Cathepsin B-Activated PET Tracer for In Vivo Tumor Imaging

Molecular Pharmaceutics, Journal Year: 2024, Volume and Issue: 21(3), P. 1382 - 1389

Published: Feb. 19, 2024

Cathepsin B, a lysosomal protease, is considered as crucial biomarker for tumor diagnosis and treatment it overexpressed in numerous cancers. A stimulus-responsive SF scaffold has been reported to detect the activity of variety tumor-associated enzymes. In this work, small-molecule PET tracer ([68Ga]NOTA-SF-CV) was developed by combining an with cathepsin B-specific recognition substrate Cit-Val. Upon activation [68Ga]NOTA-SF-CV could form cyclization product reduction environment, resulting reduced hydrophilicity. This unique property effectively prevent exocytosis B-overexpressing cells, leading prolonged retention amplified imaging signal. Moreover, had great targeting specificity B. vivo microPET results showed that able visualize expression level B various tumors. Hence, may be served potential diagnosing B-related diseases.

Language: Английский

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Plant cathepsin B, a versatile protease

Frontiers in Plant Science, Journal Year: 2024, Volume and Issue: 15

Published: Feb. 23, 2024

Plant proteases are essential enzymes that play key roles during crucial phases of plant life. Some mainly involved in general protein turnover and recycle amino acids for synthesis. Other cell signalling, cleave specific substrates players important genetically controlled molecular processes. Cathepsin B is a cysteine protease can do both because its exopeptidase endopeptidase activities. Animal cathepsin has been investigated many years, much known about mode action substrate preferences, but remains to be discovered this potent plants. development, germination, senescence, microspore embryogenesis, pathogen defence responses abiotic stress, including programmed death. This review discusses the structural features, activity enzyme differences between animal forms. We discuss maturation subcellular localisation provide detailed overview involvement life A greater understanding signalling processes involving needed applied discoveries biotechnology.

Language: Английский

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Prolonged glutamine starvation reactivates mTOR to inhibit autophagy and initiate autophagic lysosome reformation to maintain cell viability

The International Journal of Biochemistry & Cell Biology, Journal Year: 2024, Volume and Issue: 177, P. 106694 - 106694

Published: Nov. 14, 2024

Language: Английский

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Novel 1,2,4-triazoles as selective carbonic anhydrase inhibitors showing ancillary anticathepsin B activity

Future Medicinal Chemistry, Journal Year: 2024, Volume and Issue: 16(8), P. 689 - 706

Published: April 4, 2024

Background: Exploration of the multi-target approach considering both human carbonic anhydrase (hCA) IX and XII cathepsin B is a promising strategy to target cancer. Methodology & Results: 22 novel 1,2,4-triazole derivatives were synthesized evaluated for their inhibition efficacy against hCA I, II, IX, isoforms B. The compounds demonstrated effective and/or with considerable selectivity over off-target I/II. All presented significant anticathepsin activities at low concentration 10-7 M in vitro results also supported by molecular modeling studies. Conclusion: Insights present study can be utilized rational design selective inhibitors capable inhibiting

Language: Английский

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Radioactive and Fluorescent Dual Modality Cysteine Cathepsin B Activity-Based Probe for Cancer Theranostics

Molecular Pharmaceutics, Journal Year: 2023, Volume and Issue: 20(7), P. 3539 - 3548

Published: June 8, 2023

Cysteine cathepsin B (CTS-B) is a crucial enzyme that overexpressed in numerous malignancies and contributes to the invasion metastasis of cancer. Therefore, this study sets out develop evaluate an activity-based multimodality theranostic agent targeting CTS-B for cancer imaging therapy. A probe, BMX2, was synthesized labeled efficiently with 68Ga 90Y produce 68Ga-BMX2 90Y-BMX2 radiation The affinity specificity BMX2 binding were determined by fluorescent western blots using recombined active human (rh-CTS-B) four cell lines including HeLa, HepG2, MCF7, U87MG, CA074 as inhibitor control. Confocal laser scanning microscope uptake measurement also performed. Then, vivo PET fluorescence acquired on HeLa xenografts. Finally, therapeutic effect tested. could be specifically activated rh-CTS-B stably bound enzyme. time-dependent concentration-dependent. Although expression varied between lines, all showed significant 68Ga-BMX2. In optical high tumor accumulation more than 24 h. significantly inhibit growth. development 68Ga/90Y-BMX2, radioactive dual modality agent, demonstrated effective approach diagnostic imaging, radionuclide therapy cancers, which may have potential clinical translation theranostics future.

Language: Английский

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The relationship between pepsinogen C and gastric carcinogenesis: a transgene and population study

BMC Cancer, Journal Year: 2023, Volume and Issue: 23(1)

Published: June 8, 2023

Abstract Background Pepsinogen C (PGC) is expressed in chief cells, fundic mucous neck and pyloric gland cells of gastric epithelium also breast, prostate, lung, seminal vesicles. Methods We explored the clinicopathological prognostic significances PGC mRNA using pathological bioinformatics analyses. generated knockout PGC-cre transgenic mice to observe effects deletion PTEN abrogation PGC-positive on carcinogenesis. Finally, we observed altered expression aggressive phenotypes by CCK8, Annexin V staining, wound healing transwell assays analyzed partner proteins co-IP (co-immunoprecipitation) double fluorescence staining. Results level was inversely correlated with T G stage a short survival cancer ( p < 0.05). protein negatively linked lymph node metastasis, dedifferentiation, low Her-2 No difference body weight or length evident between wild-type (WT) (KO) > 0.05), but KO had shorter than WT lesions were mucosa granular stomach mice, which displayed lower frequency severity lesion after treated MNU. Transgenic showed high cre activity stomach, kidney, breast. Gastric triple-negative lobular breast adenocarcinoma found PGC-cre/PTEN f/f two previous pregnancies feeding, not seen exposed either estrogen progesterone, those no feeding. suppressed proliferation, migration, invasion, induced apoptosis, interacted CCNT1, CNDP2 CTSB. Conclusion downregulation cancer, resulted resistance chemically-induced proliferation invasion possibly interacting Spontaneous carcinogenesis closely pregnancy single exposure pregnancy. Limiting feeding might help prevent hereditary cancer.

