Last update 01 Nov 2024

LMLN

Last update 01 Nov 2024

Basic Info

Synonyms

Gp63, Invadolysin, leishmanolysin like peptidase

+ [4]

Introduction

Metalloprotease.

Drugs associated with LMLN

Leishmania multi-epitope vaccine(Shiraz University of Medical Sciences)

Target

GNB1L x LMLN

Mechanism

GNB1L modulators [+1]

Active Org.

Shiraz University of Medical Sciences

Originator Org.

Shiraz University of Medical Sciences

Active Indication

Leishmaniasis

Inactive Indication-

Drug Highest PhasePreclinical

First Approval Ctry. / Loc.-

First Approval Date20 Jan 1800

100 Clinical Results associated with LMLN

100 Translational Medicine associated with LMLN

0 Patents (Medical) associated with LMLN

504

Literatures (Medical) associated with LMLN

01 Jan 2025·American Journal of Ophthalmology

Nonredundant Role of Leishmanolysin-Like (Lmln) Zinc-Metallopeptidase in Retinal Homeostasis

Article

Author: Zegeye, Yeshumenesh ; Ludwig, Sara ; Shrestha, Sangita ; Ufret-Vincenty, Rafael L. ; Moresco, Eva Marie Y. ; Yuksel, Seher ; Ulker-Yilmazer, Gizem ; He, Yu-Guang ; Kirman, Dogan Can ; Beutler, Bruce ; Moresco, Eva Marie Y ; Ufret-Vincenty, Rafael L ; Aredo, Bogale ; Turpin, Emily

PURPOSETo determine if Lmln, a Zinc-metallopeptidase, is important for retinal homeostasis.DESIGNBasic research in mouse models of retinal degeneration.METHODSCombining an unbiased N-ethyl-N-nitrosourea mutagenesis pipeline in mice with optical coherence tomography (OCT) screening and automated meiotic mapping, we identified an allele (nemeth) that seemed to be associated with outer nuclear layer (ONL) thinning. Since nemeth was predicted to lead to a nonsense mutation of the Lmln gene, we targeted Lmln using CRISPR/Cas-9 technology and characterized the impact on retinal anatomy and function.RESULTSOCT imaging demonstrated an outer retinal degeneration in Lmln^-/- mice (P = 7.3 × 10^-9 for ONL at 2 m) that progressed over the first 6 months of life and then stabilized. Light microscopy showed loss of ONL nuclei (P ranged between .00033 and .0097 for posterior measurements), and a TUNEL assay revealed a small but significant increase in apoptosis (P = .034). Lmln^-/- mice accumulated fundus spots (P = .0030 by 2 m of age) and activated subretinal microglia (P ranged from .0007 to 8 × 10^-13 for Gal3⁺ cells). Scotopic electroretinography demonstrated a decrease in retinal function in Lmln^-/- mice both at 6 m (only a-wave, P < .01 for all stimuli) and at 10 m of age (P < .01 for both a-wave and b-wave with all stimuli).CONCLUSIONSOur work revealed a previously unknown essential role for Lmln in maintaining retinal anatomy and function. Further studies using this new model will be aimed at determining the cellular expression of Lmln and its mechanisms of action within the retina.

01 Oct 2024·Parasite Immunology

Astrocytes Can Be Key Players Against Cerebral Leishmaniasis: In Vitro Co‐Culture Model for the Assessment of Infection

