Protease is responsible for many physiological functions and can act as growth factor for both malignant and normal cells in the processes of the cell division and DNA biosynthesis. There was clear relation between metastatic tumors and protease. The protease inhibitors found in the natural environment or synthesized but both have not been used in the treatment of human cancer. Currently, the protease inhibitors are studying thoroughly on their mechanism, action and application in the anti-cancer.
Protease Inhibitors ; neoplasms ; therapeutics

Kunitz-type serine protease inhibitors are a class of ubiquitous protease inhibitors, which play important roles in various life activities. The structures of such inhibitors are generally stable, and are usually characterized by the presence of one or several Kunitz domains in tandem, which are able to bind to serine proteases in a manner similar to substrate binding, thereby inhibiting enzyme activity. In terms of function, Kunitz-type serine protease inhibitors are involved in processes such as blood coagulation and fibrinolysis, tumor immunity, inflammation regulation, and resistance to bacterial and fungal infections. This article summarizes the advances of Kunitz-type serine protease inhibitors and provides new ideas for the development of novel Kunitz-type serine protease inhibitors.
Protease Inhibitors ; Serine Proteases ; Serine Proteinase Inhibitors

Human leukocyte elastase is an important selection target of inflammation and cancer. In this paper, a high throughput screening model was established for screening human leukocyte elastase inhibitors from thousands of strains of actinomycetes. As a result, a strain, N01WA-735 with potent suppression activity was isolated. Firstly, the strain N01WA-735 was identified as Streptomyces according to morphology and biochemical analysis. The Streptomyces N01WA-735 was processed by solvent extraction, silica column chromatography, Sephadex LH-20 column chromatography and crystallization to get a pure active compound named N01WA-735E. Its chemical structure was elucidated as the same as that of the compound named BE-52440A by physicochemical properties and spectral data of UV, MS, 1H-NMR and 13C-NMR respectively. The compound showed a strong inhibitory activity against human leukocyte elastase with IC50 of 3.02 micromol/L. The compound is reported as a human leukocyte elastase inhibitor for the first time.
Humans ; Leukocyte Elastase ; antagonists & inhibitors ; Protease Inhibitors ; isolation & purification ; metabolism ; Streptomyces ; isolation & purification ; metabolism

For 16 years after the finding of HIV as an agent of AIDS in 1981, HIV therapeutic drugs of reverse transcriptase inhibitors (AZT, ddI, ddC, d4T) and protease inhibitors have been developed. Recent studies also were focused on a combination therapy by using HIV therapeutic drugs or natural compounds. Korean red ginseng (KRG) of natural compounds has been well known as a good reinforcement agent in Asia. The percentage of CD3+CD4+ T cell in nine HIV-infected patients without KRG treatment averaged 17.8% on baseline and decreased 15.8% after 6 months, whereas the percentage of the cell in fifteen HIV-infected patients with KRG treatment averaged 15.3% on baseline and increased up to 18.9% after the same period. The average percentage of CD3+CD8+ T cell of KRG-nontreated and KRG-treated HIV patients increased after 6 months 47.8% to 50.7% and 44.7% to 51.4%, respectively; and the average percentage of B and NK cell in the KRG-nontreated and KRG-treated HIV patients decreased 9.4% to 7.9% and 13.0% to 9.7%, 8.9% to 8.5% and 16.2% to 11.6%, respectively, KRG, therefore, didn't have any effects on the CD3+CD8+ T cell, B cell, and NK cell. However, it seems that KRG has a potential activity for stimulating the
Asia ; HIV ; Humans ; Killer Cells, Natural ; Lymphocyte Subsets* ; Lymphocytes* ; Panax* ; Protease Inhibitors ; Reverse Transcriptase Inhibitors

