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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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Promising effects of Persian shallot extract on the serum markers and blood pressure of patients with metabolic syndrome:a double-blinded randomized controlled trial

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Journal of Traditional Chinese medicine 2025年第1期45卷 100-106页

作者： Neda Naimipoor Zahra Bagheri-Hosseinabadi Mohammad Reza Hajizadeh Mitra Abbasifard Mohammad Reza Mirzaei Akram Ghadiri Anari Maryam Mohammad-Sadeghipour Mehdi Mahmoodi department of Clinical Biochemistry School of MedicineRafsanjan University of Medical Sciences department of internal medicine School of MedicineAli-Ibn Abi-Talib HospitalRafsanjan University of Medical Sciences Molecular medicine Research Center Research Institute of Basic Medical SciencesRafsanjan University of Medical Sciences Diabetes Research Center Shahid Sadoughi University of Medical Sciences department of Clinical Biochemistry Afzalipour School of MedicineKerman University of Medical Sciences Physiology Research Center Institute of NeuropharmacologyKerman University of Medical Sciences

OBJECTIVE: To evaluate the effect of Persian shallot extract on the serum markers and blood pressure of patients with metabolic syndrome(MetS). METHODS: Fifty patients with Met S diagnosis were randomly assigned to the intervention(Persian shallot extract) and the control(placebo) group. Both groups received treatment for three months. Before the study and at the end of the study, 5 mL peripheral blood was taken from each patient. The measured factors included total antioxidant capacity(TAC), superoxide dismutase enzyme(SOD), malondialdehyde, oxidized low-density lipoprotein(Ox-LDL), apolipoprotein H(Apo-H), fasting blood glucose(FBS), total cholesterol, triglycerides, high-density lipoprotein(HDL), LDL, and systolic and diastolic blood pressure. RESULTS: At baseline, the evaluated parameters were not significantly different between the intervention and control groups. At the end of the study, the mean serum levels of malondialdehyde and ox-LDL were significantly lower in the intervention group. The mean FBS, cholesterol, triglycerides, and LDL were significantly lower in the intervention group. The mean TAC and HDL were significantly higher in the intervention group(P < 0.05). Moreover, the intervention group significantly reduced systolic and diastolic blood pressure. No other significant association was observed. CONCLUSION: Persian shallot extract has several beneficial effects in Met S patients, including optimizing oxidative balance, reducing blood pressure, fasting blood sugar, and blood lipid profile.

关键词： antioxidants medicine, Persian metabolic syndrome shallots

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Integrating machine learning and human use experience to identify personalized pharmacotherapy in Traditional Chinese medicine:a case study on resistant hypertension

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Journal of Traditional Chinese medicine 2025年第1期45卷 192-200页

作者： CHE Qianzi LIU Dasheng XIANG Xinghua TIAN Yaxin XIE Feibiao XU Wenyuan LIU Jian WANG Xuejie WANG Liying BAI Weiguo HAN Xuejie YANG Wei department of medical Statistics Institute of Basic Research in Clinical MedicineChina Academy of Chinese Medical Sciences department of science and Education Medical Statistics Teaching and Research OfficeInstitute of Basic Research in Clinical MedicineChina Academy of Chinese Medical Sciences Computer department Xiyuan Hospital of the China Academy of Chinese Medical Sciences Traditional Chinese medicine Standards Research Center Medical Statistics Teaching and Research OfficeInstitute of Basic Research in Clinical MedicineChina Academy of Chinese Medical Sciences

OBJECTIVE: To enhance the understanding of identifying personalized pharmacotherapy options in Traditional Chinese medicine(TCM), and further support the registration of new TCM drugs. METHODS: Generalized Boosted Models and XGBoost were employed to construct a classification model to identify the bad prognosis factors in resistant hypertension(RH) patients. Furthermore, we used association analysis to explore the rules of "symptomsyndrome" and "symptom-herb" for the major influencing factors, in order to summarize prescription pattern and applicable patients of TCM. RESULTS: Patients with major adverse cardiac events mostly have complex symptoms of phlegm, stasis, deficiency and fire intermingled with each other, and finally summarized the human experience of using Chinese herbal medicine to precisely intervene in some symptoms of RH patients on the basis of conventional Western medical treatment. CONCLUSIONS: Machine learning algorithms can make full use of human use experience and evidence to save clinical trial resources and accelerate the development of TCM varieties.

