ABSTRACTUbiquitin C‐terminal hydrolase L1 (UCHL1) plays vital roles in cell proliferation, angiogenesis, inflammation and oxidative stress. Nevertheless, it is unclear whether UCHL1 could regulate the biologic behaviour of cells and ultimately influences wound healing. We aim to illustrate the roles and the underlying mechanism of UCHL1 in cutaneous wound healing. Murine full‐thickness excisional wound model was utilised to study the effects of UCHL1 on wound healing through topical administration of the UCHL1 inhibitor LDN57444, followed by assessment of wound areas and histological alterations. Subsequently, ethynyldeoxyuridine, scratch and transwell assays were performed to examine fibroblast migration and proliferation. The extracellular matrix (ECM)‐related genes expression and transforming growth factor‐β (TGF‐β)/Smad signalling pathways activation were investigated by immuno‐fluorescent staining, Western blots and quantitative reverse transcription polymerase chain reaction. We identified elevated UCHL1 expression in non‐healing wound tissues. The UCHL1 expression displayed a dynamic change and reached a peak on Day‐7 post‐wounding during the healing process in mice. Cutaneous administration of LDN57444 promoted wound healing by facilitating collagen deposition, myofibroblast activation and angiogenesis. In vitro experiments demonstrated that UCHL1 concentration dependently inhibited migration, ECM synthesis and activation of human dermal fibroblasts, which was mechanistically related to downregulation of TGF‐β/Smad signalling. Furthermore, these effects could be reversed by TGF‐β inhibitor SB431542. Our findings reveal that UCHL1 is a negative regulator of cutaneous wound healing and considered as a novel prospective therapeutic target for effective wound healing.

02 Sep 2024·Connective Tissue Research

Ubiquitin C-terminal hydrolase L1 activation in periodontal ligament cells mediates orthodontic tooth movement via the MAPK signaling pathway

Article

Author: Jiang, Jiuhui ; Li, Huazhi ; Wu, Tong ; Tang, Hongyi ; Zheng, Fu ; Wang, Feifei ; Cui, Xinyu ; Li, Cuiying

PURPOSEPeriodontal ligament cells (PDLCs) play a significant role in orthodontic force induced bone remodeling. However, the molecular mechanisms by which PDLCs respond to mechanical stimuli and influence osteoclastic activities remain unclear. This study aims to investigate the role of UCHL1, a key deubiquitinating enzyme involved in protein degradation and cellular responses, in force-treated PDLCs during orthodontic tooth movement (OTM).MATERIALS AND METHODSIn this study, we conducted in vivo and in vitro experiments using human PDLCs and a rat model of OTM. Mechanical stress was applied to PDLCs, and UCHL1 expression was analyzed through quantitative real-time polymerase chain reaction (qPCR), Western blot, and immunofluorescence staining. UCHL1 knockdown was achieved using siRNA, and its effects on osteoclast differentiation were assessed. The role of the MAPK/ERK pathway was investigated using the MEK-specific inhibitor U0126. An animal model of OTM was established, and the impact of UCHL1 inhibitor-LDN57444 on OTM and osteoclastic activity was evaluated through micro-CT analysis, histological staining, and immunohistochemistry.RESULTSMechanical force induced UCHL1 expression in PDLCs during OTM. UCHL1 knockdown downregulated the RANKL/OPG ratio in PDLCs, affecting osteoclast differentiation. LDN57444 inhibited OTM and osteoclastic activity. UCHL1 activation correlated with ERK1/2 phosphorylation in force-treated PDLCs.CONCLUSIONSMechanical force mediated UCHL1 activation in PDLCs promotes osteoclast differentiation via the ERK1/2 signaling pathway during OTM.

23 Jul 2024·Circulation

Deficiency of the Deubiquitinase UCHL1 Attenuates Pulmonary Arterial Hypertension

Article

Author: Bao, Changlei ; Shi, Yinan ; Karnes, Jason H. ; Warfel, Noel A. ; Javaheri, Ali ; Luo, Ang ; Bonnet, Sebastien ; Sangam, Shreya ; Jacobson, Jeffrey R. ; Naidu, Samisubbu R. ; Morrisroe, Seth A. ; Dharmakumar, Rohan ; Coleman, Anna W. ; Tang, Haiyang ; Garcia, Joe G.N. ; Chu, Aiai ; Desai, Ankit A. ; Yuan, Jason X.-J. ; Jheng, Jia-Rong ; Gupta, Geetanjali ; Gupta, Akash ; Sun, Yanan ; Flaherty, Daniel P. ; Boucherat, Olivier ; Pauciulo, Michael W. ; Breuils-Bonnet, Sandra ; Wu, Wen-Hui ; Mitra, Sumegha ; Ciftci-Yilmaz, Sultan ; Lutz, Katie A. ; Ramamoorthi Elangovan, Venkateswaran ; Hecker, Louise ; Liang, Shuxin ; Lai, Yen-Chun ; Nichols, William C. ; Schwantes-An, Tae-Hwi ; Duarte, Julio D.

BACKGROUND:The ubiquitin-proteasome system regulates protein degradation and the development of pulmonary arterial hypertension (PAH), but knowledge about the role of deubiquitinating enzymes in this process is limited. UCHL1 (ubiquitin carboxyl-terminal hydrolase 1), a deubiquitinase, has been shown to reduce AKT1 (AKT serine/threonine kinase 1) degradation, resulting in higher levels. Given that AKT1 is pathological in pulmonary hypertension, we hypothesized that UCHL1 deficiency attenuates PAH development by means of reductions in AKT1.METHODS: Tissues from animal pulmonary hypertension models as well as human pulmonary artery endothelial cells from patients with PAH exhibited increased vascular UCHL1 staining and protein expression. Exposure to LDN57444, a UCHL1-specific inhibitor, reduced human pulmonary artery endothelial cell and smooth muscle cell proliferation. Across 3 preclinical PAH models, LDN57444-exposed animals, Uchl1 knockout rats ( Uchl1−/− ), and conditional Uchl1 knockout mice ( Tie2Cre-Uchl1fl/fl ) demonstrated reduced right ventricular hypertrophy, right ventricular systolic pressures, and obliterative vascular remodeling. Lungs and pulmonary artery endothelial cells isolated from Uchl1−/− animals exhibited reduced total and activated Akt with increased ubiquitinated Akt levels. UCHL1-silenced human pulmonary artery endothelial cells displayed reduced lysine(K)63-linked and increased K48-linked AKT1 levels. RESULTS: Supporting experimental data, we found that rs9321, a variant in a GC-enriched region of the UCHL1 gene, is associated with reduced methylation (n=5133), increased UCHL1 gene expression in lungs (n=815), and reduced cardiac index in patients (n=796). In addition, Gadd45α (an established demethylating gene) knockout mice ( Gadd45α−/− ) exhibited reduced lung vascular UCHL1 and AKT1 expression along with attenuated hypoxic pulmonary hypertension. CONCLUSIONS:Our findings suggest that UCHL1 deficiency results in PAH attenuation by means of reduced AKT1, highlighting a novel therapeutic pathway in PAH.

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Indication	Highest Phase	Country/Location	Organization	Date
Neoplasms	Discovery	US	Purdue University	15 Mar 2024

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