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Basal forebrain cholinergic neurons (BFCNs) depend on nerve growth factor (NGF) for their survival/differentiation and innervate cortical and hippocampal regions involved in memory/learning processes. Cholinergic hypofunction and/or degeneration early occurs at prodromal stages of Alzheimer's disease (AD) neuropathology in correlation with synaptic damages, cognitive decline and behavioral disability. Alteration(s) in ubiquitin-proteasome system (UPS) is also a pivotal AD hallmark but whether it plays a causative, or only a secondary role, in early synaptic failure associated with disease onset remains unclear. We previously reported that impairment of NGF/TrkA signaling pathway in cholinergic-enriched septo-hippocampal primary neurons triggers \"dying-back\" degenerative processes which occur prior to cell death in concomitance with loss of specific vesicle trafficking proteins, including synapsin I, SNAP-25 and α-synuclein, and with deficit in presynaptic excitatory neurotransmission. Here, we show that in this neuronal model: (i) UPS stimulation early occurs following neurotrophin starvation (-1 h up to -6 h); (ii) NGF controls the steady-state levels of these three presynaptic proteins by acting on coordinate mechanism(s) of dynamic ubiquitin-C-terminal hydrolase 1 (UCHL-1)-dependent (mono)ubiquitin turnover and UPS-mediated protein degradation. Importantly, changes in miniature excitatory post-synaptic currents (mEPSCs) frequency detected in -6 h NGF-deprived primary neurons are strongly reverted by acute inhibition of UPS and UCHL-1, indicating that NGF tightly controls the presynaptic efficacy via ubiquitination-mediated pathway(s). Finally, changes in synaptic ubiquitin and selective reduction of presynaptic markers are also found in cholinergic nerve terminals from hippocampi of transgenic Tg2576 AD mice, even from presymptomatic stages of neuropathology (1-month-old). By demonstrating a crucial role of UPS in the dysregulation of NGF/TrkA signaling on properties of cholinergic synapses, these findings from two well-established cellular and animal AD models provide novel therapeutic targets to contrast early cognitive and synaptic dysfunction associated to selective degeneration of BFCNs occurring in incipient early/middle-stage of disease.

Developing strategies to enhance cartilage differentiation in mesenchymal stem cells and preserve the extracellular matrix is crucial for successful cartilage tissue reconstruction. Hypoxia‐inducible factor‐1α (HIF‐1α) plays a pivotal role in maintaining the extracellular matrix and chondrocyte phenotype, thus serving as a key regulator in chondral tissue engineering strategies. Recent studies have shown that Ubiquitin C‐terminal hydrolase L1 (UCHL1) is involved in the deubiquitylation of HIF‐1α. However, the regulatory role of UCHL1 in chondrogenic differentiation has not been investigated. In the present study, we initially validated the promotive effect of UCHL1 expression on chondrogenesis in adipose‐derived stem cells (ADSCs). Subsequently, a hybrid baculovirus system was designed and employed to utilize three CRISPR activation (CRISPRa) systems, employing dead Cas9 (dCas9) from three distinct bacterial sources to target UCHL1. Then UCHL1 and HIF‐1α inhibitor and siRNA targeting SRY‐box transcription factor 9 (SOX9) were used to block UCHL1, HIF‐1α and SOX9, respectively. Cartilage differentiation and chondrogenesis were measured by qRT‐PCR, immunofluorescence and histological staining. We observed that the CRISPRa system derived from Staphylococcus aureus exhibited superior efficiency in activating UCHL1 compared to the commonly used the CRISPRa system derived from Streptococcus pyogenes. Furthermore, the duration of activation was extended by utilizing the Cre/loxP‐based hybrid baculovirus. Moreover, our findings show that UCHL1 enhances SOX9 expression by regulating the stability and localization of HIF‐1α, which promotes cartilage production in ADSCs. These findings suggest that activating UCHL1 using the CRISPRa system holds significant potential for applications in cartilage regeneration.

