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Signal Transduction and Targeted Therapy 2024年第3期9卷 1174-1185页

作者： Sumit Bhattacharyya Joanne K.Tobacman Jesse Brown va medical center and University of Illinois at Chicago ChicagoIL 60612USA

Immunostaining in lungs of patients who died with CovID-19 infection showed increased intensity and distribution of chondroitin sulfate and decline in N-acetylgalactostamine-4-sulfatase(Arylsulfatase B;ARSB).To explain these findings,human small airway epithelial cells were exposed to the SARS-CoV-2 spike protein receptor binding domain(SPRBD)and transcriptional mechanisms were ***-p38 MAPK and phospho-SMAD3 increased following exposure to the SPRBD,and their inhibition suppressed the promoter activation of the carbohydrate sulfotransferases CHST15 and CHST11,which contributed to chondroitin sulfate *** in ARSB was mediated by phospho-38 MAPK-induced N-terminal Rb phosphorylation and an associated increase in Rb-E2F1 binding and decline in E2F1 binding to the ARSB *** increases in chondroitin sulfotransferases were inhibited when treated with phospho-p38-MAPK inhibitors,SMAD3(SIS3)inhibitors,as well as antihistamine desloratadine and antibiotic *** the mouse model of carrageenan-induced systemic inflammation,increases in phosphop38 MAPK and expression of CHST15 and CHST11 and declines in DNA-E2F binding and ARSB expression occurred in the lung,similar to theobserved effects in this SPRBD model of COVID-19 *** accumulation of chondroitin sulfates is associated with fibrotic lung conditions and diffuse alveolar damage,increased attention to p38-MAPK inhibition may be beneficial in amelioratingCovid-19infections.

关键词： ACE2 lung inhibited

Metabolites and micronutrition in modulating amyotrophic lateral sclerosis

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Neural Regeneration Research 2024年第6期19卷 1183-1184页

作者： Katerina Claud Jun Sun Department of Medicine University of Illinois ChicagoChicagoILUSA Jesse Brown va medical center Chicago ChicagoILUSA

Amyotrophic lateral sclerosis(ALS)is a progressive neurodegenerative *** majority of ALS cases are sporadic with only about 20%of familial *** in families with genetic predisposition,there is significant phenotypic va... 详细信息

关键词： sclerosis amyotrophic cases

Blood-brain barrier pathology in cerebral small vessel disease

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Neural Regeneration Research 2024年第6期19卷 1233-1240页

作者： Ruxue Jia Gemma Solé-Guardia Amanda J.Kiliaan Department of medical Imaging AnatomyRadboud University Medical CenterDonders Institute for BrainCognition&BehaviorCenter for Medical NeurosciencePreclinical Imaging Center PRIMERadboud Alzheimer CenterNijmegenthe Netherlands

Cerebral small vessel disease is a neurological disease that affects the brain microvasculature and which is commonly observed among the *** at first it was considered innocuous,small vessel disease is nowadays regarded as one of the major vascular causes of *** signs of small vessel disease include small subcortical infarcts,white matter magnetic resonance imaging hyperintensities,lacunes,enlarged perivascular spaces,cerebral microbleeds,and brain atrophy;however,great heterogeneity in clinical symptoms is observed in small vessel disease *** pathophysiology of these lesions has been linked to multiple processes,such as hypoperfusion,defective cerebrovascular reactivity,and blood-brain barrier ***,studies on small vessel disease suggest that blood-brain barrier dysfunction is among the earliest mechanisms in small vessel disease and might contribute to the development of the hallmarks of small vessel ***,the purpose of this review is to provide a new foundation in the study of small vessel disease ***,we discuss the main structural domains and functions of the blood-brain ***,we review the most recent evidence on blood-brain barrier dysfunction linked to small vessel ***,we conclude with a discussion on future perspectives and propose potential treatment targets and interventions.

