A5031633451- Ubiquitin and proteasome pathways
- Chemokine receptors and signaling
- Histone Deacetylase Inhibitors Research
- Immunotherapy and Immune Responses
- Peptidase Inhibition and Analysis
- Protein Degradation and Inhibitors
- Glycosylation and Glycoproteins Research
- Cancer-related Molecular Pathways
- Cell death mechanisms and regulation
- Autophagy in Disease and Therapy
- Endoplasmic Reticulum Stress and Disease
- Multiple Myeloma Research and Treatments
- Monoclonal and Polyclonal Antibodies Research
- Plant Diversity and Evolution
- Graphene and Nanomaterials Applications
- Genomics, phytochemicals, and oxidative stress
- Nanoparticles: synthesis and applications
- Genetics and Neurodevelopmental Disorders
- Image and Signal Denoising Methods
- Microtubule and mitosis dynamics
- Nanoparticle-Based Drug Delivery
- Redox biology and oxidative stress
- Image Enhancement Techniques
- NF-κB Signaling Pathways
- Nanoplatforms for cancer theranostics
McMaster University Medical Centre
2024
Universidad Francisco de Vitoria
2024
Biomedical Research Networking Center on Neurodegenerative Diseases
2024
Instituto de Salud Carlos III
2024
Linköping University
2015-2024
Bharathidasan University
2013-2016
Abstract Inhibition of deubiquitinase (DUB) activity is a promising strategy for cancer therapy. VLX1570 an inhibitor proteasome DUB currently in clinical trials relapsed multiple myeloma. Here we show that binds to and inhibits the ubiquitin-specific protease-14 (USP14) vitro, with comparatively weaker inhibitory towards UCHL5 (ubiquitin-C-terminal hydrolase-5). Exposure myeloma cells resulted thermostabilization USP14 at therapeutically relevant concentrations. Transient knockdown or...
Abstract A large number of natural products have been advocated as anticancer agents. Many these compounds contain functional groups characterized by chemical reactivity. It is not clear whether distinct mechanisms action can be attributed to such compounds. We used a library screening approach demonstrate that substantial fraction (~20%) cytotoxic synthetic containing Michael acceptor inhibit proteasome substrate processing and induce cellular response characteristic inhibition. Biochemical...
Inhibitors of the 20S proteasome such as bortezomib (Velcade®) and carfilzomib (Kypriolis®) are in clinical use for treatment patients with multiple myeloma mantle cell lymphoma. In an attempt to identify novel inhibitors ubiquitin-proteasome system (UPS) we used connectivity map (CMap) resource, based on alterations gene expression profiles by perturbagens, performed COMPARE analyses drug sensitivity patterns NCI60 panel. Cmap analysis identified a large number small molecules strong...
The non-genotoxic nature of proteasome inhibition makes it an attractive therapeutic option for the treatment pediatric malignancies. We recently described small molecule VLX1570 as inhibitor deubiquitinase (DUB) activity that induces proteotoxic stress and apoptosis in cancer cells. Here we show acute lymphoblastic leukemia (ALL) cells are highly sensitive to with VLX1570, resulting accumulation polyubiquitinated substrates loss cell viability. increased levels a number proteins, including...
The proteasome is a validated target of cancer therapeutics. Inhibition activity results in the activation unfolded protein response (UPR) characterized by phosphorylation eukaryotic initiation factor 2α (eIF2α), global translational arrest, and increased expression proapoptotic CHOP (C/EBP homologous protein) protein. Defects UPR has been reported to result altered sensitivity tumor cells inhibitors. Here, we effects deubiquitinase (DUB) inhibitor VLX1570 on homeostasis, both at level...
Images captured underwater frequently have a low resolution as result of number issues including light attenuation, backscattering, and colour distortion. The restoration images, which serves an essential building block for the field vision research, remains difficult endeavor. process removing haziness distortion caused by environs is main focus work that goes into images. Within confines this we present enhanced approach enhancement images called Improved Cycle GAN (Generative Adversarial...
CXCR4 is a ubiquitously expressed chemokine receptor that regulates leukocyte trafficking and arrest in both homeostatic pathological states. It also participates organogenesis, HIV-1 infection, tumor development. Despite the potential therapeutic benefit of antagonists, only one, plerixafor (AMD3100), which blocks ligand-binding site, has reached clinic. Recent advances imaging biophysical techniques have provided richer understanding membrane organization dynamics this receptor. Activation...
CXCR4 is a ubiquitously expressed chemokine receptor that regulates leukocyte trafficking and arrest in both homeostatic pathological states. It also participates organogenesis, HIV-1 infection, tumor development. Despite the potential therapeutic benefit of antagonists, only one, plerixafor (AMD3100), which blocks ligand-binding site, has reached clinic. Recent advances imaging biophysical techniques have provided richer understanding membrane organization dynamics this receptor. Activation...
Background b-AP15/VLX1570 are small molecule inhibitors of the ubiquitin specific peptidase 14 (USP14) and carboxyl-terminal hydrolase 5 (UCHL5) deubiquitinases (DUBs) 19S proteasome. have been shown to be cytotoxic cells resistant bortezomib, raising possibility that this class drugs can used as a second-line therapy for treatment-resistant multiple myeloma. Limited information is available with regard potential resistance mechanisms b-AP15/VLX1570. Results We found b-AP15-induced cell...
Dienone compounds have been demonstrated to display tumor-selective anti-cancer activity independently of the mutational status TP53. Previous studies shown that cell death elicited by this class is associated with inhibition ubiquitin-proteasome system (UPS). Here we extend previous findings showing dienone compound b-AP15 inhibits proteasomal degradation long-lived proteins. We show exposure results in increased association chaperones VCP/p97/Cdc48 and BAG6 proteasomes. Comparisons between...
Dienone compounds with a 1,5-diaryl-3-oxo-1,4-pentadienyl pharmacophore have been widely reported to show tumor cell selectivity. These target the ubiquitin-proteasome system (UPS), known be essential for viability of cells. The induction oxidative stress, depletion glutathione, and high-molecular-weight (HMW) complexes also reported. We here examined response acute myeloid leukemia (AML) cells dienone compound VLX1570. AML relatively high protein turnover rates sensitive reduced...
CXCR4 is a ubiquitously expressed chemokine receptor that regulates leukocyte trafficking and arrest in homeostatic pathological states, also participates organogenesis, HIV-1 infection tumor development. Despite the potential therapeutic benefit of antagonists, so far only one, plerixafor (AMD3100), which blocks ligand-binding site, has reached clinic. Recent advances imaging biophysical techniques have provided richer understanding membrane organization dynamics this receptor. CXCL12...
Abstract The proteasome-associated deubiquitinase USP14 is a potential drug target. Using an inducible knockout system in colon cancer cells, we found that depletion impedes cellular proliferation, induces cell cycle arrest, and leads to senescence-like phenotype. Transcriptomic analysis revealed altered gene expression related division differentiation. cells also exhibited changes morphology, actin distribution, of cytoskeletal components. Increased ubiquitin turnover was observed, offset...
CXCR4 is a ubiquitously expressed chemokine receptor that regulates leukocyte trafficking and arrest in both homeostatic pathological states. It also participates organogenesis, HIV-1 infection tumor development. Despite the potential therapeutic benefit of antagonists, only one, plerixafor (AMD3100), which blocks ligand-binding site, has reached clinic. Recent advances imaging biophysical techniques have provided richer understanding membrane organization dynamics this receptor. Activation...