L-Leucyl-L-Leucine Methyl Ester(L-Leucyl-L-Leucine Methyl Ester)

概要

基本信息

药物类型

小分子化药

别名

LLME、LeuLeuOMe

靶点-

作用机制

免疫调节剂

治疗领域

免疫系统疾病消化系统疾病肿瘤+ [1]

在研适应症-

非在研适应症

移植物抗宿主病血液肿瘤非酒精性脂肪性肝炎

原研机构

Thomas Jefferson University

在研机构-

非在研机构

National Cancer InstituteSidney Kimmel Cancer Center at Thomas Jefferson University

Nusirt Sciences, Inc.

+ [1]

最高研发阶段终止临床2期

首次获批日期-

最高研发阶段(中国)-

特殊审评-

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结构

分子式C13H26N2O3

InChIKeyAJMOLNFDYWTVQW-QWRGUYRKSA-N

CAS号13022-42-9

关联

2

项与 L-Leucyl-L-Leucine Methyl Ester 相关的临床试验

NCT00429416 / Completed临床1/2期IIT

A Phase I/II Study of Llme Treated Non-Myeloablative Allogeneic Hematopoietic Stem Cell Transplantation for Patients With Hematological Malignancies

The purpose of this research study is to determine if an experimental agent, LLME can decrease the incidence and severity of Graft-Versus-Host-Disease (GVHD) following blood (hematopoietic) stem cell transplantation

开始日期2004-03-01

申办/合作机构

Sidney Kimmel Cancer Center at Thomas Jefferson University

NCT00429039 / Terminated临床2期IIT

LLME Treated Cellular Immunotherapy Following T-cell Depleted Allogeneic Heamtopoietic Stem Cell Transplantation for Acceleration of Immune Reconstitution

The purpose of this study is to determine if pre-treating donor lymphocytes with an investigational drug known as L-leucyl-L-leucine methyl ester (LLME, prior to donor lymphocyte infusion (DLI) will improve the recovery of the immune system following stem cell transplant.

开始日期2000-09-01

申办/合作机构

Sidney Kimmel Cancer Center at Thomas Jefferson University

[+1]

100 项与 L-Leucyl-L-Leucine Methyl Ester 相关的临床结果

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100 项与 L-Leucyl-L-Leucine Methyl Ester 相关的转化医学

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100 项与 L-Leucyl-L-Leucine Methyl Ester 相关的专利（医药）

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1,356

项与 L-Leucyl-L-Leucine Methyl Ester 相关的文献（医药）

2023-12-01·Chemico-Biological Interactions

Inhibiting HNF4A suppresses inflammation whilst promoting trophoblast invasion and migration: A promising target for the treatment of preeclampsia

Article

作者: Zhang, Xuan ; Sun, Lei

Preeclampsia (PE) is a complex disease of pregnancy, and an important cause of this disease is insufficient trophoblast invasion and migration. However, the underlying mechanism of PE remains largely unknown. Here, transcriptome sequencing analysis found the high expression of hepatocyte nuclear factor 4 alpha (HNF4A) in PE placentas. Meanwhile, we found that HNF4A expression was up-regulated in the placentas of PE patients. Thus, we assumed that HNF4A might be involved in PE progression. To validate our hypothesis, l-arginine methyl ester (l-NAME) or lipopolysaccharide (LPS)-treated rats were used to mimic the pathological status of PE in vivo. Consistently, HTR8/SVneo cells were treated with hypoxia/reoxygenation (H/R) or LPS to simulate PE progression in vitro. The results observed an increase in elevated urine protein levels, systolic blood pressure (SBP), diastolic blood pressure (DBP), and mean arterial pressure (MAP), which indicated that the PE-like rat model was successfully established. Meanwhile, the expression of pro-inflammatory cytokines interleukin (IL)-6 and IL-1β was increased in PE placentas. HTR8/SVneo cells were used to further explore the underlying mechanism of PE in vitro. H/R conditions up-regulated the acetylation level of HNF4A. Further analysis showed that HNF4A overexpression inhibited trophoblast invasion and migration, while HNF4A knockdown promoted the progression. Additionally, inhibiting HNF4A was found to reduce the levels of IL-6 and IL-1β secretion in HTR8/SVneo cells following H/R or LPS exposure. Conclusively, these findings suggest that inhibiting HNF4A suppresses inflammation whilst promoting trophoblast invasion and migration in PE, providing a promising target for the treatment of PE.

