Ubiquitin C-terminal hydrolase L1 (UCHL1) is a neuronal protein important in maintaining axonal integrity and motor function and may be important in the pathogenesis of many neurological disorders. UCHL1 may ameliorate acute injury and improve recovery after cerebral ischemia. In the current study, the hypothesis that UCHL1’s hydrolase activity underlies its effect in maintaining axonal integrity and function is tested after ischemic injury. Hydrolase activity was inhibited by treatment with a UCHL1 hydrolase inhibitor or by employing knockin mice bearing a mutation in the hydrolase active site (C90A). Ischemic injury was induced by oxygen-glucose deprivation (OGD) in brain slice preparations and by transient middle cerebral artery occlusion (tMCAO) surgery in mice. Hydrolase activity inhibition increased restoration time and decreased the amplitude of evoked axonal responses in the corpus callosum after OGD. Mutation of the hydrolase active site exacerbated white matter injury as detected by SMI32 immunohistochemistry, and motor deficits as detected by beam balance and cylinder testing after tMCAO. These results demonstrate that UCHL1 hydrolase activity ameliorates white matter injury and functional deficits after acute ischemic injury and support the hypothesis that UCHL1 activity plays a significant role in preserving white matter integrity and recovery of function after cerebral ischemia.

01 Oct 2024·Experimental Dermatology

Inhibition of Ubiquitin C‐Terminal Hydrolase L1 Facilitates Cutaneous Wound Healing via Activating TGF‐β/Smad Signalling Pathway in Fibroblasts

Article

Author: Zhang, Litian ; Song, Jinru ; Zheng, Wenyue ; An, Qing ; Gu, Jingjing ; Chen, Junyi ; Pan, Huihui ; Yang, Bin ; Deng, Chengcheng

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.

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

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