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Targeting TrkB–PSD-95 coupling to mitigate neurological disorders

Neural Regeneration Research 2025年第3期20卷 715-724页

作者： Xin Yang Yu-Wen Alvin Huang John Marshall Department of Molecular Biology Cell Biology and BiochemistryBrown UniversityProvidenceRIUSA Department of Neurology Warren Alpert Medical School of Brown UniversityProvidenceRIUSA center for Translational Neuroscience Robert J.and Nancy D.Carney Institute for Brain Science and Brown Institute for Translational ScienceBrown UniversityProvidenceRIUSA

Tropomyosin receptor kinase B(TrkB)signaling plays a pivotal role in dendritic growth and dendritic spine formation to promote learning and *** activity-dependent release of brain-derived neurotrophic factor at synapses binds to pre-or postsynaptic TrkB resulting in the strengthening of synapses,reflected by long-term ***,the association of postsynaptic density protein-95 with TrkB enhances phospholipase Cγ-Ca^(2+)/calmodulin-dependent protein kinaseⅡand phosphatidylinositol 3-kinase-mechanistic target of rapamycin signaling required for long-term *** this review,we discuss TrkB-postsynaptic density protein-95 coupling as a promising strategy to magnify brain-derived neurotrophic factor signaling towards the development of novel therapeutics for specific neurological disorders.A reduction of TrkB signaling has been observed in neurodegenerative disorders,such as Alzheimer's disease and Huntington's disease,and enhancement of postsynaptic density protein-95 association with TrkB signaling could mitigate the observed deficiency of neuronal connectivity in schizophrenia and *** with brain-derived neurotrophic factor is problematic,due to poor pharmacokinetics,low brain penetration,and side effects resulting from activation of the p75 neurotrophin receptor or the truncated TrkB.T1 *** TrkB agonists and antibodies that activate TrkB are being intensively investigated,they cannot distinguish the multiple human TrkB splicing isoforms or cell type-specific *** TrkB–postsynaptic density protein-95 coupling provides an alternative approach to specifically boost TrkB signaling at localized synaptic sites versus global stimulation that risks many adverse side effects.

关键词： Angelman syndrome autism brain-derived neurotrophic factor depression neurodegenerative disorder neurodevelopmental disorder postsynaptic density protein-95 synaptic plasticity TrkB

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Arylamine N-acetyltransferase 2 genotype-dependent N-acetylation of isoniazid in cryopreserved human hepatocytes

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Acta Pharmaceutica Sinica B 2017年第4期7卷 517-522页

作者： Mark A.Doll Raúl A.Salazar-González Srineil Bodduluri David W.Hein Department of Pharmacology and Toxicology and James Graham brown cancer center University of LouisvilleLouisvilleKY 40202USA

Cryopreserved human hepatocytes were used to investigate the role of arylamine N-acetyltransferase 2 (NAT2; EC 2.***.1.5) polymorphism on the N-acetylation of isoniazid (INH). NAT2 genotype was determined by Taqman allelic discrimination assay and INH N-acetylation was measured by high performance liquid chromatography. INH N-acetylation rates in vitro exhibited a robust and highly significant (P<0.005) NAT2 phenotype-dependent metabolism. N-acetylation rates in situ were INH concentration- and time-dependent. Following incubation for 24 h with 12.5 or 100 µmol/L INH, acetyl-INH concentrations varied significantly (P = 0.0023 and P = 0.0002) across cryopreserved human hepatocytes samples from rapid, intermediate, and slow acetylators, respectively. The clear association between NAT2 genotype and phenotype supports use of NAT2 genotype to guide INH dosing strategies in the treatment and prevention of tuberculosis.

