harmful to neurons(Nag and Schneider,2023).Recently,the role of nuclear TDP-43 in repressing the inclusion of intronic sequences,named cryptic exons(CEs),into mature mRNAs gained much attention.

关键词： Huntington metabolism TDP

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Understanding the link between type 2 diabetes mellitus and Parkinson's disease:role of brain insulin resistance

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Neural Regeneration Research 2025年第11期20卷 3113-3123页

作者： Theodora Ntetsika Sergiu-Bogdan Catrina Ioanna Markaki department of Clinical Neuroscience Karolinska InstituteStockholmSweden department of neurology Karolinska University HospitalStockholmSweden department of Molecular medicine and Surgery Karolinska InstituteStockholmSweden Center for Diabetes Academic Specialist CenterStockholmSweden Center for neurology Academic Specialist CenterStockholmSweden

Type 2 diabetes mellitus and Parkinson's disease are chronic diseases linked to a growing pandemic that affects older adults and causes significant socio-economic *** data supporting a close relationship between these two aging-related diseases have resulted in the investigation of shared pathophysiological molecular *** insulin signaling in the brain has gained increasing attention during the last decade and has been suggested to contribute to the development of Parkinson's disease through the dysregulation of several pathological *** contribution of type 2 diabetes mellitus and insulin resistance in neurodegeneration in Parkinson's disease,with emphasis on brain insulin resistance,is extensively discussed in this article and new therapeutic strategies targeting this pathological link are presented and reviewed.

关键词： brain insulin resistance brain insulin signaling diabetes type 2 GLP-1 receptor agonists GLP-1 signaling insulin resistance insulin signaling neurodegeneration Parkinson's disease targeted therapy

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Exploiting fly models to investigate rare human neurological disorders

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Neural Regeneration Research 2025年第1期20卷 21-28页

作者： Tomomi Tanaka Hyung-Lok Chung department of neurology Houston Methodist Research InstituteHoustonTXUSA department of neurology Weill Cornell Medical CollegeNew YorkNYUSA

Rare neurological diseases,while individually are rare,collectively impact millions globally,leading to diverse and often severe neurological *** attributed to genetic mutations that disrupt protein function or structure,understanding their genetic basis is crucial for accurate diagnosis and targeted *** investigate the underlying pathogenesis of these conditions,researchers often use non-mammalian model organisms,such as Drosophila(fruit flies),which is valued for their genetic manipulability,cost-efficiency,and preservation of genes and biological functions across evolutionary *** tools available in Drosophila,including CRISPR-Cas9,offer a means to manipulate gene expression,allowing for a deep exploration of the genetic underpinnings of rare neurological *** boasts a versatile genetic toolkit,rapid generation turnover,and ease of large-scale experimentation,making it an invaluable resource for identifying potential drug *** can expose flies carrying disease-associated mutations to various compounds,rapidly pinpointing promising therapeutic agents for further investigation in mammalian models and,ultimately,clinical *** this comprehensive review,we explore rare neurological diseases where fly research has significantly contributed to our understanding of their genetic basis,pathophysiology,and potential therapeutic *** discuss rare diseases associated with both neuron-expressed and glial-expressed *** cases include mutations in CDK19 resulting in epilepsy and developmental delay,mutations in TIAM1 leading to a neurodevelopmental disorder with seizures and language delay,and mutations in IRF2BPL causing seizures,a neurodevelopmental disorder with regression,loss of speech,and abnormal *** we explore mutations in EMC1 related to cerebellar atrophy,visual impairment,psychomotor retardation,and gain-of-function mutations in ACOX1 causing Mitchell ***-of-fun

关键词： ACOX1 Drosophila melanogaster glia lipid metabolism model organisms neuroinflammation neurologic disorders neuron rare disease VLCFA

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Complement-dependent neuroinflammation in spinal cord injury:from pathology to therapeutic implications

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Neural Regeneration Research 2025年第5期20卷 1324-1335页

作者： Hassan Saad Bachar El Baba Ali Tfaily Firas Kobeissy Juanmarco Gutierrez Gonzalez Daniel Refai Gerald R.Rodts Christian Mustroph David Gimbel Jonathan Grossberg Daniel L.Barrow Matthew F.Gary Ali M.Alawieh department of Neurosurgery Emory University School of MedicineAtlantaGAUSA department of neurology Yale UniversityNew HavenCTUSA Center for Neurotrauma Multiomics&Biomarkers(CNMB)Morehouse School of MedicineAtlantaGAUSA