关键词： blood-brain barrier dysfunction cerebral blood flow cerebral hypoperfusion endothelial dysfunction hypertension inflammation magnetic resonance imaging neurovascular unit oxidative stress small vessel disease tight junctions transcytosis

ATP6AP2,a regulator of LRP6/β-catenin protein trafficking,promotes Wnt/β-catenin signaling and bone formation in a cell type dependent manner

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Bone Research 2024年第2期12卷 453-468页

作者： Lei Xiong Hao-Han Guo Jin-Xiu Pan Xiao Ren Daehoon Lee Li Chen Lin Mei Wen-Cheng Xiong Department of Neurosciences School of MedicineCase Western Reserve UniversityClevelandOH 44106USA Louis Stoke va medical center ClevelandOH 44106USA

Wnt/β-catenin signaling is critical for various cellular processes in multiple cell types,including osteoblast(OB)differentiation and *** how Wnt/β-catenin signaling is regulated in OBs remain ***6AP2,an accessory subunit of V-ATPase,plays important roles in multiple cell types/organs and multiple signaling ***,little is known whether and how ATP6AP2 in OBs regulates Wnt/β-catenin signaling and bone *** we provide evidence for ATP6AP2 in the OB-lineage cells to promote OB-mediated bone formation and bone homeostasis selectively in the trabecular bone *** knocking out(CKO)ATP6AP2 in the OB-lineage cells(Atp6ap2^(Ocn-Cre))reduced trabecular,but not cortical,bone formation and bone *** and cellular biochemical studies revealed that LRP6 and N-cadherin were reduced in ATP6AP2-KO BMSCs and OBs,but not *** in vitro and in vivo studies revealed impairedβ-catenin signaling in ATP6AP2-KO BMSCs and OBs,but not osteocytes,under both basal and Wnt stimulated conditions,although LRP5 was decreased in ATP6AP2-KO osteocytes,but not *** cell biological studies uncovered that osteoblastic ATP6AP2 is not required for Wnt3a suppression ofβ-catenin phosphorylation,but necessary for LRP6/β-catenin and N-cadherin/β-catenin protein complex distribution at the cell membrane,thus preventing their *** of activeβ-catenin diminished the OB differentiation deficit in ATP6AP2-KO *** together,these results support the view for ATP6AP2 as a critical regulator of both LRP6 and N-cadherin protein trafficking and stability,and thus regulatingβ-catenin levels,demonstrating an un-recognized function of osteoblastic ATP6AP2 in promoting Wnt/LRP6/β-catenin signaling and trabecular bone formation.

关键词： LRP6 impaired organs

Mixed neuroendocrine and adenocarcinoma of gastrointestinal tract:A complex diagnosis and therapeutic challenge

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World Journal of Gastrointestinal Oncology 2024年第6期16卷 2295-2299页

作者： Santosh Shenoy Department of General Surgery Kansas City VA Medical CenterUniversity of Missouri-Kansas CityKansas CityMO 64128United States

In this editorial we comment on the manuscript describing a case of adenocarcinoma mixed with a neuroendocrine carcinoma of the gastroesophageal *** neuroendocrine and non-neuroendocrine neoplasms of the gastrointestinal system are rare heterogeneous group of tumors characterized by a high malignant potential,rapid growth,and poor *** to the rarity of these cancers,the standard therapy is poorly *** diagnosis of these tumors is based on combination of morphological features,immunohistochemical and neuroendocrine and epithelial cell *** endocrine and epithelial cell components can act independently of each other and thus,careful grading of each component separately is *** cancers are aggressive in nature and the potential of each component has paramount importance in the choice of treatment and *** of the organ of origin,these tumors portend poor prognosis with increased proportion of neuroendocrine *** services and strategies are required for the management of these mixed malignancies to provide the best oncological *** etiopathogenesis of these mixed tumors remains obscure but poses interesting *** briefly discuss a few salient points in this editorial.

关键词： Mixed adenocarcinoma and neuroendocrine carcinoma Mixed neuroendocrine and non-neuroendocrine neoplasm Mixed adeno-neuroendocrine cancer Cell reprograming Tumor plasticity

Carrimycin ameliorates lipopolysaccharide and cecal ligation and puncture-induced sepsis in mice

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Chinese Journal of Natural Medicines 2024年第3期22卷 235-248页