Language: Английский

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Cysteine Cathepsins and Their Diagnostic Role in Breast Cancer

Egyptian Academic Journal of Biological Sciences. C, Physiology and Molecular Biology/Egyptian Academic Journal of Biological Sciences. C, Physiology and Molecular Biology, Journal Year: 2024, Volume and Issue: 16(1), P. 1 - 14

Published: Jan. 10, 2024

Background: A large class of proteolytic enzymes known as cysteine cathepsins are created pro-enzymes and activated in slightly acidic conditions.They crucial for both healthy cellular function illness.Cysteine a family proteases that play important roles variety processes, including protein turnover, cell adhesion, migration.Main body: In breast cancer, have been shown to be overexpressed tumor cells associated with poor prognosis.This review article discusses the role focusing on their diagnostic potential.The provides an overview cathepsins, structure, function, regulation addition evidence overexpression cancer association prognosis.Conclusions: The current demonstrates potential use biomarkers early detection diagnosis cancer.

Language: Английский

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Novel thiazolotriazole and triazolothiadiazine scaffolds as selective tumor associated carbonic anhydrase inhibitors endowed with cathepsin B inhibition

Archiv der Pharmazie, Journal Year: 2024, Volume and Issue: 357(10)

Published: July 11, 2024

Abstract The present research focused on the tail‐approach synthesis of novel extended thiazolotriazoles ( 8a – 8j ) and triazolothiadiazines 11a 11j including aminotriazole intermediate 10 . After successful synthesis, all compounds were evaluated for their inhibition potential against cytosolic isoforms human carbonic anhydrase (hCA I, II), tumor‐linked transmembrane IX, XII), cathepsin B. As per data, newly synthesized showed poor hCA I. Many effective toward IX and/or XII in low nanomolar concentration. Despite strong to moderate II by these compounds, more than half them demonstrated better XII, comparatively. Further, insights CA data analogs comparison with earlier reported thiazolotriazole triazolothiadiazine derivatives might help rational design potent selective inhibitors. also found possess anti‐cathepsin B at a concentration −7 M. Broadly, series presented counterparts Moreover, vitro results respect supported silico obtained via molecular modeling studies.

Language: Английский

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Myeloid-derived β-hexosaminidase is essential for neuronal health and lysosome function: implications for Sandhoff disease

bioRxiv (Cold Spring Harbor Laboratory), Journal Year: 2024, Volume and Issue: unknown

Published: Oct. 22, 2024

ABSTRACT Lysosomal storage disorders (LSDs) are a large disease class involving lysosomal dysfunction, often resulting in neurodegeneration. Sandhoff (SD) is an LSD caused by deficiency the β subunit of β-hexosaminidase enzyme ( Hexb ). Although expression brain specific to microglia, SD primarily affects neurons. To understand how microglial gene involved maintaining neuronal homeostasis, we demonstrated that secreted microglia and integrated into compartment. assess therapeutic relevance, treated mice with bone marrow transplant colony stimulating factor 1 receptor inhibition, which broadly replaced -/- -sufficient cells. This intervention reversed apoptotic signatures, improved behavior, restored enzymatic activity expression, ameliorated substrate accumulation, normalized phenotypes. These results underscore critical role myeloid-derived β- hexosaminidase function establish replacement as potential therapy.

Language: Английский

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Identification of biomarkers related to autophagy in osteoarthritis via bioinformatics analysis and experimental validation (Preprint)

Published: Nov. 7, 2024

Osteoarthritis(OA) is a degenerative disease with few effective early interventions and therapeutic options, autophagy thought to play significant role in progression of OA. We used bioinformatics analysis experimental validation identify biomarkers related OA the aim targets. The series matrix file GSE82107 was downloaded from Gene Expression Omnibus (GEO) public databases. data were processed differentially expressed genes (DEGs) identified via R 4.2.2 software. related-DEGs subsequently defined as DEGs that overlapped autophagy-related selected on basis Venn diagram. screened Ontology (GO) analysis, Kyoto Encyclopedia Genes Genomes (KEGG) enrichment protein-protein interaction (PPI) immune cell infiltration analysis. Based constructed PPI network, hub CytoHubba plugin. Moreover, confirmed receiver operating characteristic (ROC) curve GSE129147 GSE169077 datasets. In addition, we collected synovial tissue knees ten patients: five patients who underwent total knee arthroplasty young arthroscopic surgery for anterior cruciate ligament rupture. samples subjected RNA extraction followed by real-time quantitative RT-PCR.Finally, verified expression HUB gene calculating corresponding mRNA levels. Five namely, BCL2L1, CTSD, ATG3, GABARAPL2 CTSB related-DEGs. ROC revealed almost all had good diagnostic value, but Q-PCR results clinical GABARAPL2, upregulated (p < 0.05). relative expressions CTSD ATG3 not significantly different between group control > This study OA, including CTSB. These are promising targets treatment.

Language: Английский

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