关键词： Isoniazid N-Acetyltransferase 2 Acetylation polymorphism Human hepatocytes Genotype Phenotype

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New insights of T cells in the pathogenesis of psoriasis

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Cellular & Molecular Immunology 2012年第4期9卷 302-309页

作者： Yihua Cai Chris Fleming Jun Yan Department of Medicine and Tumor I mmunobiology Program James Graham Brown Cancer Center University of Louisville Louisville KY USA Department of Microbiology and Immunology University of Louisville School of Medicine Louisville KY USA

Psoriasis is one of the most common immune-mediated chronic, inflammatory skin diseases characterized by hyperproliferative keratinocytes and infiltration of T cells, dendritic cells, macrophages and neutrophils. Although the pathogenesis of psoriasis is not fully understood, there is ample evidence suggesting that the dysregulation of immune cells in the skin, particularly T cells, plays a critical role in psoriasis development. In this review, we mainly focus on the pathogenic T cells and discuss how these T cells are activated and involved in the disease pathogenesis. Newly identified ＇professional＇ IL-17-producing dermal γδ T cells and their potential role in psoriasis will also be included. Finally, we will briefly summarize the recent progress on the T cell and its related cytokine-targeted therapy for psoriasis treatment.

关键词： Psoriasis,TH1/TH17 cells Gammadelta T cells T cell-targeted theraphy

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Chemoprotective effects of curcumin in esophageal epithelial cells exposed to bile acids

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World Journal of Gastroenterology 2010年第33期16卷 4152-4158页

作者： Matthew R Bower Harini S Aiyer Robert CG Martin Yan Li Division of Surgical Oncology Department of Surgery and James Graham Brown Cancer CenterUniversity of Louisville School of MedicineLouisvilleKY40202United States

AIM:To investigate the ability of curcumin to counteract the impact of bile acids on gene expression of esophageal epithelial ***:An esophageal epithelial cell line(HET1A)was treated with curcumin in the presence of deoxycholic *** proliferation and viability assays were used to establish an appropriate dose range for *** combined and individual effects of curcumin and bile acid on cyclooxygenase-2(COX-2)and superoxide dismutase(SOD-1 and SOD-2)gene expression were also ***:Curcumin in a dose range of 10-100μmol/L displayed minimal inhibition of HET-1A cell *** acid at a concentration of 200μmol/L caused a 2.4-fold increase in COX-2 gene expression compared to vehicle *** increased expression of COX-2 induced by deoxycholic acid was partially reversed by the addition of curcumin,and curcumin reduced COX-2 expression 3.3-to ***-1A cells exposed to bile acid yielded reduced expression of SOD-1 and SOD-2 genes with the exception that high dose deoxycholic acid at 200μmol/L led to a 3-fold increase in SOD-2 *** addition of curcumin treatment partially reversed the bile acid-induced reduction in SOD-1 expression at all concentrations of curcumin ***:Curcumin reverses bile acid suppression of gene expression of *** is also able to inhibit bile acid induction of COX-2 gene expression.

关键词： Esophageal cancer Curcumin Cyclooxy- genase-2 Superoxide dismutase Chemoprevention

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Immunotherapy in human colorectal cancer: challenges and prospective

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World Journal of Gastroenterology 2016年第28期22卷 6362-6372页

作者： Xuan Sun Jian Suo Jun Yan Department of Gastrointestinal Surgery The First Hospital Jilin University James Graham brown cancer center Department of Medicine University of Louisville School of Medicine

Human colorectal cancer(CRC) is the third most commonly diagnosed malignancies and the prognosis for patients with recurrent or metastatic disease is extremely poor. Although new chemotherapeutic regimen improves survival rates, therapy with better efficacy and less adverse effects is drastically needed. Immunotherapy has been investigated in human CRC for decades with limited success. However, recent developments of immunotherapy, particularly immune checkpoint inhibitor therapy, have achieved promising clinical benefits in many types of cancer and revived the hope for utilizing such therapy in human CRC. In this review, we will discuss important immunological landscape within the CRC microenvironment and introduce immunoscore system to better describe immunophenotyping in CRC. We will also discuss different immunotherapeutic approaches currently utilized in different phases of clinical trials. Some of those completed or ongoing trials are summarized. Finally, we provide a brief prospective on the future human CRC immunotherapy.