Stroke is one of the leading causes of death in the world, but its underlying mechanisms remain unclear. Both conventional protein kinase C (cPKC)γ and ubiquitin C‐terminal hydrolase L1 (UCHL1) are neuron‐specific proteins. In the models of 1‐hr middle cerebral artery occlusion (MCAO)/24‐hr reperfusion in mice and 1‐hr oxygen–glucose deprivation (OGD)/24‐hr reoxygenation in cortical neurons, we found that cPKCγ gene knockout remarkably aggravated ischaemic injuries and simultaneously increased the levels of cleaved (Cl)‐caspase‐3 and LC3‐I proteolysis product LC3‐II, and the ratio of TUNEL‐positive cells to total neurons. Moreover, cPKCγ gene knockout could increase UCHL1 protein expression via elevating its mRNA level regulated by the nuclear factor κB inhibitor alpha (IκB‐α)/nuclear factor κB (NF‐κB) pathway in cortical neurons. Both inhibitor and shRNA of UCHL1 significantly reduced the ratio of LC3‐II/total LC3, which contributed to neuronal survival after ischaemic stroke, but did not alter the level of Cl‐caspase‐3. In addition, UCHL1 shRNA reversed the effect of cPKCγ on the phosphorylation levels of mTOR and ERK rather than that of AMPK and GSK‐3β. In conclusion, our results suggest that cPKCγ activation alleviates ischaemic injuries of mice and cortical neurons through inhibiting UCHL1 expression, which may negatively regulate autophagy through ERK‐mTOR pathway.

Post-traumatic stress disorder (PTSD) is frequently comorbid with persistent depressive disorder (dysthymia), indicating shared neurobiological pathways that influence stress modulation, emotional regulation, and neurohormonal adaptation. This study examines the roles of serum biomarkers—small ubiquitin-like modifier 1 (SUMO1), malondialdehyde (MDA), fractalkine (CX3CL1), and ubiquitin C-terminal hydrolase L1 (UCHL1)—involved in oxidative stress management, neuroimmune regulation, and neuronal proteostasis. In this cross-sectional analysis, biomarker expression was assessed in 92 male trauma-exposed participants aged 19–50 years, divided into three groups: PTSD duration ≤ 5 years (n = 33, median age 34.0 years [IQR 31.0–41.0]), PTSD duration > 5 years (n = 31, median age 36.0 years [IQR 29.5–41.0]), and controls without current or past PTSD (n = 28, median age 33.5 years [IQR 24.3–41.5]). Participants were stratified into younger (19–34 years) and older (35–50 years) cohorts to account for age-related neurobiological variability. Dysthymic symptomatology was evaluated using the Cornell Dysthymia Rating Scale (CDRS), focusing on chronic subthreshold depressive features. Results indicated a significant association between PTSD and elevated dysthymic symptom burden (p < 0.001), with both PTSD subgroups demonstrating mild to moderate CDRS severity compared to euthymic controls. Biomarker analysis revealed phase-dependent alterations: SUMO1 levels were significantly elevated in the ≤5 years PTSD group compared to controls (p = 0.002), suggesting early compensatory neuroprotection, whereas UCHL1 was markedly increased in the >5 years PTSD group (p = 0.015), which is indicative of chronic neuronal damage and proteostatic disruption. No significant differences were observed in MDA or CX3CL1 across groups (p > 0.05). These findings highlight PTSD’s contribution to sustained affective dysregulation, potentially mediated by temporal shifts in oxidative stress and protein homeostasis markers. Clinically, this supports the utility of biomarker profiling for risk stratification, early intervention, and personalized therapeutic strategies, such as targeted modulation of SUMOylation or UCHL1 activity, to enhance neuroresilience and mitigate progression to severe mood disorders.

Background Aberrant angiogenesis is an important pathological feature of periodontitis, which is regulated by angiogenic paracrine factors derived from periodontal ligament stem cells (PDLSCs). We have previously demonstrated that ubiquitin C-terminal hydrolase L1 (UCHL1) was upregulated in PDLSCs from periodontitis patients, but its role in aberrant angiogenesis in periodontitis remains unclear. Methods PDLSCs were isolated from healthy individuals and periodontitis patients. To mimic inflammatory conditions in vitro, PDLSCs from healthy individuals were treated with tumor necrosis factor-alpha and interleukin-1beta. Human umbilical vein endothelial cells were cultured with conditioned media from PDLSCs, and their proliferation, migration, and tube formation were detected to evaluate the pro-angiogenic capacity of PDLSCs. Vascular endothelial growth factor A (VEGFA) and angiopoietin 1 (ANGPT1) levels were measured using RT-qPCR, Western blotting, Immunofluorescence, and enzyme-linked immunosorbent assay. UCHL1 was knocked down using shRNA to validate its function and regulation of Yes-associated protein (YAP) activity. Co-immunoprecipitation was used to verify the interaction of UCHL1 with hypoxia-inducible factor 1 alpha (HIF-1α), and chromatin immunoprecipitation was used to analyze the effect of HIF-1α on YAP transcription. UCHL1 inhibitor was administered in a periodontitis murine model to investigate its function in vivo. Results The pro-angiogenic capacity of PDLSCs from periodontitis patients was enhanced, accompanied by increased expressions of VEGFA and ANGPT1, which were positively correlated with UCHL1 expression. UCHL1 knockdown in PDLSCs abrogated the increased secretion of VEGFA and ANGPT1 and the enhanced pro-angiogenic capacity under inflammatory conditions. Mechanistically, UCHL1 functioned through facilitating YAP expression and nuclear translocation, a process that was mediated by the stabilization and activation of HIF-1α, which in turn promoted YAP transcription. In vivo inhibition of UCHL1 in a periodontitis murine model alleviated aberrant angiogenesis and reduced the expressions of VEGFA and ANGPT1, thus attenuating periodontitis progression by reducing lymphocyte infiltration, inflammatory cytokine levels, and alveolar bone resorption. Conclusions This study demonstrated that UCHL1 promoted the pro-angiogenic capacity of PDLSCs in periodontitis through the HIF-1α/YAP signaling, which provides insights into the pathogenesis of periodontitis and paves the way for novel treatment strategies.

