scholarly journals Calpain-2 participates in the process of calpain-1 inactivation by Shinkai-Ouchi et al.

2021 ◽  
Author(s):  
Tushar Kanti Maiti ◽  
Raniki Kumari
Keyword(s):  
Specific Substrate ◽  
Neuronal Function ◽  
Future Studies ◽  
Calcium Dependent ◽  
Important Mediator ◽  
Lysosomal Cysteine Protease ◽  
Substrate Cleavage ◽  
Calpain 2 ◽  
Cellular Pathways

Calpain belongs to the calcium-dependent non-lysosomal cysteine protease. Calpain-1 and calpain-2 expression are ubiquitous in mammals and an important mediator of the action of calcium. Specific substrate cleavage by calpain-1 and calpain-2 is critical for several calcium-dependent cellular pathways including neuronal function, muscle contraction, signal transduction, cell differentiation, proliferation, and apoptosis.Research suggests that calpain-1 and calpain-2 perform similar functions due to their structurally highly similar isoforms. Increasing evidence suggests that calpain-1 and calpain-2 carry out their specific function in vivo. A recent paper published by Shinkai-Ouchi et al. (Bioscience Reports (2020) 40, https://doi.org/10.1042/BSR20200552) elucidated the mechanism to differentiate the function of each calpain in respect to the efficiency and longevity for proteolysis after activation. Further, the study represented that calpain-1 and calpain-2 do not synergistically perform their workin vitro. On the other hand, the activity of calpain-1 is reduced in presence of calpain-2. This insight establishes the platform for future studies to examine how calpain-2 regulates the calpain-1 for substrate proteolysis.

scholarly journals Visualizing cell death in live retina: Using calpain activity detection as a biomarker for retinal degeneration

2021 ◽  
Author(s):  
Soumaya Belhadj ◽  
Nina Hermann ◽  
Gustav Christensen ◽  
Torsten Strasser ◽  
François Paquet-Durand
Keyword(s):  
Cell Death ◽  
Retinal Degeneration ◽  
Imaging Techniques ◽  
Death Process ◽  
Specific Substrate ◽  
Activity Detection ◽  
Wild Type ◽  
Calpain Activity ◽  
Calpain 2

AbstractCalpains are a family of calcium-activated proteases involved in numerous disorders. Notably, previous studies have shown that calpain activity was substantially increased in various models for inherited retinal degeneration (RD). In the present study, we tested the capacity of the t-BOC-Leu-Met-CMAC calpain-specific substrate to detect calpain activity in living retina, in organotypic retinal explant cultures derived from wild-type mice, as well as from rd1 and RhoP23H/+ RD-mutant mice. Test conditions were refined until the calpain substrate readily detected large numbers of cells in the photoreceptor layer of RD retina but not in wild-type retina. At the same time, the calpain substrate was not obviously toxic to photoreceptor cells. Comparison of calpain activity with an immunostaining for activated calpain-2 furthermore suggested that individual calpain isoforms may be active in distinct temporal stages of photoreceptor cell death. Notably, calpain-2 activity may be a relatively short-lived event, occurring only towards the end of the cell death process. Finally, our results support the development of calpain activity detection as a novel in vivo biomarker for RD, suitable for combination with non-invasive imaging techniques.

scholarly journals Proteolysis in Caenorhabditis elegans sex determination: cleavage of TRA-2A by TRA-3

2000 ◽  
Vol 14 (8) ◽  
pp. 901-906
Author(s):  
Sharon B. Sokol ◽  
Patricia E. Kuwabara
Keyword(s):  
Caenorhabditis Elegans ◽  
Membrane Protein ◽  
Cell Fate ◽  
Calcium Binding ◽  
Female Development ◽  
C Elegans ◽  
Calcium Dependent ◽  
Substrate Cleavage ◽  
Ef Hands

The Caenorhabditis elegans tra-3 gene promotes female development in XX hermaphrodites and encodes an atypical calpain regulatory protease lacking calcium-binding EF hands. We report that despite the absence of EF hands, TRA-3 has calcium-dependent proteolytic activity and its proteolytic domain is essential for in vivo function. We show that the membrane protein TRA-2A, which promotes XX female development by repressing the masculinizing protein FEM-3, is a TRA-3 substrate. Cleavage of TRA-2A by TRA-3 generates a peptide predicted to have feminizing activity. These results indicate that proteolysis regulated by calcium may control some aspects of sexual cell fate in C. elegans.

scholarly journals Oligonucleotide Therapies in the Treatment of Arthritis: A Narrative Review