关键词： Immunotherapy Human colorectal cancer Adoptive cell therapy Immune checkpoint inhibitor therapy Immunosuppression

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Microbiome data analysis with applications to pre-clinical studies using QIIME2: Statistical considerations

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Genes & Diseases 2021年第2期8卷 215-223页

作者： Shesh N.Rai Chen Qian Jianmin Pan Jayesh P.Rai Ming Song Juhi Bagaitkar Michael Merchant Matthew Cave Nejat K.Egilmez Craig J.McClain Biostatistics and Bioinformatics Facility James Graham Brown Cancer CenterUniversity of LouisvilleLouisvilleKY40202USA Department of Biostatistics and Bioinformatics University of LouisvilleLouisvilleKY40202USA university of louisville Alcohol Research center University of LouisvilleLouisvilleKY40202USA university of louisville Hepatobiology&Toxicology center University of LouisvilleLouisvilleKY40202USA Department of Oral Immunology&Infectious Diseases University of LouisvilleLouisvilleKY40202USA Department of Medicine University of LouisvilleLouisvilleKY40202USA Robley Rex louisville VAMC LouisvilleKY40206USA Department of Microbiology&Immunology University of LouisvilleLouisvilleKY40202USA

Diversity analysis and taxonomic profiles can be generated from marker-gene sequence data with the help of many available computational *** Quantitative Insights into Microbial Ecology Version 2(QIIME2)has been widely used for 16S rRNA data *** many articles have demonstrated the use of QIIME2 with suitable datasets,the application to preclinical data has rarely been talked *** issues involved in the pre-clinical data include the low-quality score and small sample size that should be addressed properly during *** addition,there are few articles that discuss the detailed statistical methods behind those alpha and beta diversity significance tests that researchers are eager to *** the program without knowing the logic behind it is extremely *** this article,we first provide a guideline for analyzing 16S rRNA data using *** we will talk about issues in pre-clinical data,and how they could impact the ***,we provide brief explanations of statistical methods such as group significance tests and sample size calculation.

关键词： 16S rRNA gene Alpha diversity ANOVA Beta diversity Bioinformatics Microbiome data QIIME Sample size calculation

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Stereotactic radiosurgery in the era of novel systemic therapy for lung cancer brain metastases

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Journal of cancer Metastasis and Treatment 2019年第4期4卷 17-25页

作者： Sarah Mudra Shruti Bhandari Prashant Tripathi Neal Dunlap Goetz Kloecker university of louisville School of Medicine LouisvilleKY 40202USA Department of Internal Medicine Division of Hematology and Medical OncologyJames Graham Brown Cancer CenterUniversity of Louisville School of MedicineLouisvilleKY 40202USA Division of Infectious Disease University of Louisville School of MedicineLouisvilleKY 40202USA Department of Radiation Oncology James Graham Brown Cancer CenterUniversity of Louisville School of MedicineLouisvilleKY 40202USA

The emergence of novel systemic therapies has spurred a dramatic paradigm shift in lung cancer *** has revealed greater intracranial efficacy in targeted agents and immune checkpoint inhibitors(ICI)compared to conventional ***,advances in stereotactic radiosurgery(SRS)have contributed to the increased use of this highly localized,minimally-invasive treatment modality for local tumor *** this era of precision medicine,the combination of these novel agents and SRS demands further prospective exploration-particularly as questions regarding their sequence of administration and the risk of neurotoxicity remain ***,although data are limited and largely retrospective,literature supports the concurrent administration of ICI and radiation,with no observed increases in immune-related adverse events or acute neurologic *** the case of patients with driver mutations,newer generations of tyrosine kinase inhibitors(TKI)display improved intracranial efficacy and are currently preferred alone upfront in patients with asymptomatic brain metastases(BM)due to lack of *** of combining TKI and SRS is limited with mixed *** this review,we explore the evidence regarding the use of novel systemic agents and SRS for treatment of lung cancer *** practice will continue to be refined as larger,prospective studies yield results.

