Delving into the Latest Updates on L-Leucyl-L-Leucine Methyl Ester with Synapse

Overview

Basic Info

Drug Type

Small molecule drug

Synonyms

LLME, LeuLeuOMe

Target-

Mechanism

Immunomodulators

Therapeutic Areas

Immune System DiseasesDigestive System DisordersNeoplasms+ [1]

Active Indication-

Inactive Indication

Graft vs Host DiseaseHematologic NeoplasmsNonalcoholic Steatohepatitis

Originator Organization

Thomas Jefferson University

Active Organization-

Inactive Organization

National Cancer InstituteSidney Kimmel Cancer Center at Thomas Jefferson University

Nusirt Sciences, Inc.

+ [1]

Drug Highest PhaseDiscontinuedPhase 2

First Approval Date-

Regulation-

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Structure

Molecular FormulaC13H26N2O3

InChIKeyAJMOLNFDYWTVQW-QWRGUYRKSA-N

CAS Registry13022-42-9

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.

10 Nov 2023·Circulation Research

Myeloid Cell Derived IL1β Contributes to Pulmonary Hypertension in HFpEF

Article

Author: 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.

01 Oct 2023·Journal of Ethnopharmacology

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

Article

Author: 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 Deals associated with L-Leucyl-L-Leucine Methyl Ester

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R&D Status

10 top R&D records.

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Indication	Highest Phase	Country/Location	Organization	Date
Nonalcoholic Steatohepatitis	Phase 2	US	Nusirt Sciences, Inc.	19 Nov 2015
Hematologic Neoplasms	Phase 2	US	Sidney Kimmel Cancer Center at Thomas Jefferson University	01 Mar 2004
Graft vs Host Disease	Phase 2	-	National Cancer Institute	-
Graft vs Host Disease	Phase 2	-	Thomas Jefferson University	-
Graft vs Host Disease	Phase 2	-	Thomas Jefferson University	-
Graft vs Host Disease	Phase 2	-	National Cancer Institute	-

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Clinical Result

Indication

Phase

Evaluation

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Study	Phase	Population	Analyzed Enrollment	Group	Results	Evaluation	Publication Date


NCT00429416 (CTgov)	Phase 1/2	Hematologic Neoplasms \| Graft vs Host Disease	14	Hematopoietic stem cell transplantation (HSCT)+Mesna+Fludarabine+Cyclophosphamide+Tacrolimus+L-leucyl-L-leucine Methyl Ester (LLME)+Cytarabine	klgkxqdxfd(odqrspnyzp) = illxalfggf fkvuwkxnfo (qsswsleluu, ftuphttuue - isehlypbjy) View more	-	10 Dec 2013
Tandem Meetings ASTCT and CIBMTR2011	Not Applicable	Hematologic Neoplasms	-	L-Leucyl-L-Leucine Methyl Ester (LLME) (LLME treated CD34- fraction)	aiqjcqyirm(uhqufejatk) = xpqdqmzxla ticqmsoanj (qhqvhqxbfz ) View more	-	01 Feb 2011
Tandem Meetings ASTCT and CIBMTR2011	Not Applicable	Hematologic Neoplasms	-	L-Leucyl-L-Leucine Methyl Ester (LLME) (CD34 selected stem cell product)	aiqjcqyirm(uhqufejatk) = izmfklvabt ticqmsoanj (qhqvhqxbfz ) View more	-	01 Feb 2011