Folate Receptor-Targeted and Cathepsin B-Activatable Nanoprobe forIn SituTherapeutic Monitoring of Photosensitive Cell Death

2015 ◽  
Vol 87 (7) ◽  
pp. 3841-3848 ◽  
Author(s):  
Jiangwei Tian ◽  
Lin Ding ◽  
Quanbo Wang ◽  
Yaoping Hu ◽  
Li Jia ◽  
...  
Keyword(s):  
Cell Death ◽  
Cathepsin B ◽  
Folate Receptor ◽  
Photosensitive Cell

scholarly journals Legionella pneumophila induces cathepsin B-dependent necrotic cell death with releasing high mobility group box1 in macrophages

2010 ◽  
Vol 11 (1) ◽  
Author(s):  
Yoshitomo Morinaga ◽  
Katsunori Yanagihara ◽  
Shigeki Nakamura ◽  
Hiroo Hasegawa ◽  
Masafumi Seki ◽  
...  
Keyword(s):  
Cell Death ◽  
Legionella Pneumophila ◽  
Cathepsin B ◽  
High Mobility ◽  
High Mobility Group ◽  
Necrotic Cell Death ◽  
Necrotic Cell

scholarly journals Disease-associated mutations in CIAS1 induce cathepsin B–dependent rapid cell death of human THP-1 monocytic cells

Blood ◽  
2006 ◽  
Vol 109 (7) ◽  
pp. 2903-2911 ◽  
Author(s):  
Akihiro Fujisawa ◽  
Naotomo Kambe ◽  
Megumu Saito ◽  
Ryuta Nishikomori ◽  
Hideaki Tanizaki ◽  
...  
Keyword(s):  
Cell Death ◽  
Cathepsin B ◽  
Membrane Damage ◽  
Specific Inhibitor ◽  
Nuclear Factor Κb ◽  
Dependent Manner ◽  
Autoinflammatory Syndrome ◽  
Monocytic Cells ◽  
Wells Syndrome ◽  
Recognition Receptor

Abstract Mutations in the cold-induced autoinflammatory syndrome 1 (CIAS1) gene are associated with a spectrum of autoinflammatory diseases, including familial cold autoinflammatory syndrome, Muckle-Wells syndrome, and chronic infantile neurologic, cutaneous, articular syndrome, also known as neonatal-onset multisystem inflammatory disease. CIAS1 encodes cryopyrin, a protein that localizes to the cytosol and functions as pattern recognition receptor. Cryopyrin also participates in nuclear factor-κB regulation and caspase-1–mediated maturation of interleukin 1β. In this study, we showed that disease-associated mutations in CIAS1 induced rapid cell death of THP-1 monocytic cells. The features of cell death, including 7-AAD staining, the presence of cellular edema, and early membrane damage resulting in lactate dehydrogenase (LDH) release, indicated that it was more likely to be necrosis than apoptosis, and was effectively blocked with the cathepsin B–specific inhibitor CA-074-Me. CA-074-Me also suppressed induced by disease-associated mutation lysosomal leakage and mitochondrial damage. In addition, R837, a recently identified activator of cryopyrin-associated inflammasomes, induced cell death in wild type CIAS1-transfected THP-1 cells. These results indicated that monocytes undergo rapid cell death in a cathepsin B–dependent manner upon activation of cryopyrin, which is also a specific phenomenon induced by disease-associated mutation of CIAS1.

scholarly journals Streptococcus oralis Induces Lysosomal Impairment of Macrophages via Bacterial Hydrogen Peroxide

2016 ◽  
Vol 84 (7) ◽  
pp. 2042-2050 ◽  
Author(s):  
Nobuo Okahashi ◽  
Masanobu Nakata ◽  
Hirotaka Kuwata ◽  
Shigetada Kawabata
Keyword(s):  
Hydrogen Peroxide ◽  
Cell Death ◽  
Cathepsin B ◽  
Opportunistic Infections ◽  
Specific Inhibitor ◽  
Fluorescent Labeling ◽  
Dependent Manner ◽  
Content Type ◽  
Acridine Orange Staining ◽  
Streptococcus Oralis

Streptococcus oralis, an oral commensal, belongs to the mitis group of streptococci and occasionally causes opportunistic infections, such as bacterial endocarditis and bacteremia. Recently, we found that the hydrogen peroxide (H2O2) produced byS. oralisis sufficient to kill human monocytes and epithelial cells, implying that streptococcal H2O2is a cytotoxin. In the present study, we investigated whether streptococcal H2O2impacts lysosomes, organelles of the intracellular digestive system, in relation to cell death.S. oralisinfection induced the death of RAW 264 macrophages in an H2O2-dependent manner, which was exemplified by the fact that exogenous H2O2also induced cell death. Infection with either a mutant lackingspxB, which encodes pyruvate oxidase responsible for H2O2production, orStreptococcus mutans, which does not produce H2O2, showed less cytotoxicity. Visualization of lysosomes with LysoTracker revealed lysosome deacidification after infection withS. oralisor exposure to H2O2, which was corroborated by acridine orange staining. Similarly, fluorescent labeling of lysosome-associated membrane protein-1 gradually disappeared during infection withS. oralisor exposure to H2O2. The deacidification and the following induction of cell death were inhibited by chelating iron in lysosomes. Moreover, fluorescent staining of cathepsin B indicated lysosomal destruction. However, treatment of infected cells with a specific inhibitor of cathepsin B had negligible effects on cell death; instead, it suppressed the detachment of dead cells from the culture plates. These results suggest that streptococcal H2O2induces cell death with lysosomal destruction and then the released lysosomal cathepsins contribute to the detachment of the dead cells.