Article

Author: Ucisik, Mehmet Hikmet ; Islek, Zeynep ; Sahin, Fikrettin

ABSTRACTLeishmaniasis is a neglected tropical disease, caused by protozoan parasites of Leishmania (L.), and is transmitted by bite of phlebotomine sandflies. There are several studies on central nervous system infection to indicate that Leishmania can cross the blood–brain barrier, resulting in neurological manifestations, known as “cerebral leishmaniasis.” This study highlighted the notions: (i) polarisation of bone marrow‐derived macrophages (BMDM) incubated following stimulation with lipopolysaccharide (LPS) or soluble Leishmania antigen (SLA), (ii) quantification of parasites within co‐culture of Leishmania‐infected macrophages, and astrocytes, and (iii) effect of interferon‐gamma (IFN‐γ) on the infection rate of co‐culture populations. Accordingly, 83% of overall macrophage population was identified on day 7 for CD11b and F4/80 macrophage markers. Flow cytometry analysis revealed significant increases in CD11b and F4/80 surface markers in LPS and SLA‐stimulated BMDMs at 24 h, compared to untreated cells. TNF‐α levels increased significantly in both LPS and SLA‐treated BMDMs after 48 h. Additionally, SLA treatment induced a more elongated, spindle‐like shape in the cells, indicative of M2 macrophage polarisation over the M1 phenotype. When non‐infected astrocytes with/without stimulation with IFN‐γ before co‐culture, gp63 FITC‐labelled parasite populations (%) in co‐culture decreased to 25% at 72 h, thus indicating a lower infection rate in a time‐dependent manner. IFN‐γ and IL‐6 levels significantly increased to 71.66 ± 3.51 and 184 ± 14.42 pg/mL, resulting in the inflammatory response in the co‐culture system at 48 h (p ≤ 0.0001), when compared to the control (30 ± 2.52 pg/mL for IFN‐γ and 8.66 ± 2.37 pg/mL for IL‐6) at 0 h of the incubation. It is the first study to emphasize the communication between Leishmania‐infected macrophages and astrocytes regarding Leishmania parasite load. The results suggest that astrocytes can lead to the reduction in Leishmania parasites, thereby controlling the incidence of cerebral leishmaniasis.

19 Sep 2024·Protein & Peptide Letters

Immunogenicity and Neutralization Potential of Recombinant Chimeric Protein Comprising the Catalytic Region of Gp63 of Leishmania and LTB against Leishmania Donavani

Article

Author: Malik, Gunjan ; Garg, Lalit C. ; Krishnan, Anuja

Aim:To study the inhibition potential of antibody against a recombinant chimera comprising of the catalytic epitope of gp63 of Leishmania donovani and B subunit of heat-labile enterotoxin [LTB] in the functional activity of L. donovani.Background:Visceral leishmaniasis, caused by the protozoan parasite Leishmania donavani, is a major health problem and causes mortality in tropical regions. Protozoan proteases play a crucial role in the pathogenesis of the disease and in establishing infection by countering the host's innate immune responses, namely complement-mediated lysis and phagocytosis. A surface-bound metalloprotease [gp63] has been reported to be a major virulence factor resulting in the evasion of complement- mediated lysis, cleaving host extracellular and intracellular substrates, resulting in intra- phagolysosomal survivalMethod:The epitope corresponding to the catalytic motif of gp63 of Leishmania donovani has fused with the B subunit of heat-labile enterotoxin, which is known to be immunogenic. The chimera was cloned to a prokaryotic expression vector and purified using Ni NTA affinity chromatography. Antibodies were generated against the purified fusion protein and analyzed for its ability to bind to the gp63 catalytic motif peptide by ELISA. The effect of fusion protein antibody on the functional activity of gp63 was evaluated by assessing the effect of purified IgGs on the protease activity and complement-mediated lysis of L. donovani promastigotes in vitro.Results:The present study reports that a recombinant chimera of the catalytic epitope of gp63 and B subunit of heat-labile enterotoxin [LTB] of E. coli, a potent adjuvant of humoral response can mount significant immune response towards the catalytic epitope. ELISA and Western blot analysis showed that the anti-fusion protein antiserum could recognize the native gp63. Also, it significantly inhibited the protease activity of promastigotes and subsequently increased complement-mediated lysis of the promastigotes in vitro.Conclusion:It could be concluded that the hybrid protein containing catalytic motif L. donovani gp63 protein and carrier protein [LTB] could elicit antibodies that could neutralise the functional activity of gp63 and thus could be a potential candidate for subunit leishmaniasis vaccine.

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LMLN

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