Disease relevance of CALPAIN IHIBITOR I

• Calpain inhibitor I reduces the activation of nuclear factor-kappaB and organ injury/dysfunction in hemorrhagic shock [1].
• CONCLUSION: Calpain inhibitor I reduces the degree of colitis caused by DNBS [2].
• We propose that calpain inhibitor I may be useful in the treatment of inflammatory bowel disease [2].
• Calpain inhibitor I (5 mg/kg daily intraperitoneally) significantly reduced the degree of haemorrhagic diarrhoea and weight loss caused by administration of DNBS [2].
• The enhancement of fodrin breakdown was completely blocked by omission of extracellular Ca2+ and significantly inhibited by calpain inhibitors such as E-64 and calpain inhibitor-I, thereby suggesting that the fodrin breakdown induced by hypoxia/hypoglycemia is due to the activation of Ca2+-stimulated neutral protease calpain [3].

High impact information on CALPAIN IHIBITOR I

• The retinoid-mediated degradation of cyclin D1 was blocked by cotreatment with calpain inhibitor I. CONCLUSIONS: Retinoid-dependent cyclin D1 proteolysis is a common chemoprevention signal in normal and neoplastic human bronchial epithelial cells [4].
• The cell permeant agent, calpain inhibitor I, limited EGF-induced motility and de-adhesion similarly to IP-10 [5].
• Lactacystin and calpain inhibitor I, specific inhibitors of the 26S proteasome, blocked progestin-induced down-regulation, and ubiquitinated conjugates of PR accumulated in cells [6].
• The cytotoxic neutral cysteine protease inhibitor N-acetylleucylleucylnorleucinal (ALLN) inhibits cell-cycle progression in CHO cells, affecting the G1/S and metaphase-anaphase transition points, as well as S phase [7].
• Pretreatment (for 1 h) of murine macrophages or rat aortic smooth muscle cells (activated with endotoxin) with calpain inhibitor I attenuated the binding of activated NF-kappaB to DNA and the degradation of IkappaBalpha, IkappaBbeta, and IkappaBvarepsilon [1].

Chemical compound and disease context of CALPAIN IHIBITOR I

• Exposure of PAEC to hypoxia also caused time-dependent decreases of heat shock protein 90 (HSP90) that were prevented by calpain inhibitor I and calpeptin [8].
• 5. Thus, calpain inhibitor I and dexamethasone attenuate (i) the circulatory failure, (ii) the multiple organ dysfunction (liver and pancreatic dysfunction/injury, lactic acidosis, hypoglycaemia), as well as (iii) the induction of iNOS and COX-2 protein and activity in rats with endotoxic shock [9].
• Leupeptin and calpain inhibitor I had no reliable effects on the rate at which synaptic transmission declined during hypoxia or the time required for loss of action potentials, but both drugs did substantially improve the degree of recovery [10].
• Adenine nucleotide and calpain inhibitor I protect against atractyloside-induced toxicity in rat renal cortical slices in vitro [11].

Biological context of CALPAIN IHIBITOR I

• These results indicate that gadd153 gene expression increase occurs downstream of events sensitive to N-tosyl-L-phenylalanine chloromethylketone, calpain inhibitor I, and Bcl-2 and upstream of interleukin 1beta-converting enzyme-related proteases activation in leukemic cells in which treatment with VP-16 induces rapid apoptosis [12].
• There was a 1.6-fold increase in calpain activity in T3A-infected cells compared to mock-infected cells; this increase was completely inhibited by preincubation with calpain inhibitor I (N-acetyl-leucyl-leucyl-norleucinal [aLLN]), an active-site inhibitor [13].
• To probe this mechanism in greater detail, we explored the kinetic mechanism of inhibition of the 20S proteasome-catalyzed hydrolysis of Suc-Leu-Leu-Val-Tyr-AMC by the peptide aldehyde, Ac-Leu-Leu-Nle-H [14].
• When macrophages and CHO cells were incubated with the cysteine protease inhibitor N-acetylleucylleucylnorleucinal (ALLN), the ability of beta-very-low-density lipoprotein (beta-VLDL) and free cholesterol-rich liposomes to stimulate cholesterol esterification was inhibited by 60-90% [15].
• Calpain inhibitor I produced a significant reduction in the degree of long-term potentiation induced by theta-burst stimulation in hippocampal slices prepared from 14-20 postnatal day-old animals [16].