Spinal cord injury remains a major cause of disability in young adults,and beyond acute decompression and rehabilitation,there are no pharmacological treatments to limit the progression of injury and optimize recovery in this *** the thorough investigation of the complement system in triggering and propagating cerebral neuroinflammation,a similar role for complement in spinal neuroinflammation is a focus of ongoing *** this work,we survey the current literature investigating the role of complement in spinal cord injury including the sources of complement proteins,triggers of complement activation,and role of effector functions in the *** study relevant data demonstrating the different triggers of complement activation after spinal cord injury including direct binding to cellular debris,and or activation via antibody binding to damage-associated molecular *** effector functions of complement have been implicated in spinal cord injury,and we critically evaluate recent studies on the dual role of complement anaphylatoxins in spinal cord injury while emphasizing the lack of pathophysiological understanding of the role of opsonins in spinal cord *** this pathophysiological review,we systematically review the different translational approaches used in preclinical models of spinal cord injury and discuss the challenges for future translation into human *** review emphasizes the need for future studies to dissect the roles of different complement pathways in the pathology of spinal cord injury,to evaluate the phases of involvement of opsonins and anaphylatoxins,and to study the role of complement in white matter degeneration and regeneration using translational strategies to supplement genetic models.

关键词： complement neuroinflammation neuroplasticity regeneration spinal cord injury targeted therapy

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Assessment of new pathological markers in early stage colon cancer:Insights and limitations

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World Journal of Gastrointestinal Oncology 2025年第3期17卷 113-121页

作者： Bulent Erdogan Fatma Elif UsturalıKeskin ErkanÖzcan Ahmet Küçükarda Ali Kaan Güren Osman Köstek Bekir Muhammet Hacioglu Hilmi Kodaz department of Medical Oncology Division of Medical OncologyDepartment of Internal MedicineTrakya University School of MedicineEdirne 22000Türkiye department of Pathology Trakya University School of MedicineTrakya UniversityEdirne 22000Türkiye Division of Medical Oncology Trakya University School of MedicineEdirne 22000Türkiye Division of Medical Oncology Department of Internal MedicineTrakya University School of MedicineEdirne 22000Türkiye Division of Medical Oncology Department of Internal MedicineMarmara University School of MedicineMarmara UniversityIstanbul 34000Türkiye Division of Medical Oncology Department of Internal MedicineMarmara University School of MedicineIstanbul 34000Türkiye department of Medical Oncology Acibadem Eskisehir HospitalEskisehir 26130Türkiye

BACKGROUND The decision to administer adjuvant chemotherapy to patients with local stage depends on specific high-risk features that are T4 tumor stage,presence of perineural invasion,lymphovascular invasion,poorly differentiated tumor histology,inadequate lymph node sampling(fewer than 12 lymph nodes),and evidence of tumor perforation or ***-stroma ratio,tumor infiltrating lymphocytes(TIL),Crohn-like reaction(CLR),desmoid reaction,poorly differentiated clusters(PDC)are new pathological markers that are being *** To examine the relationship between new pathological markers and defined high METHODS We evaluated 155 patients with the diagnosis stage I and II colorectal cancer between the years 2007 and 2021 who were treated at Trakya University Hospital,department of Medical *** divided those with and without high-risk factors into two *** examined the relationship of new pathological markers with these groups and with pathological markers in risk *** There was no statistically significant correlation between presence of TIL,presence of PDC,presence of tumor budding,presence of CLR,presence of desmoid reaction and low and high-risk groups according to the degree of those with PDC(P=0.82,P=0.51,P=0.77,P=0.37,P=0.83,respectively).In addition,no statistically significant correlation was found between the tumor-stroma ratio and low and high risk groups(P=0.80).We found a statistically significant correlation between the presence of PDC and the presence of PDC grade 3 and T stage(P=0.001,P=0.001,respectively).It was determined that the presence of PDC and the frequency of grade 3 PDC increased with the advanced T *** No relationship was found between the presence of new pathological markers and high-low risk *** we examined the relationship between new and old pathological markers,only the frequency of detection of PDC and PDC grade 3 was found to be correlated with advanced T stage.

关键词： Colon cancer Early stage Risk factors New pathological markers Tumor-stroma ratio Tumor infiltrating lymphocytes Crohn-like reaction Desmoid reaction Poorly differentiated clusters

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Blood biomarkers of Alzheimer’s disease:important considerations for use in clinical practice

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Neural Regeneration Research 2025年第1期20卷 205-206页

作者： Sarah Fullam Sean O’Dowd Antoinette O’Connor department of neurology Tallaght University HospitalDublinIreland Academic Unit of neurology Trinity College DublinIreland

Introduction:Fluid and positron emission tomography(PET)biomarkers that enable the detection of the hallmark proteins of Alzheimer’s disease(AD)(amyloid and tau)have revolutionized our approach to the diagnosis of *** evolution of AD diagnostic criteria to include biological characterization(Alzheimer’s Association Working Group,2023)provides an appropriate framework to reduce levels of clinico-pathologic mismatch and improve in-vivo diagnostic *** the therapeutic landscape for neurodegenerative disease evolves,it is increasingly incumbent on clinicians to provide timely,and pathologically precise diagnoses for ***,the expensive and invasive nature of these tests limits their scalability.