关键词： human clinical experience machine learning new drugs registration personalized pharmacotherapy

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Endothelial dysfunction in the kidney transplant population:Current evidence and management strategies

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World Journal of Transplantation 2025年第1期15卷 24-43页

作者： Arun Prabhahar Akshey Batta Juniali Hatwal Vivek Kumar Raja Ramachandran Akash Batta department of Telemedicine(internal medicine and Nephrology) Post Graduate Institute of Medical Education and ResearchChandigarh 160012India department of Urology and Renal Transplant Neelam HospitalRajpura 140401PunjabIndia department of internal medicine Post Graduate Institute of Medical Education and ResearchChandigarh 160012India department of Nephrology Post Graduate Institute of Medical Education and ResearchChandigarh 160012India department of Cardiology Dayanand Medical College and HospitalLudhiana 141001PunjabIndia

The endothelium modulates vascular homeostasis owing to a variety of vasoconstrictors and *** dysfunction(ED),characterized by impaired vasodilation,inflammation,and thrombosis,triggers future cardiovascular(CV)*** kidney disease,a state of chronic inflammation caused by oxidative stress,metabolic abnormalities,infection,and uremic toxins damages the *** is also associated with a decline in estimated glomerular filtration *** kidney transplantation,endothelial functions undergo immediate but partial restoration,promising graft longevity and enhanced CV ***,the anticipated CV outcomes do not happen due to various transplant-related and unrelated risk factors for ED,culminating in poor CV health and graft *** in kidney transplant recipients is an underrecognized and poorly studied *** diseases are the leading cause of death among kidney transplant candidates with functioning *** contributes to the pathogenesis of many of the CV *** biomarkers and vasoreactivity tests are available to study endothelial *** an increasing number of transplants happening every year,and improved graft rejection rates due to the availability of effective immunosuppressants,the focus has now shifted to endothelial protection for the prevention,early recognition,and treatment of CV diseases.

关键词： Endothelial dysfunction Endothelium Cardiovascular disease Kidney transplantation Chronic kidney disease Nitric oxide Flow-mediated dilatation Nitro-glycerine-mediated dilatation Biomarkers

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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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Comprehensive molecular characterization to predict immunotherapy response in advanced biliary tract cancer:a phase II trial of pembrolizumab

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Oncology Research 2025年第1期33卷 57-65页

作者： RYUL KIM JOO KYUNG PARK MINSUK KWON MINAE AN JUNG YONG HONG JOON OH PARK SUNG HEE LIM SEUNG TAE KIM Division of Hematology-Oncology Department of MedicineSamsung Medical CenterSungkyunkwan University School of MedicineSeoulKorea Division of Gastroenterology Department of MedicineSamsung Medical CenterSungkyunkwan University School of MedicineSeoulKorea department of Hematology-Oncology Ajou University School of MedicineSuwon-siGyeonggi-doKorea Samsung Advanced institute of Health science and Technology Sungkyunkwan University School of MedicineSeoulKorea

Background:Immune checkpoint inhibitors(ICIs)are effective in a subset of patients with metastatic solid ***,the patients who would benefit most from ICIs in biliary tract cancer(BTC)are still *** and methods:We molecularly characterized tissues and blood from 32 patients with metastatic BTC treated with the ICI pembrolizumab as second-line ***:All patients had microsatellite stable(MSS)type *** of the 32 patients achieved partial response(PR),with an objective response rate(ORR)of 9.4%(95%confidence interval[CI],2.0–25.2)and nine showed stable disease(SD),exhibiting a disease control rate(DCR)of 37.5%(95%CI,21.1–56.3).For the 31 patients who had access to PD-1 ligand 1(PD-L1)combined positive score(CPS)testing(cut-off value≥1%),the ORR was not different between those who had PD-L1-positive(PD-L1+;1/11,9.1%)and PDL1-(2/20,10.0%)tumors(p=1.000).The tumor mutational burden(TMB)of PD-L1+BTC was comparable to that of PD-L1-BTC(p=0.630).TMB and any exonic somatic mutations were also not predictive of pembrolizumab *** analysis of blood and tumor samples demonstrated a relatively high natural killer(NK)cell proportion in the peripheral blood before pembrolizumab treatment in patients who achieved tumor ***,the tumors of these patients presented high enrichment scores for NK cells,antitumor cytokines,and Th1 signatures,and a low enrichment score for cancer-associated ***:This study shows the molecular characteristics associated with the efficacy of pembrolizumab in BTC of the MSS type.

关键词： Pembrolizumab Whole-exome sequencing Whole-transcriptome sequencing Biliary tract cancer

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Clinical and endoscopic characteristics of colorectal traditional serrated adenomas with dysplasia/adenocarcinoma in a Korean population

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World Journal of Gastrointestinal Oncology 2025年第2期17卷 119-131页

作者： Ki-Hyun Kim Eun Myung Hyung Hoon Oh Chan-Muk Im Young-Eun Seo Je-Seong Kim Chae-June Lim Ga-Ram You Sung-Bum Cho Wan-Sik Lee Myung-Giun Noh Kyung-Hwa Lee Young-Eun Joo department of internal medicine Chonnam National University Medical SchoolHwasun-eup 58128South Korea department of Pathology Chonnam National University Medical SchoolHwasun-eup 58128South Korea