2023-11-10·Circulation Research

Myeloid Cell Derived IL1β Contributes to Pulmonary Hypertension in HFpEF

Article

作者: Gokey, Jason J. ; Fortune, Niki L. ; Hemnes, Anna R. ; Moore, Christy S. ; Murphy, Matthew B. ; Meoli, David F. ; Kropski, Jonathan A. ; Murray, Katherine T. ; Kobeck, Elizabeth ; Carrier, Erica J. ; West, James D. ; Blackwell, Thomas ; Gladson, Santhi ; Monahan, Ken ; Agrawal, Vineet ; Gupta, Deepak K. ; Ru Su, Yan ; Talati, Megha H.

BACKGROUND:Pulmonary hypertension (PH) in heart failure with preserved ejection fraction (HFpEF) is a common and highly morbid syndrome, but mechanisms driving PH-HFpEF are poorly understood. We sought to determine whether a well-accepted murine model of HFpEF also displays features of PH, and we sought to identify pathways that might drive early remodeling of the pulmonary vasculature in HFpEF.METHODS: Eight-week-old male and female C57BL/6J mice received either N γ -nitro-L-arginine methyl ester and high-fat diet or control water and diet for 2, 5, and 12 weeks. The db/db mice were studied as a second model of HFpEF. Early pathways regulating PH were identified by bulk and single-cell RNA sequencing. Findings were confirmed by immunostain in lungs of mice or lung slides from clinically performed autopsies of patients with PH-HFpEF. ELISA was used to verify IL-1β (interleukin-1 beta) in mouse lung, mouse plasma, and also human plasma from patients with PH-HFpEF obtained at the time of right heart catheterization. Clodronate liposomes and an anti–IL-1β antibody were utilized to deplete macrophages and IL-1β, respectively, to assess their impact on pulmonary vascular remodeling in HFpEF in mouse models. RESULTS: N γ -nitro-L-arginine methyl ester/high-fat diet–treated mice developed PH, small vessel muscularization, and right heart dysfunction. Inflammation-related gene ontologies were overrepresented in bulk RNA sequencing analysis of whole lungs, with an increase in CD68 + cells in both murine and human PH-HFpEF lungs. Cytokine profiling showed an increase in IL-1β in mouse and human plasma. Finally, clodronate liposome treatment in mice prevented PH in N γ -nitro-L-arginine methyl ester/high-fat diet–treated mice, and IL-1β depletion also attenuated PH in N γ -nitro-L-arginine methyl ester/high-fat diet–treated mice. CONCLUSIONS:We report a novel model for the study of PH and right heart remodeling in HFpEF, and we identify myeloid cell–derived IL-1β as an important contributor to PH in HFpEF.

2023-10-01·Journal of Ethnopharmacology

Multi-omics approach for identification of molecular alterations of QiShenYiQi dripping pills in heart failure with preserved ejection fraction

Article

作者: Yang, Zhihui ; Zhang, Kai ; Fan, Guanwei ; Huang, Yuting ; Li, Sheng ; Guo, Kaimin ; Wang, Xiao ; Wang, Wenjia ; Chen, Feng ; Li, Lan ; Zhuo, Danping ; Wang, Bingkai ; Du, Ruijiao ; Hu, Yunhui ; Li, Xiaoqiang ; Jiang, Miaomiao