scholarly journals Cathepsin-Cleavable BIM BH3 Peptide Amphiphiles Are Potent Inducers of Cellular Apoptosis

Blood ◽  
2015 ◽  
Vol 126 (23) ◽  
pp. 4438-4438
Author(s):  
Joseph Bellairs ◽  
Ravand Samaeekia ◽  
Handan Acar ◽  
Matthew Tirrell ◽  
James LaBelle
Keyword(s):  
Cell Death ◽  
Cellular Uptake ◽  
Cathepsin B ◽  
Immune Modulation ◽  
Bioactive Peptides ◽  
Conflicts Of Interest ◽  
Peptide Amphiphiles ◽  
Mitochondrial Outer Membrane ◽  
High Concentration ◽  
Apoptotic Proteins

Abstract The BCL-2 family of proteins forms a complex interaction network that regulates cellular life and death decisions and contributes to cancer development, maintenance, and chemoresistance. BH3 only member proteins (e.g. BIM) serve as cellular stress sentinels and, when triggered, signal irreversible activation of apoptosis through their α-helical BH3 death domains. These pro-apoptotic signals are normally held in check by the multidomain anti-apoptotic proteins (e.g. BCL-XL, MCL-1) but when they are unable to do so the multidomain pro-apoptotic proteins BAX and BAK induce cell death through pore formation in the mitochondrial outer membrane. Therapeutic manipulation of the BCL-2 family with BH3 mimetics (including small molecules and synthetic peptides) is an emerging paradigm in cancer treatment and immune modulation. The design of next-generation therapeutics based on the BIM BH3 helix offers the unique advantage of recapitulating BIM's natural capacity to directly target the full complement of anti- and pro-apoptotic BCL-2 proteins. Here, we utilize the highly active BH3 domain of BIM as part of a peptide amphiphile nanostructure designed to overcome malignant cell death blockade. Peptide amphiphiles consist of bioactive peptides linked to hydrophobic lipid-like tail groups. In aqueous solutions, amphiphiles spontaneously assemble into micelles. Micelle-based peptide delivery provides several advantages: single micelles deliver high concentration of peptides into cells, they stabilize peptide secondary structure(s), and they have the potential for combinatorial synthesis using multiple bioactive moieties targeting non-redundant cell death escape pathways. While the exact mechanism behind cellular uptake of peptide amphiphiles remains controversial, recent work has shown that peptide amphiphiles intracellularly traffic through lysosomes and endosomes. In order to prevent the bioactive peptides from being sequestered within these structures, a system of escape is needed. Lysosomes contain many well-characterized proteases, and cathepsin B has previously been utilized to release chemotherapeutics in the context of targetable antibody-based treatments. Here, we generate peptide amphiphiles with BIM BH3 peptides and show that these nanostructures are able to specifically bind recombinant BCL-2 proteins, are stable at physiologic temperatures and pH, quickly enter into cells, and induce dose-responsive apoptosis in malignant hematologic cancers as measured by viability and caspase 3/7 activation. We further demonstrate that incorporating a cathepsin B-cleavable linker between the BIM BH3 peptide and the hydrophobic tail within individual amphiphiles results in increased binding to recombinant BCL-2 proteins while also allowing for increased cellular uptake and mitochondrial localization leading to faster and more potent dose-dependent cytotoxicity and caspase activation in malignant cells. Thus, we have developed a modular and potentially targetable nanostructure that represents a new promising strategy for BCL-2 family modulation and apoptosis induction in cancer. Disclosures No relevant conflicts of interest to declare.

Upregulation of Cathepsin B-like Protease Activity During Apoptosis inGiardia duodenalis

2019 ◽  
Vol 16 (4) ◽  
pp. 330-337
Author(s):  
Sergio Alonso Durán-Pérez ◽  
Héctor Samuel López-Moreno ◽  
Maribel Jiménez-Edeza ◽  
Jesús Ricardo Parra-Unda ◽  
Edgar Rangel-López ◽  
...  
Keyword(s):  
Cell Death ◽  
Dna Fragmentation ◽  
In Silico ◽  
Cathepsin B ◽  
Giardia Duodenalis ◽  
Cysteine Proteases ◽  
Inhibitory Effect ◽  
Death Process ◽  
Catalytic Active Site ◽  
Parasite Survival

Background:In eukaryotic cells, apoptosis signaling pathways are controlled mainly by aspartic acid cysteine proteases (caspases). However, certain unicellular microorganisms, such as Giardia duodenalis, lack these proteins. Thus, other cysteine proteases may play an important role in the parasite apoptosis signaling pathway.Objective:To understand the effect of cathepsin B-like inhibition on the cell viability of Giardia duodenalis and its cell death process.Methods:Bioinformatics analysis was performed to identify apoptotic proteases. Analysis showed that cathepsin B-like protease genes from G. duodenalis were the best candidate. A homology modeling technique was used to explore in silico the inhibitory effect of E-64 against cathepsin B-like proteases from G. duodenalis genome and to examine the effect of curcumin on cathepsin B-like activity regulation. In addition, the effect of E-64 on parasite survival and DNA fragmentation was tested.Results:Eight cathepsin B-like protease coding genes were identified in silico. Interestingly, while these sequences lacked the cathepsin B characteristic occluding loop, they maintained the catalytic active- site responsible for cathepsin B activity, which was evidenced by the increase in the degradation of the Z-RR-AMC substrate, suggesting the upregulation of the activity of these proteins. Additionally, inhibition of E-64 against G. duodenalis trophozoites caused a decrease in DNA fragmentation compared to control cells and had a positive effect on parasite survival after exposure to curcumin.Conclusion:Overall, these results suggested that Giardia duodenalis might have a cell death mechanism in which cathepsin B-like proteases play an important role.

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