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Immunologic Mechanisms in Renal Disease
Published in Robin S. Goldstein, Mechanisms of Injury in Renal Disease and Toxicity, 2020
Brian D. Schreiber, Gerald C. Groggel
A specific cysteine proteinase inhibitor, iran.s-epoxysuccinyl-2-leucylamido-(4-guanidine) butane (E-64), was studied in a complement-and neutrophil-independent model of anti-GBM antibody disease (Baricos et al., 1988). E-64, administered prior to and following anti-GBM antibody administration, significantly reduced the degree of proteinuria. The specific activity of cathepsin B and L in the glomeruli was found to be decreased. This study is particularly compelling in that a protease inhibitor was effective in altering a model of glomerulonephritis that is not dependent on cellular infiltration.
Optimizing Dose and Schedule
Published in Ying Yuan, Hoang Q. Nguyen, Peter F. Thall, Bayesian Designs for Phase I–II Clinical Trials, 2017
Ying Yuan, Hoang Q. Nguyen, Peter F. Thall
For the auto-SCT MM trial, months. Table 11.3 gives the intervals for each outcome that determined the subrectangles. The numerical values of obtained estimates in a nonlinear least squares fit were . Table 11.3 gives both the elicited utility U(e) and fitted utility for each of the 25 subrectangles, where ymid denotes the subrectangle midpoint. For example, the rectangle defined by the two intervals 1 < yE < 3 and 3 < yT < 6 has midpoint ymid = (2, 4.5), elicited utility U(e) = 64, and Û = 65.5. The surface Û(y) is illustrated by Figure 11.1. This utility function is the basis for the auto-SCT MM trial design.
Role of NF-κB in Macrophage Activation
Published in Helmut Brade, Steven M. Opal, Stefanie N. Vogel, David C. Morrison, Endotoxin in Health and Disease, 2020
NF-κB–activating stimuli have recently been shown to lead not only to phosphorylation but also to a rapid degradation of IκBα protein (5–7,57–66). As shown in Figure 1, Western analysis shows that IκBα present in the cytosol of J774 cells becomes undetectable by 15 minutes after stimulation of the cells with LPS (10 ng/ml), reappears by 30 minutes, and returns to the prestimulation level by 3 hours. The loss of IκBα from cytosol coincides with the appearance of NF-κB proteins in nuclear fraction (see lower panel). However, NF-κB remains activated for the entire period of observation (8 hr), despite the reappearance of IκBα in the cytosol 30 minutes after LPS treatment. Pretreatment of J774 cells with either phenylalanine-chloromethyl ketone (PCK) or tosylphenylalanine chloromethyl ketone (TPCK) effectively blocked LPS-triggered IκBα degradation and NF-κB activation, although in contrast to the other cell types, Na-p-tosyl-L-lysine chloromethyl ketone (TLCK) pretreatment did not lead to a substantial inhibition (64). Other types of protease inhibitors such as E-64, PMSF, 4-amidinophenyl-p-(6-amidino-2-indolyl)phenyl ether (APMSF), 4-(2-aminoethyl)benzenesulfonyl fluoride (AEBSF) or their structural analogs [p-toluenesulfonamide (TSDA) or p-toluene-sulfonylfluoride (TSF)] or a chymotrypsin/trypsin substrate [N-benzoyl-l-tyrosine ethyl ester (BTEE) or its structural analogs (N-benzoyl-d, l-phenylalanine (β-naphthyl ester (BPNE) or N-benzoyl-l-phenylalanine (BP)] had no demonstrable effect on LPS-triggered NF-κB activation in J774 cells (64). A comparison of the structures of these protease inhibitors or their structural analogs suggests the importance of a benzene ring and a chloromethyl ketone group within the phenylalanine backbone of TPCK and PCK for manifestation of the inhibitory action. The two most effective inhibitors, PCK and TPCK, possess these chemical groups, whereas TLCK, which differs from TPCK by the substitution of a benzene ring by an amino group, loses substantial inhibitory activity. A tosyl group in TPCK does not appear to be involved in the inhibition, because PCK, which lacks this group, was a very effective inhibitor and none of its structural analogs such as AEBSF, TSAD, TLCK, TSF, PMSF, or APMSF was capable of inhibiting LPS-triggered NF-κB activation.