Biomedicines ◽  
2021 ◽  
Vol 9 (8) ◽  
pp. 902
Author(s):  
Susanne N. Wijesinghe ◽  
Mark A. Lindsay ◽  
Simon W. Jones
Keyword(s):  
Rheumatoid Arthritis ◽  
Articular Cartilage ◽  
Joint Diseases ◽  
Synovial Joint ◽  
Pharmacological Treatments ◽  
In Vivo Models ◽  
Inflammatory Joint Diseases ◽  
Joint Pathology ◽  
Cellular Pathways

Osteoarthritis (OA) and rheumatoid arthritis (RA) are two of the most common chronic inflammatory joint diseases, for which there remains a great clinical need to develop safer and more efficacious pharmacological treatments. The pathology of both OA and RA involves multiple tissues within the joint, including the synovial joint lining and the bone, as well as the articular cartilage in OA. In this review, we discuss the potential for the development of oligonucleotide therapies for these disorders by examining the evidence that oligonucleotides can modulate the key cellular pathways that drive the pathology of the inflammatory diseased joint pathology, as well as evidence in preclinical in vivo models that oligonucleotides can modify disease progression.

scholarly journals A Selective ATP-Binding Cassette Subfamily G Member 2 Efflux Inhibitor Revealed via High-Throughput Flow Cytometry

2012 ◽  
Vol 18 (1) ◽  
pp. 26-38 ◽  
Author(s):  
J. Jacob Strouse ◽  
Irena Ivnitski-Steele ◽  
Hadya M. Khawaja ◽  
Dominique Perez ◽  
Jerec Ricci ◽  
...  
Keyword(s):  
Molecular Probes ◽  
Atp Binding ◽  
Specific Substrate ◽  
Tumor Resistance ◽  
Drug Concentrations ◽  
Efflux Inhibition ◽  
Substrate Inhibitor ◽  
Atp Binding Cassette

Chemotherapeutics tumor resistance is a principal reason for treatment failure, and clinical and experimental data indicate that multidrug transporters such as ATP-binding cassette (ABC) B1 and ABCG2 play a leading role by preventing cytotoxic intracellular drug concentrations. Functional efflux inhibition of existing chemotherapeutics by these pumps continues to present a promising approach for treatment. A contributing factor to the failure of existing inhibitors in clinical applications is limited understanding of specific substrate/inhibitor/pump interactions. We have identified selective efflux inhibitors by profiling multiple ABC transporters against a library of small molecules to find molecular probes to further explore such interactions. In our primary screening protocol using JC-1 as a dual-pump fluorescent reporter substrate, we identified a piperazine-substituted pyrazolo[1,5-a]pyrimidine substructure with promise for selective efflux inhibition. As a result of a focused structure-activity relationship (SAR)–driven chemistry effort, we describe compound 1 (CID44640177), an efflux inhibitor with selectivity toward ABCG2 over ABCB1. Compound 1 is also shown to potentiate the activity of mitoxantrone in vitro as well as preliminarily in vivo in an ABCG2-overexpressing tumor model. At least two analogues significantly reduce tumor size in combination with the chemotherapeutic topotecan. To our knowledge, low nanomolar chemoreversal activity coupled with direct evidence of efflux inhibition for ABCG2 is unprecedented.

Identification and functional characterization of legumain in amphioxus Branchiostoma belcheri

2009 ◽  
Vol 30 (3) ◽  
pp. 177-186 ◽  
Author(s):  
Lei Teng ◽  
Hiroshi Wada ◽  
Shicui Zhang
Keyword(s):  
Functional Characterization ◽  
Specific Substrate ◽  
Glycosylation Sites ◽  
Branchiostoma Belcheri ◽  
Hen’S Egg ◽  
Hind Gut ◽  
Catalytic Dyad ◽  
Pepstatin A