关键词： Lung cancer stereotactic radiosurgery brain metastasis tyrosine kinase inhibitors immunotherapy

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Spatial TIME landscape and its prognostic value in the lung and brain tumor:location matters

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Signal Transduction and Targeted Therapy 2023年第6期8卷 2437-2439页

作者： Yunke Wang Anne E.Geller Jun Yan Division of Immunotherapy The Hiram C.PolkJr.MD Department of SurgeryImmuno-Oncology ProgramBrown Cancer CenterUniversity of Louisville School of MedicineLouisvilleKYUSA Department of Microbiology and Immunology University of Louisville School of MedicineLouisvilleKYUSA

In two recently published papers in Nature,^(1,2)Logan Walsh and colleagues utilized imaging mass cytometry(IMC)to create comprehensive single-cell spatial landscapes of the tumor immune microenvironment(TIME)in lung tumors from 416 lung adenocarcinoma(LUAD)patients,as well as brain tumors from 139 high-grade glioma and 46 brain metastasis(BrM)*** conducting a thorough analysis to characterize cellular spatial interactions and neighborhood patterns,and correlating these spatial features with clinical outcomes(Fig.1),the researchers gained novel insights into the complexities of tumoral ***,they identified two sets of clinically relevant predictive immune markers that could be used to assist in guiding clinical decisions.

关键词： lung landscape gained

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Unexpected Breg-NK crosstalk in STING agonist therapy

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Cellular & Molecular Immunology 2022年第12期19卷 1330-1332页

In a recent paper published in Nature,Li et *** that resistance to stimulator of interferon genes(STING)monotherapy in solid tumors is attributable to the unexpected surge of IL-35-producing regulatory B(Breg)cells that impair NK-cell cytotoxicity[1].They depict STING-induced Breg-NK-cell crosstalk and propose that combining the STING agonist 2'3'cyclic GMP-AMP(cGAMP)with anti-IL-35 blockade is a promising strategy to overcome tumor immunosuppression,especially in pancreatic cancers[1].

关键词： Breg interferon

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Gene therapy for spinal muscular atrophy:perspectives on the possibility of optimizing SMN1 delivery to correct all neurological and systemic perturbations

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Neural Regeneration Research 2025年第7期20卷 2011-2012页

作者： Sharon J.brown Rafael J.Yáñez-Muñoz Heidi R.Fuller School of Pharmacy and Bioengineering Keele UniversityKeeleUK Wolfson center for Inherited Neuromuscular Disease TORCH BuildingRJAH Orthopaedic HospitalOswestryUK *** Center of Gene and Cell TherapyDepartment of Biological SciencesSchool of Life Sciences and the EnvironmentRoyal Holloway University of LondonEghamUK

Spinal muscular atrophy(SMA)is a genetic condition that results in selective lower motor neuron loss with concomitant muscle weakness and *** genetic cause of SMA was understood in 1995 when loss or impairment of the survival motor neuron 1(SMN1)gene was identified as the main contributing factor(Lefebvre et al.,1995).This,in combination with the discovery that humans have a“back-up”gene,SMN2,which can produce low levels(approximately 10%)of the full-length functional SMN protein,has led to the generation of SMA-specific gene *** was traditionally classified according to age of symptom onset and developmental milestones achieved,with life expectancy and severity varying between ***,SMN2 copy number is used as a proxy for the prediction of disease severity,with higher SMN2 copy number typically being associated with reduced severity of SMA,although this relationship is not absolute:some individuals with low SMN2 copy number have less severe SMA phenotypes and vice ***,the etiology of SMA is further complicated by other factors,such as non-typical nucleotide variants and SMN2-independent modifiers of disease severity.

关键词： atrophy traditionally absolute

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