Anatomical context of CALPAIN IHIBITOR I

• The membrane-permeable calpain inhibitors MDL 28,170 and calpain inhibitor-I (10-100 microM) were effective at reducing spectrin breakdown in anoxic and reoxygenated optic nerves, but no electrophysiological improvement was observed [17].
• Treatment of cultured L6 myotubes with the calpain inhibitors calpeptin and Calpain Inhibitor I and II resulted in increased C/EBPbeta concentrations but did not influence cellular levels of the other C/EBP transcription factor family members [18].
• Calpain inhibitor I retards seizure offset in the hippocampus of freely moving rats [19].
• CHP addition to hemolysate produced a decrease in membrane-bound microCANP levels comparable to that observed with erythrocytes; addition of the Ca2+ chelator EGTA or Calpain Inhibitor I (N-acetyl-leucyl-leucyl-leucyl-nor-leucinal) to hemolysate effectively inhibited this decrease [20].
• Calpain inhibitor I, given intraperitoneally 30 min before ischemia at a dose of 15 mg/kg, significantly improved mean arterial blood pressure, markedly reduced IkappaB-alpha degradation and the intensity of P-selectin and ICAM-1 in the reperfused ileum [21].

Associations of CALPAIN IHIBITOR I with other chemical compounds

• Findings were extended by showing treatment with ubiquitin-dependent proteasome inhibitors: calpain inhibitor I and lactacystin each prevented this decreased cyclin D1 protein expression, despite RA treatment [22].
• Furthermore, pretreating platelets with the calpain inhibitors calpeptin and calpain inhibitor I prevented the calpain-mediated reduction in clot retraction [23].
• Treatment of Chinese hamster ovary (CHO) cells by the aldehyde containing calpain inhibitor I resulted in the induction of a 35-kDa protein that was partially sequenced and shown to be a member of the aldo-keto reductase superfamily (Inoue, S., Sharma, R. C., Schimke, R. T., and Simoni, R. D. (1993) J. Biol. Chem. 268, 5894-5898) [24].
• Furthermore, calpain inhibitor I reduced (1) the staining for nitrotyrosine and poly (ADP-ribose) polymerase (immunohistochemistry) and (2) the expression of inducible nitric oxide synthase and cyclooxygenase-2 in the lungs of carrageenan-treated rats and in joints from collagen-treated rats [25].
• Cleavage of p35 was also induced in primary cultured neurons by treatment with a Ca(2+) ionophore and Ca(2+) and inhibited by calpain inhibitor I. The cleavage changed the solubility of the CDK5 active complex from the particulate fraction to the soluble fraction but did not affect the histone H1 kinase activity [26].

Gene context of CALPAIN IHIBITOR I

• Calpain inhibitor I (ALLN), a protease inhibitor, inhibits TNF-alpha-mediated down-regulation of TbetaRII [27].
• The disappearance of exogenous IkappaB-alpha by the overexpression of MEK kinase is prevented by calpain inhibitor-I, an inhibitor of IkappaB-alpha degradation [28].
• This decrease was partially blocked by concurrent treatment with the proteasome inhibitor calpain inhibitor I. Using a luciferase-based reporter assay, resveratrol did not inhibit cyclin D1 promoter activity in SW480 cells [29].
• Calpain inhibitor I (ALLN) prevented epidermal growth factor-stimulated cell de-adhesion and resulted in a significantly slower decay of matrix contraction, with only a slight decrease of the peak magnitude of contraction [30].
• Addition of ALLN/calpain inhibitor I to the culture medium after UV resulted in similar survival (14 - 18%) between RSa and UVr-1 cells [31].

Analytical, diagnostic and therapeutic context of CALPAIN IHIBITOR I

• The reduction of Abeta(1-40) after treatment with 50 microM calpain inhibitor I or 5 microM carbobenzoxyl-Leu-Leu-leucinal was accompanied by a slight increase of Abeta(1-42) released into the medium [32].
• Here we investigate the effects of calpain inhibitor I in animal models of acute and chronic inflammation (carrageenan-induced pleurisy and collagen-induced arthritis) [25].
• Continuous intrahippocampal microperfusion of 500 microM calpain inhibitor I had no effect on basal EEG, but doubled (P < 0.05) average seizure duration, and increased more than five-fold (P < 0.01) the total seizure time and three-fold (P < 0.01) the seizure offset time compared to picrotoxin alone, in each individual rat [19].
• Intravenous injections of vehicle or calpain inhibitor I were administered 30 min before ischemia [33].
• The implications of increased calpain-mediated proteolysis during epileptic seizures are still unclear, and in this study we investigate the effect of the continuous perfusion of calpain inhibitor I on picrotoxin-induced seizures in chronic freely moving rats [19].

References