作者： LAI Junzhong LIANG Jiadi CHEN Kunsen GUAN Biyun CHEN Zhirong CHEN Linqin FAN Jiqiang ZHANG Yong LI Qiumei SU Jingqian CHEN Qi LIN Jizhen The Cancer center Fujian Medical University Union HospitalFuzhou 350001China Fujian Key Laboratory of Innate Immune Biology Biomedical Research Center of South ChinaFujian Normal UniversityFuzhou 350117China The Department of Otolaryngology Head&Neck SurgeryUniversity of Minnesota Medical SchoolMinneapolisMN 55455USA

Carrimycin(CA),sanctioned by China’s National medical Products Administration(NMPA)in 2019 for treating acute bronchitis and sinusitis,has recently been observed to exhibit multifaceted biological activities,encompassing anti-inflammatory,antiviral,and anti-tumor *** these applications,its efficacy in sepsis treatment remains *** study introduces a novel function of CA,demonstrating its capacity to mitigate sepsis induced by lipopolysaccharide(LPS)and cecal ligation and puncture(CLP)in mice *** research employed in vitro assays,real-time quantitative polymerase chain reaction(RT-qPCR),and RNA-seq analysis to establish that CA significantly reduces the levels of pro-inflammatory cytokines,namely tumor necrosis factor-alpha(TNF-α),interleukin 1 beta(IL-1β),and interleukin 6(IL-6),in response to LPS ***,Western blotting and immunofluorescence assays revealed that CA impedes Nuclear Factor Kappa B(NF-κB)activation in LPS-stimulated RAW264.7 *** these findings,in vivo experiments demonstrated that CA effectively alleviates LPS-and CLP-triggered organ inflammation in C57BL/6 *** insights were gained through 16S sequencing,highlighting CA’s pivotal role in enhancing gut microbiota diversity and modulating metabolic pathways,particularly by augmenting the production of short-chain fatty acids in mice subjected to ***,a comparative analysis revealed that CA’s anti-inflammatory efficacy surpasses that of equivalent doses of aspirin(ASP)and ***,these findings suggest that CA exhibits significant therapeutic potential in sepsis *** discovery provides a foundational theoretical basis for the clinical application of CA in sepsis management.

关键词： Carrimycin Inflammation Lipopolysaccharide Cecal ligation and puncture Sepsis Gut microbiota

Synchronous gastric and colon cancers:Important to consider hereditary syndromes and chronic inflammatory disease associations

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World Journal of Gastrointestinal Oncology 2024年第3期16卷 571-576页

作者： Santosh Shenoy Department of General Surgery Kansas City VA Medical CenterUniversity of Missouri-Kansas CityKansasMO 64128United States

In this editorial we comment on the manuscript,describing management and surveillance strategies in synchronous and metachronous,gastric and colon *** or metachronous primary malignancies at different sites of the gastrointestinal tract pose a unique diagnostic and therapeutic *** services and strategies are required for the management of multiple site primary malignancies,to provide the best oncological *** this study highlights the dual cancers in 76 sporadic cases,the authors excluded 55 patients due to combination of factors which includes;incomplete clinical data,genetic syndrome,gastric stump *** addition,the authors did not elaborate if any patients presented with signet ring cell morphology,E-cadherin mutations or presence of inflammatory bowel *** and mutational errors and epithelial field defects from chronic inflammatory diseases of the gastrointestinal tract are important when considering synchronous gastric and colonic *** will briefly discuss these in this editorial.

关键词： Synchronous gastric Colon cancers Gene mutation Chronic inflammation

Closing the Experiment-Modeling-Perturbation Loop in Whole-Brain Neuroscience

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Neuroscience Bulletin 2024年第8期40卷 1212-1214页

作者： Misha B.Ahrens Janelia Research Campus Howard Hughes Medical InstituteAshburnVAUSA

Understanding the mechanisms by which the central nervous system processes information,forms memories,makes decisions,and executes actions is a challenging *** is an interdisciplinary field in which cell biology,anatomy,network theory,and other scientific disciplines come together to jointly push our knowledge of brain function forward.