BACKGROUND Traditional serrated adenoma(TSA)is a rare and precancerous lesion of colorectal *** clinical and endoscopic differentiations between TSAs without dysplasia or adenocarcinoma(TSAOs)and TSAs with dysplasia or adenocarcinoma(TSADs)remain *** To evaluate the characteristics of colorectal TSAs and compare the characteristics of TSAOs with those of *** This retrospective study included 193 patients who underwent endoscopic resection and received a pathologic diagnosis of *** reviewed the medical,endoscopic,and histopathologic records of patients who underwent endoscopic resection of TSAs between January 2010 and December *** TSAs were more frequently located in the rectosigmoid *** TSAs had 0-Ip,0-Isp,or 0-Is *** TSAD lesions were larger than TSAO *** lesions more commonly had a red color and an irregular border than TSAO *** were usually treated using conventional endoscopic mucosal resection,whereas TSADs were treated using conventional endoscopic mucosal resection,endoscopic submucosal dissection,and ***-polypectomy bleeding was more common with TSADs than with *** analysis showed that gastrointestinal bleeding,red color,0-IIa,irregular border,and lobular mucosal surface were significantly associated with *** analysis showed that gastrointestinal bleeding,an irregular border,and a lobular mucosal surface were significantly associated with *** TSAs with gastrointestinal bleeding,an irregular border,and a lobular mucosal surface are associated with an increased risk of dysplasia or adenocarcinoma.

关键词： Traditional serrated adenoma Dysplasia Carcinoma Endoscopic features Gastrointestinal bleeding

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Repetitive traumatic brain injury–induced complement C1–related inflammation impairs long-term hippocampal neurogenesis

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Neural Regeneration Research 2025年第3期20卷 821-835页

作者： Jing Wang Bing Zhang Lanfang Li Xiaomei Tang Jinyu Zeng Yige Song Chao Xu Kai Zhao Guoqiang Liu Youming Lu Xinyan Li Kai Shu department of Neurosurgery Tongji HospitalTongji Medical CollegeHuazhong University of Science and TechnologyWuhanHubei ProvinceChina department of Neurosurgery Shanxi Bethune HospitalShanxi Academy of Medical SciencesTongji Shanxi HospitalThird Hospital of Shanxi Medical UniversityTaiyuanShanxi ProvinceChina department of Pathophysiology School of Basic Medicine and Tongji Medical CollegeHuazhong University of Science and TechnologyWuhanHubei ProvinceChina institute for Brain Research Wuhan Center of Brain ScienceHuazhong University of Science and TechnologyWuhanHubei ProvinceChina department of Graduate Student Chongqing Medical UniversityChongqingChina department of Basic medicine School of Medical ScienceHubei University for NationalitiesEnshiHubei ProvinceChina department of Anatomy School of Basic Medicine and Tongji Medical CollegeHuazhong University of Science and TechnologyWuhanHubei ProvinceChina

Repetitive traumatic brain injury impacts adult neurogenesis in the hippocampal dentate gyrus,leading to long-term cognitive ***,the mechanism underlying this neurogenesis impairment remains *** this study,we established a male mouse model of repetitive traumatic brain injury and performed long-term evaluation of neurogenesis of the hippocampal dentate gyrus after repetitive traumatic brain *** results showed that repetitive traumatic brain injury inhibited neural stem cell proliferation and development,delayed neuronal maturation,and reduced the complexity of neuronal dendrites and *** with repetitive traumatic brain injuryalso showed deficits in spatial memory ***,following repetitive traumatic brain injury,neuroinflammation was enhanced in the neurogenesis microenvironment where C1q levels were increased,C1q binding protein levels were decreased,and canonical Wnt/β-catenin signaling was *** inhibitor of C1 reversed the long-term impairment of neurogenesis induced by repetitive traumatic brain injury and improved neurological *** findings suggest that repetitive traumatic brain injury–induced C1-related inflammation impairs long-term neurogenesis in the dentate gyrus and contributes to spatial memory retrieval dysfunction.