Legumain has been reported from diverse sources such as plants, parasites (animals) and mammals, but little is known in the lower chordates. The present study reports the first characterization of legumain cDNA from the protochordate Branchiostoma belcheri. The deduced 435-amino-acid-long protein is structurally characterized by the presence of a putative N-terminal signal peptide, a peptidase_C13 superfamily domain with the conserved Lys123-Gly124-Asp125 motif and catalytic dyad His153 and Cys195 and two potential Asn-glycosylation sites at Asn85 and Asn270. Phylogenetic analysis demonstrates that B. belcheri legumain forms an independent cluster together with ascidian legumain, and is positioned at the base of vertebrate legumains, suggesting that B. belcheri legumain gene may represent the archetype of vertebrate legumain genes. Both recombinant legumain expressed in yeast and endogenous legumain are able to be converted into active protein of ~37 kDa via a C-terminal autocleavage at acid pH values. The recombinant legumain efficiently degrades the legumain-specific substrate Z-Ala-Ala-Asn-MCA (benzyloxycarbonyl-L-alanyl-L-alanyl-L-asparagine-4-methylcoumaryl-7-amide) at optimum pH 5.5; and the enzymatic activity is inhibited potently by iodoacetamide and N-ethylmaleimide, partially by hen's-egg white cystatin, but not by E-64 [trans-epoxysuccinyl-L-leucylamido-(4-guanidino)butane], PMSF and pepstatin A. In addition, legumain is expressed in vivo in a tissue-specific manner, with main expression in the hepatic caecum and hind-gut of B. belcheri. Altogether, these results suggest that B. belcheri legumain plays a role in the degradation of macromolecules in food.

scholarly journals Adhesion molecules during somitogenesis in the avian embryo.

1987 ◽  
Vol 104 (5) ◽  
pp. 1361-1374 ◽  
Author(s):  
J L Duband ◽  
S Dufour ◽  
K Hatta ◽  
M Takeichi ◽  
G M Edelman ◽  
...  
Keyword(s):  
Adhesion Molecules ◽  
Tissue Remodeling ◽  
Cell Aggregation ◽  
Avian Embryo ◽  
Primary Role ◽  
Calcium Dependent ◽  
Tissue Dissociation ◽  
Spatio Temporal

In avian embryos, somites constitute the morphological unit of the metameric pattern. Somites are epithelia formed from a mesenchyme, the segmental plate, and are subsequently reorganized into dermatome, myotome, and sclerotome. In this study, we used somitogenesis as a basis to examine tissue remodeling during early vertebrate morphogenesis. Particular emphasis was put on the distribution and possible complementary roles of adhesion-promoting molecules, neural cell adhesion molecule (N-CAM), N-cadherin, fibronectin, and laminin. Both segmental plate and somitic cells exhibited in vitro calcium-dependent and calcium-independent systems of cell aggregation that could be inhibited respectively by anti-N-cadherin and anti-N-CAM antibodies. In vivo, the spatio-temporal expression of N-cadherin was closely associated with both the formation and local disruption of the somites. In contrast, changes in the prevalence of N-CAM did not strictly accompany the remodeling of the somitic epithelium into dermamyotome and sclerotome. It was also observed that fibronectin and laminin were reorganized secondarily in the extracellular spaces after CAM-mediated contacts were modulated. In an in vitro culture system of somites, N-cadherin was lost on individual cells released from somite explants and was reexpressed when these cells reached confluence and established intercellular contacts. In an assay of tissue dissociation in vitro, antibodies to N-cadherin or medium devoid of calcium strongly and reversibly dissociated explants of segmental plates and somites. Antibodies to N-CAM exhibited a smaller disrupting effect only on segmental plate explants. In contrast, antibodies to fibronectin and laminin did not perturb the cohesion of cells within the explants. These results emphasize the possible role of cell surface modulation of CAMs during the formation and remodeling of some transient embryonic epithelia. It is suggested that N-cadherin plays a major role in the control of tissue remodeling, a process in which N-CAM is also involved but to a lesser extent. The substratum adhesion molecules, fibronectin and laminin, do not appear to play a primary role in the regulation of these processes but may participate in cell positioning and in the stabilization of the epithelial structures.

Targeting Trained Innate Immunity With Nanobiologics to Treat Cardiovascular Disease

2021 ◽  
Author(s):  
Abraham J.P. Teunissen ◽  
Mandy M.T. van Leent ◽  
Geoffrey Prevot ◽  
Eliane E.S. Brechbuhl ◽  
Carlos Pérez-Medina ◽  
...  
Keyword(s):  
Cardiovascular Disease ◽  
Myeloid Cells ◽  
Myeloid Cell ◽  
Apolipoprotein A1 ◽  
New Paradigm ◽  
Trained Immunity ◽  
Atherosclerosis Progression ◽  
Cardiovascular Patients ◽  
Cellular Pathways