关键词： execute knowledge jointly

Emergency department management of acute agitation in the reproductive age female and pregnancy

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World Journal of Emergency Medicine 2024年第2期15卷 83-90页

作者： Ariella Gartenberg Kayla Levine Alexander Petrie Department of Emergency Medicine Jacobi Medical Center and Montefiore Medical CenterNY 10461USA Department of Psychiatry and Behavioral Sciences Albert Einstein College of Medicine and Montefiore Medical CenterNY 10461USA Department of Emergency Medicine Jacobi Medical Center and North Central Bronx HospitalNY 10461USA

BACKGROUND:Agitation is a common presentation within emergent departments(EDs).Agitation during pregnancy should be treated as an obstetric emergency,as the distress may jeopardize both the patient and *** safety of psychotropic medications in the reproductive age female has not been well *** review aimed to explore a summary of general agitation recommendations with an emphasis on ED management of agitation during ***:A literature review was conducted to explore the pathophysiology of acute agitation and devise a preferred treatment plan for ED management of acute agitation in the reproductive age or pregnant ***:While nonpharmacological management is preferred,ED visits for agitation often require medical *** should be selected based on the etiology of agitation and the clinical setting to avoid major adverse *** effects are common in pregnant *** mild to moderate agitation in pregnancy,diphenhydramine is an effective sedating agent with minimal adverse *** moderate to severe agitation,high-potency typical psychotropics are preferred due to their neutral effects on *** has become the most frequently utilized psychotropic for agitation during *** generation psychotropics are often utilized as second-line therapy,including *** and ketamine have demonstrated adverse fetal ***:While randomized control studies cannot be ethically conducted on pregnant patients requiring sedation,animal models and epidemiologic studies have demonstrated the effects of psychotropic medication exposure in *** the fetal risk associated with multiple doses of psychotropic medications remains unknown,weighing the risks and benefits of each agent,while utilizing the lowest effective dose remains critical in the treatment of acute agitation within the EDs.

关键词： Agitation Pregnancy Haloperidol Ketamine Benzodiazepines

CD4^(+)T cells produce IFN-I to license cDC1s for induction of cytotoxic T-cell activity in human tumors

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Cellular & Molecular Immunology 2024年第4期21卷 374-392页

作者： Xin Lei Daniël C.de Groot Marij J.P.Welters Tom de Wit Ellen Schrama Hans van Eenennaam Saskia J.Santegoets Timo Oosenbrug Annemarthe van der Veen Joris L.Vos Charlotte L.Zuur Noel F.C.C.de Miranda Heinz Jacobs Sjoerd H.van der Burg Jannie Borst Yanling Xiao Department of Immunology Leiden University Medical CenterLeidenThe Netherlands Oncode Institute Leiden University Medical CenterLeidenThe Netherlands Department of Tumor Biology and Immunology The Netherlands Cancer InstituteAmsterdamThe Netherlands Department of medical Oncology Oncode InstituteLeiden University Medical CenterLeidenThe Netherlands IMMIOS B.V. OssThe Netherlands Division of medical Oncology The Netherlands Cancer InstituteAmsterdamThe Netherlands Department of Otorhinolaryngology Leiden University medical center LeidenThe Netherlands Department of Pathology Leiden University Medical CenterLeidenThe Netherlands

CD4^(+)T cells can"help"or"license" conventional type 1 dendritic cells(cDC1s)to induce CD8^(+)cytotoxic T lymphocyte(CTL)anticancer responses,as proven in mouse *** recently identified cDC1s with a transcriptomic imprint of CD4^(+)T-cell help,specifically in T-cell-infiltrated human cancers,and these cells were associated with a good prognosis and response to PD-1-targeting ***,we delineate the mechanism of cDC1 licensing by CD4^(+)T cells in *** CD4^(+)T cells produce IFNβvia the STING pathway,which promotes MHC-I antigen(cross-)presentation by cDC1s and thereby improves their ability to induce CTL anticancer *** cooperation with CD40 ligand(L),IFNβalso optimizes the costimulatory and other functions of cDC1s required for CTL response ***-I-producing CD4^(+)T cells are present in diverse T-cell-infiltrated cancers and likely deliver“help”signals to CTLs locally,according to their transcriptomic profile and colocalization with“helped/licensed”cDCs and tumor-reactive CD8^(+)T *** agreement with this scenario,the presence of IFN-I-producing CD4^(+)T cells in the TME is associated with overall survival and the response to PD-1 checkpoint blockade in cancer patients.

关键词： CD4^(+)T-cell help cDC1 licensing IFN-I signaling CD40 costimulation (cross-)presentation CTL priming Tumor control