关键词： complement C1 dendrite dentate gyrus hippocampus neural stem cell neurogenesis neuroinflammation neurological function neuron traumatic brain injury

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Demographic trends in mortality with older population due to atrial fibrillation and flutter from 1999-2020

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World Journal of Cardiology 2025年第1期17卷 1-7页

作者： Mahnoor Sukaina Marium Waheed Shafi Rehman Md Al Hasibuzzaman Rabab Meghani department of internal medicine Karachi Medical and Dental CollegeKarachi 75270Pakistan department of Histopathology Khyber Medical UniversityPeshawar25000Pakistan institute of Nutrition and Food science University of DhakaDhaka 1000Bangladesh department of Bioethics Columbia UniversityNew YorkNY 10027United States

Atrial fibrillation(AF)/atrial flutter(AFL)is the most common sustained cardiac *** known risk factors for developing AF/AFL include age,structural heart disease,hypertension,diabetes mellitus,or *** study aims to attribute the trends in AF/AFL-related mortalities over the past two decades 1999-2020 concerning race and sex and disparity among *** the best of our knowledge,this is the first study that estimates the trends and mortality due to AF/AFL from 1999-2020 in older adults in the United *** this 21-year analysis of mortality data,we found a constant increase in mortality rates due to AF/AFL in older *** 1999 to 2020,the overall mortality in older adults aged 65 and above,regardless of sex and race,is found to be almost doubled *** a 50.2%increase in the number of deaths due to AF/***,other confounding risk factors such has obesity,prior myocardial infarction,inflammation,hypertension,birth weight,diabetes mellitus,hyperthyroidism,hormone replacement therapy in menopausal women increases the risk in the occurrence or recurrent occurrence of AF.

关键词： Demographic trends United States Atrial fibrillation Atrial flutter Older population

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Fibrotic liver extracellular matrix induces cancerous phenotype in biomimetic micro-tissues of hepatocellular carcinoma model

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Hepatobiliary & Pancreatic Diseases International 2025年第1期24卷 92-103页

作者： Kosar Nouri Abbas Piryaei Homeyra Seydi Ibrahim Zarkesh Ibrahim Ghoytasi Bahare Shokouhian Mustapha Najimi Massoud Vosough department of Developmental Biology University of Science and CultureACECR 14155-4364 TehranIran department of Regenerative medicine Cell Science Research CenterRoyan Institute for Stem Cell Biology and TechnologyACECR 14155-4364 TehranIran department of Stem Cells and Developmental Biology Cell Science Research CenterRoyan Institute for Stem Cell Biology and TechnologyACECR 14155-4364 TehranIran department of Biology and Anatomical sciences School of MedicineShahid Beheshti University of Medical SciencesTehranIran department of Tissue Engineering and Applied Cell sciences School of Advanced Technologies in MedicineShahid Beheshti University of Medical SciencesTehranIran department of Cell Engineering Cell Science Research CenterRoyan Institute for Stem Cell Biology and TechnologyACECR 14155-4364 TehranIran department of medical Biotechnology School of Advanced Technologies in MedicineTehran University of Medical SciencesTehranIran Laboratory of Pediatric Hepatology and Cell Therapy Institute of Experimental and Clinical Research(IREC)UCLouvainBrusselsBelgium Experimental Cancer medicine Institution for Laboratory MedicineKarolinska InstituteStockholmSweden

Background: Despite considerable advancements in identifying factors contributing to the development of hepatocellular carcinoma(HCC), the pathogenesis of HCC remains unclear. In many cases, HCC is a consequence of prolonged liver fibrosis, resulting in the formation of an intricate premalignant microenvironment. The accumulation of extracellular matrix(ECM) is a hallmark of premalignant microenvironment. Given the critical role of different matrix components in regulating cell phenotype and function, this study aimed to elucidate the interplay between the fibrotic matrix and malignant features in HCC. Methods: Liver tissues from both control(normal) and carbon tetrachloride(CCl_(4))-induced fibrotic rats were decellularized using sodium dodecyl sulfate(SDS) and Triton X-100. The resulting hydrogel from decellularized ECM was processed into micro-particles via the water-in-oil emulsion method. Microparticles were subsequently incorporated into three-dimensional liver biomimetic micro-tissues(MTs) comprising Huh-7 cells, human umbilical vein endothelial cells(HUVECs), and LX-2 cells. The MTs were evaluated using the 3-(4,5-dimethylthiazol-2-yl)-5-(3-carboxymethoxyphenyl)-2-(4-sulfophenyl)-2H-tetrazolium(MTS) assay at day 11, immunofluorescence staining, immunoblotting, and spheroid migration assay at day 14 after co-culture. Results: Fibrotic matrix from CCl4-treated rat livers significantly enhanced the growth rate of the MTs and their expression of CCND1 as compared to the normal one. Fibrotic matrix, also induced the expression of epithelial-to-mesenchymal transition(EMT)-associated genes such as TWIST1, ACTA2, MMP9, CDH2, and VIMENTIN in the MTs as compared to the normal matrix. Conversely, the expression of CDH1 and hepatic maturation genes HNF4A, ALB, CYP3A4 was decreased in the MTs when the fibrotic matrix was used. Furthermore, the fibrotic matrix increased the migration of the MTs and their secretion of alpha-fetoprotein. Conclusions: Our findings suggest a

关键词： Liver fibrosis Decellularized extracellular matrix Spheroid Epithelial-to-mesenchymal transition Cell differentiation Hepatocellular carcinoma

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