Objective To screen for specific differentially expressed genes in small cell neuroendocrine carcinoma of the cervix (SCNEC) and to further explore their roles and mechanisms in tumor progression. Methods Differentially expressed genes in SCNEC compared with squamous cell carcinoma (SCC) and adenocarcinoma (AC) were screened by microarray and immunohistochemical analyses. The biological functions of the identified genes were examined in a SCNEC cell line using RNA interference and over-expression plasmid-transfection technologies. Co-expression network analysis and immunoprecipitation technology were used to explore the potential mechanisms. Results Compared with SCC and AC, UCHL1 (encoding ubiquitin C-terminal hydrolase L1) was identified as a specific differentially expressed gene in SCNEC, which was positively related to lymph node metastasis (LNM). Migration and invasion of SCNEC tumor cells were induced by UCHL1 over-expression and suppressed by UCHL1 down-regulation, as shown by scratch and transwell invasion assays. Co-expression network analysis suggested that Prospero homeobox protein 1 (PROX1) might interact with UCHL1, and in vivo immunoprecipitation and western blots verified that levels of ubiquitinated PROX1 were significantly decreased following UCHL1 overexpression. Conclusion UCHL1 is a potential biomarker of LNM in SCNEC. UCHL1 might promote SCNEC cell migration and invasion by reducing PROX1 ubiquitination.

Background: Multidrug-resistant cancer cells overexpressing P-glycoprotein (P-gp) display variations in invasive and metastatic ability through the upregulation of the extracellular matrix metalloproteinase (MMP) inducer (CD147). However, the direct linkage between these two proteins is still unclear. Methods: We used immunoprecipitation, immunofluorescence analysis, migration and invasion assays, drug sensitivity assay and Western blot to measure the physical and functional interaction between P-gp and CD147. Then we transfected vectors carrying ubiquitin C-terminal hydrolase L1 (UCH-L1) or UCH-L1 siRNA into MCF7 and MCF7/Adr cells, respectively, and investigated the role of UCH-L1 in the regulation of the expression and degradation of P-gp, CD147 and MMP-1, MMP-2, and MMP-9 by quantitative real-time polymerase chain reaction, Western blot and immunoprecipitation. Results: In this paper, we showed that P-gp and CD147 interacted with each other, and that the ubiquitin-proteasome pathway played an important role in the turnover of them. In addition, we found that inhibition of N-glycosylation increased the ubiquitination and degradation of P-gp and CD147, and affected their function. UCH-L1 not only regulated the expression of P-gp, CD147 and MMP-1, MMP-2, and MMP-9, but also the ubiquitination and degradation of P-gp and CD147 in breast cancer cells. Conclusion: Our results demonstrate a mechanism underlying the linkage between multidrug resistance and tumor metastasis, and suggest for the first time that modulating the ubiquitination of P-gp and CD147 might be a novel method for tumor therapy.

Complete and limited proteolysis represents key events that regulate many biological processes. At least 5% of the human genome codes for components of proteolytic processes if proteases, inhibitors, and cofactors are taken into account. Accordingly, disruption of proteolysis is involved in numerous pathological conditions. In particular, molecular genetic studies have identified a growing number of monogenic disorders caused by mutations in protease coding genes, highlighting the importance of this class of enzymes in development, organogenesis, immunity, and brain function. This review provides insights into the current knowledge about the molecular genetic causes of these disorders. It should be noted that most are due to loss of function mutations, indicating absolute requirement of proteolytic activities for normal cellular functions. Recent progress in understanding the function of the implicated proteins and the disease pathogenesis is detailed. In addition to providing important clues to the diagnosis, treatment, and pathophysiology of disease, functional characterisation of mutations in proteolytic systems emphasises the pleiotropic functions of proteases in the body homeostasis.