ETHNOPHARMACOLOGICAL RELEVANCETraditional Chinese medicine theory believes that qi deficiency and blood stasis are the key pathogenesis of heart failure with preserved ejection fraction (HFpEF). As a representative prescription for replenishing qi and activating blood, QiShenYiQi dripping pills (QSYQ) has been used for treating heart diseases. However, the pharmacological mechanism of QSYQ in improving HFpEF is not well understood.AIM OF THE STUDYThe objective of the study is to investigate the cardioprotective effect and mechanism of QSYQ in HFpEF using the phenotypic dataset of HFpEF.MATERIALS AND METHODSHFpEF mouse models established by feeding mice combined high-fat diet and N^ω-nitro-L-arginine methyl ester drinking water were treated with QSYQ. To reveal causal genes, we performed a multi-omics study, including integrative analysis of transcriptomics, proteomics, and metabolomics data. Moreover, adeno-associated virus (AAV)-based PKG inhibition confirmed that QSYQ mediated myocardial remodeling through PKG.RESULTSComputational systems pharmacological analysis based on human transcriptome data for HFpEF showed that QSYQ could potentially treat HFpEF through multiple signaling pathways. Subsequently, integrative analysis of transcriptome and proteome showed alterations in gene expression in HFpEF. QSYQ regulated genes involved in inflammation, energy metabolism, myocardial hypertrophy, myocardial fibrosis, and cGMP-PKG signaling pathway, confirming its function in the pathogenesis of HFpEF. Metabolomics analysis revealed fatty acid metabolism as the main mechanism by which QSYQ regulates HFpEF myocardial energy metabolism. Importantly, we found that the myocardial protective effect of QSYQ on HFpEF mice was attenuated after RNA interference-mediated knock-down of myocardial PKG.CONCLUSIONThis study provides mechanistic insights into the pathogenesis of HFpEF and molecular mechanisms of QSYQ in HFpEF. We also identified the regulatory role of PKG in myocardial stiffness, making it an ideal therapeutic target for myocardial remodeling.

100 项与 L-Leucyl-L-Leucine Methyl Ester 相关的药物交易

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研发状态

10 条进展最快的记录,

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适应症	最高研发状态	国家/地区	公司	日期
非酒精性脂肪性肝炎	临床2期	美国	Nusirt Sciences, Inc.	2015-11-19
血液肿瘤	临床2期	美国	Sidney Kimmel Cancer Center at Thomas Jefferson University	2004-03-01
移植物抗宿主病	临床2期	-	National Cancer Institute	-
移植物抗宿主病	临床2期	-	Thomas Jefferson University	-
移植物抗宿主病	临床2期	-	Thomas Jefferson University	-
移植物抗宿主病	临床2期	-	National Cancer Institute	-

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临床结果

适应症

分期

评价

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研究	分期	人群特征	评价人数	分组	结果	评价	发布日期


NCT00429416 (CTgov)	临床1/2期	血液肿瘤 \| 移植物抗宿主病	14	Hematopoietic stem cell transplantation (HSCT)+Mesna+Fludarabine+Cyclophosphamide+Tacrolimus+L-leucyl-L-leucine Methyl Ester (LLME)+Cytarabine	憲艱觸觸窪鹽糧簾艱網(製遞窪築願網襯窪艱餘) = 淵願鹽顧選襯壓淵糧簾積糧構鹽製醖夢鹽築範 (遞獵網膚製選蓋鬱獵鹹, 範觸醖鹹鹽窪窪壓簾憲 ~ 壓製鬱遞壓鹹觸築襯願) 更多	-	2013-12-10
Tandem Meetings ASTCT and CIBMTR2011	N/A	血液肿瘤	-	L-Leucyl-L-Leucine Methyl Ester (LLME) (LLME treated CD34- fraction)	壓餘醖餘構築鑰鹹蓋願(餘艱網築網襯觸鹹壓鏇) = 積構網築淵襯鹹齋願鬱廠窪築獵觸蓋膚艱齋鹹 (夢壓艱簾獵網蓋廠夢築 ) 更多	-	2011-02-01
Tandem Meetings ASTCT and CIBMTR2011	N/A	血液肿瘤	-	L-Leucyl-L-Leucine Methyl Ester (LLME) (CD34 selected stem cell product)	壓餘醖餘構築鑰鹹蓋願(餘艱網築網襯觸鹹壓鏇) = 齋膚鹽選憲餘繭觸願範廠窪築獵觸蓋膚艱齋鹹 (夢壓艱簾獵網蓋廠夢築 ) 更多	-	2011-02-01