The innate immune system plays a key role in atherosclerosis progression and the pathogenesis of cardiovascular disease. Trained immunity, an epigenetically regulated hyperresponsive state of myeloid cells, is a driving force underlying chronic inflammation in atherosclerosis. Therapeutically targeting innate trained immunity therefore may mature into a compelling new paradigm for the effective treatment of cardiovascular patients, which would require effective engagement of myeloid cells. For over a decade, we have worked on apolipoprotein A1-based nanomaterials, referred to as nanobiologics, which we have utilized for myeloid cell-directed immunotherapy. Here, we review the application of our nanobiologic immunotherapies in treating vascular disease. The design of nanobiologic therapeutics, as well as their use in targeting myeloid cells and cellular pathways related to trained immunity, is discussed. Furthermore, we show that nanobiologic biocompatibility and in vivo behavior are conserved across species, from mice to larger animals, including rabbits, pigs, and nonhuman primates. Last, we deliberate on the hurdles that currently prevent widespread translation of trained immunity targeting cardiovascular nanotherapies.

scholarly journals CCL2 as an Important Mediator of Prostate Cancer Growth In Vivo through the Regulation of Macrophage Infiltration

Neoplasia ◽  
2007 ◽  
Vol 9 (7) ◽  
pp. 556-562 ◽  
Author(s):  
Robert D. Loberg ◽  
Chi Ying ◽  
Matt Craig ◽  
Li Yan ◽  
Linda A. Snyder ◽  
...  
Keyword(s):  
Prostate Cancer ◽  
Macrophage Infiltration ◽  
Cancer Growth ◽  
Important Mediator

Influence of estrogen on individual exercise motivation and bone protection in ovariectomized rats

2018 ◽  
Vol 52 (5) ◽  
pp. 479-489 ◽  
Author(s):  
Sebastian T Müller ◽  
Annekathrin M Keiler ◽  
Kristin Kräker ◽  
Oliver Zierau ◽  
Ricardo Bernhardt
Keyword(s):  
Bone Loss ◽  
Ex Vivo ◽  
Voluntary Exercise ◽  
Ovariectomized Rats ◽  
Protective Effects ◽  
Exercise Motivation ◽  
Running Wheel ◽  
Future Studies ◽  
Bone Protection

Bone protection and metabolism are directly linked to estrogen levels, but exercise is also considered to have bone protective effects. Reduced estrogen levels lead to a variety of disorders, for example, bone loss and reduced movement drive. The objective of this study was to investigate the effects of estrogen on individual voluntary exercise motivation and bone protection. We investigated sham operated, ovariectomized, and ovariectomized with estrogen supplemented Wistar rats (20 weeks old) either with or without access to exercise wheels. We selected an experimental approach where we could monitor the individual exercise of group-housed rats with ad libitum access to a running wheel with the help of a subcutaneous chip. In vivo and ex vivo microcomputed tomography analyses of the tibia were performed at two-week intervals from week 0 to week 6. Furthermore, tibial trabecular structure was evaluated based on histomorphometric analyses. We observed a significant bone protective effect of E2. For exercise performance, a substantially high intra-group variability was observed, especially in the E2 group. We presume that dominant behavior occurs within the group-housed rats resulting in a hierarchical access to the running wheel and a high variability of distance run. Exercise did not prevent ovariectomy-induced bone loss. However, lack of estrogen within the ovariectomized rats led to a drastically reduced activity prevented by estrogen supplementation. Our findings are important for future studies working with group-housed rats and exercise. The reason for the high intra-group variability in exercise needs to be investigated in future studies.

Preclinical studies conducted on nanozyme antioxidants: shortcomings and challenges based on US FDA regulations

Nanomedicine ◽  
2021 ◽  
Author(s):  
Milad Ghorbani ◽  
Zhila Izadi ◽  
Samira Jafari ◽  
Eudald Casals ◽  
Foroogh Rezaei ◽  
...  
Keyword(s):  
Oxidative Stress ◽  
Clinical Trials ◽  
Clinical Studies ◽  
In Vivo Studies ◽  
Preclinical Studies ◽  
Future Studies ◽  
Clinical Stages ◽  
Us Fda ◽  
Considerable Body

The wide prevalence of oxidative stress-induced diseases has led to a growing demand for antioxidant therapeutics worldwide. Nanozyme antioxidants are drawing enormous attention as practical alternatives for conventional antioxidants. The considerable body of research over the last decade and the promising results achieved signify the potential of nanozyme antioxidants to secure a place in the expanding market of antioxidant therapeutics. Nonetheless, there is no report on clinical trials for their further evaluation. Through analyzing in-depth selected papers which have conducted in vivo studies on nanozyme antioxidants, this review aims to pinpoint and discuss possible reasons impeding development of research toward clinical studies and to offer some practical solutions for future studies to bridge the gap between preclinical and clinical stages.

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