Synthesis and evaluation of highly releasable and structurally stable antibody-SN-38-conjugates
Published in Drug Delivery, 2021
Lianqi Liu, Fei Xie, Dian Xiao, Xin Xu, Zheng Su, Yanming Wang, Shiyong Fan, Xinbo Zhou, Song Li
We reported a novel SN-38-based ADC, Mil40-11, with a high DAR value of 7.1, the linker-drug part of which was constructed by directly connecting the phenolic hydroxyl group of SN-38 to the CTSB cleavable linker through ether bonds. In this study, the feasibility of directly connecting SN-38 to a VA-based linker through the ether bond was determined. With the advantages of the self-fluorescence of SN-38, the high SN-38 release efficiency of compound 21 was observed in the presence of CTSB. Upon exposure to CTSB, the emission maximum of compound 21 quickly shifted from 427 nM to 550 nM, characteristic of SN-38. After CTSB was pretreated with the CTSB inhibitor E-64, no emission maximum was observed. Thus, it was concluded that an ether bond connection could quickly release SN-38 after self-elimination of PAB and CTSB played a key role in this process.
Cysteine cathepsins as therapeutic targets in inflammatory diseases
Published in Expert Opinion on Therapeutic Targets, 2020
Matej Vizovišek, Eva Vidak, Urban Javoršek, Georgy Mikhaylov, Andreja Bratovš, Boris Turk
However, the challenge of targeting cathepsins in cancer development and progression is that neither selective nor broad-spectrum inhibitors were able to completely block cancer progression but were only able to reduce tumor growth and metastasis spread, similarly to genetic models [31,107]. This suggests that solely targeting cathepsins would not work as a cancer monotherapy but could be useful in combination therapy. This was demonstrated in vivo in a mammary gland mouse cancer model when cathepsin inhibition substantially improved taxol treatment [108]. A good example of the latter is also the cathepsin K inhibitor odanacatib that showed good results in the prevention of bone metastasis [109]. Recently, the use of a cysteine cathepsin-trapping agent structurally similar to the cysteine cathepsin inhibitor E-64 proved to enhance tumor retention time of receptor-targeted agents [110]. In the case of neuroblastoma cells, inhibition of cathepsins sensitized the resistant cells to doxorubicin chemotherapy and decreased their migratory potential [111]. Additionally, cathepsin inhibition can influence the fate of immune cells present in the tumor microenvironment. Simultaneous inhibition of cathepsins B, L, and S was shown to induce apoptosis of TAM (tumor-associated macrophages) [112], while selective inhibition of cathepsin S in Treg cells resulted in increased proliferation and reduced apoptosis of CD 8+ T-cell in presence of bladder cancer cells [113].
Proteolytic activity accelerates the TH17/TH22 recall response to an epicutaneous protein allergen-induced TH2 response
Published in Journal of Immunotoxicology, 2022
Akira Ogasawara, Takuo Yuki, Asuka Katagiri, Yi-Ting Lai, Yutaka Takahashi, David Basketter, Hitoshi Sakaguchi
Papain (Calbiochem, San Diego, CA), HDM (Stallergenes Greer, Lenoir, NC), OVA (Fujifilm Wako Pure Chemical, Osaka, Japan), and BSA (Fujifilm) were purchased. E64-papain and E64-HDM were prepared according to a previously described protocol using E-64 (Sigma, St Louis, MO, USA; Kamijo et al. 2013). According to manufacturer instructions, biotinylated protein allergens were prepared using the EZ-Link™ Sulfo-NHS-LC-Biotinylation Kit (ThermoFisher Scientific, Tokyo, Japan). Protein concentrations were determined by the Lowry method using the DC™ Protein Assay Kit II (BioRad, Hercules, CA, USA).