关键词： Blood Alzheimer diagnosis

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Bile acid therapy for primary biliary cholangitis:Pathogenetic validation

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World Journal of Experimental medicine 2025年第1期15卷 53-64页

作者： Vasiliy I Reshetnyak Igor V Maev department of Propaedeutics of internal Diseases and Gastroenterology Russian University of MedicineMoscow 127473Russia

Knowledge of the etiological and pathogenetic mechanisms of the development of any disease is essential for its *** the cause of primary biliary cholangitis(PBC),a chronic,slowly progressive cholestatic liver disease,is still unknown,treatment remains *** of the physicochemical properties of various bile acids and the adaptive responses of cholangiocytes and hepatocytes to them has provided an important basis for the development of relatively effective drugs based on hydrophilic bile acids that can potentially slow the progression of the *** in the use of hydrophilic bile acids for the treatment of PBC are also associated with the discovery of pathogenetic mechanisms of the development of cholangiocyte damage and the appearance of the first signs of this *** 35 years,ursodeoxycholic acid(UDCA)has been the unique drug of choice for the treatment of patients with *** recent years,the list of hydrophilic bile acids used to treat cholestatic liver diseases,including PBC,has *** addition to UDCA,the use of obeticholic acid,tauroursodeoxycholic acid and norursodeoxycholic acid as drugs is *** pathogenetic rationale for treatment of PBC with various bile acid drugs is discussed in this *** is made on the mechanisms explaining the beneficial therapeutic effects and potential of each of the bile acid as a drug,based on the understanding of the pathogenesis of the initial stages of PBC.

关键词： Primary biliary cholangitis Treatment of primary biliary cholangitis with bile acids Ursodeoxycholic acid Obeticholic acid Tauroursodeoxycholic acid Norursodeoxycholic acid

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Gel immersion in endoscopy:Exploring potential applications

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World Journal of Gastroenterology 2025年第4期31卷 24-41页

作者： Hiroki Sato Hidemasa Kawabata Mikihiro Fujiya department of internal medicine Asahikawa Medical UniversityAsahikawa 078-8510HokkaidoJapan

The challenge of effectively eliminating air during gastrointestinal endoscopy using ultrasound techniques is *** difficulty arises from the intricacies of removing concealed air within the folds of the gastrointestinal tract,resulting in artifacts and compromised *** addition,the overlap of folds with lesions can obscure their depth and size,presenting challenges for an accurate ***,in intricately folded regions of the gastrointestinal tract,such as the stomach,intestine,and colon,insufficient delivery of air or CO_(2) into the cavity impedes luminal expansion,hindering the accurate visualization of lesions concealed within the *** this underscores the requirement for substantial airflow,excessive airflow can hinder visualization of bleeding lesions and other *** these challenges,an ideal endoscopic device would facilitate the observation of lesions without the requirement for air or CO_(2) delivery whereas,ensuring optimal expansion of the gastrointestinal ***,transparent gels with specific viscosities have been employed more frequently to address this *** review aims to elucidate how these gels address these challenges and provide a solution for enhanced endoscopic visualization.

关键词： Gel immersion Endoscopy Endoscopic visualization Gastrointestinal endoscopy Endoscopic ultrasonography

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Predictive value of the systemic immune inflammation index in recurrence of atrial fibrillation after radiofrequency catheter ablation

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World Journal of Cardiology 2025年第1期17卷 22-27页

作者： Alexander E Berezin department of internal medicine-II Paracelsus Medical University SalzburgSalzburg 5020Austria

The recurrence of atrial fibrillation(AF)in patients after successful radiofrequency catheter ablation(RFCA)appears to be an unresolved clinical issue and needs to be clearly *** are many factors associated with AF recurrence,such as duration of AF,male sex,concomitant heart failure,hemodynamic parameters,chronic obstructive pulmonary disease,hypertension,obstructive sleep apnea,hyperthyroidism,smoking and ***,the inflammatory changes are strongly associated with electrical and structural cardiac remodeling,cardiac damage,myocardial fibrotic changes,microvascular dysfunction and altered reparative *** this context,biomarkers reflecting the different stages of AF pathogenesis deserve thorough *** authors of the retrospective study revealed that one-year recurrence rate of non-valvular AF in the high systemic immune inflammation(SII)index group was significantly increased compared to that of the low SII index group and provided additional predictive value to the ***,the authors suggest that this biomarker may help physicians to optimize the selection of AF patients and to develop a personalized treatment *** conclusion,the SII index may serve as a valuable indicator of recurrent AF in patients after RFCA and may be a biomarker with plausible predictive value for poor clinical outcomes.

关键词： Systemic immune inflammation index Recurrent atrial fibrillation Radiofrequency catheter ablation Biomarkers APPLE score Prediction

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