The efficacy and safety of a single tablet regimen (STR) of elvitegravir/cobicistat/emtricitabine/tenofovir disoproxil fumarate (E/C/F/TDF) were analyzed in Phase 3 clinical trials in antiretroviral therapy (ART)-naïve and ART-experienced Asian subjects infected with human immunodeficiency virus (HIV)-1. Studies GS-US-236-102 and GS-US-236-103 were randomized, double-blind, placebo-controlled, 144-week studies conducted in ART-naïve subjects, comparing E/C/F/TDF versus efavirenz (EFV)/F/TDF or ritonavir-boosted atazanavir (ATV+RTV) plus emtricitabine/tenofovir DF (F/TDF), respectively. Studies GS-US-236-115 and GS-US-236-121 were randomized, open-label, 96-week long conducted in ART-experienced subjects, who switched to E/C/F/TDF from ritonavir-boosted protease inhibitors (PI+RTV)+F/TDF, or non-nucleoside reverse transcriptase inhibitors (NNRTI)+F/TDF regimens. The E/C/F/TDF appeared to have sustained efficacy and safety and was well tolerated in the small number of ART-naïve and ART-experienced Asian subjects.
Asian Continental Ancestry Group* ; Atazanavir Sulfate ; HIV* ; HIV-1* ; Humans ; Humans* ; Protease Inhibitors ; Reverse Transcriptase Inhibitors

A large number of protease inhibitors have been found from leeches, which are essential in various physiological and biological processes. In the curret study, a novel elastase inhibitor was purified and characterized from the leech of Hirudinaria manillensis, which was named HMEI-A. Primary structure analysis showed that HMEI-A belonged to a new family of proteins. HMEI-A exerted inhibitory effects on elastase and showed potent abilities to inhibit elastase with an inhibition constant (K
Amino Acid Sequence ; Animals ; Leeches/chemistry* ; Pancreatic Elastase/antagonists & inhibitors* ; Protease Inhibitors/pharmacology* ; Proteins

PURPOSE: The purpose of this study was to determine if ceramide, which is known as secondary messenger of programmed cell death (apoptosis), can cause apoptosis in lens epithelial cell (LEC) and if so, to identify the pathway by which apoptosis occurs. METHODS: After LECs were exposed to various concentrations of ceramide and phytoceramide, we evaluated the resulting apoptosis response using the Hoechst-EthD stain and Annexin stain. To search for the apoptosis pathway, LECs were preincubated in various concentrations of CPP32-like protease inhibitor, specific caspase-8 inhibitor, and specific caspase-9 inhibitor, then treated with ceramide and phytoceramide. We performed LDH assay 12 hours later. Cytochrome c immunostaining was done after exposure to the ceramide and phytoceramide. RESULTS: All kinds of ceramide induced time and concentration dependent apoptosis in LEC. Caspase 8 inhibitor and caspase 9 inhibitor reduced the apoptosis in ceramide VI, phytoceramide II, and phytoceramide VI. In all ceramides, cytochrome c staining was positive. CONCLUSIONS: Ceramide and phytoceramide can cause apoptosis in LEC. Ceramide and phytoceramide may be used to prevent the posterior capsular opacity after cataract surgery.
Apoptosis* ; Caspase 8 ; Caspase 9 ; Cataract ; Cell Death ; Ceramides ; Cytochromes c ; Epithelial Cells* ; Protease Inhibitors

We have reported that serum amylase and lipase level elevate immediately after total gastrectomy independent to whether the pancreas is manipulated or not. Although we found high levels of amylase and lipase from the draining fluid via intraabdominal drain, none of them became pancreatic fistula. To check the amylase and lipase level after distal gastrectomy and to check whether the protease inhibitor (gabexate mesilate) reduce the elevated amylase and lipase, we made a prospective study. A Jackson-Pratt drain was inserted intraperitoneally during the operation to check amylase and lipase levels postoperatively. We present the postoperative changing patterns of amylase and lipase levels in the draining fluid. Serum amylase and lipase levels were also monitored. We found elevation of amylase and lipase concentrations in the draining fluid for a few days after distal gastrectomy. However, none of the patients developed pancreatic fistula, although all of the surgical methods showed hyperamylasemia and hyperlipasemia. Postoperative treatment with protease inhibitor was not effective against the elevated amylase and lipase levels in serum or draining fluid.
Amylases ; Gabexate ; Gastrectomy* ; Humans ; Hyperamylasemia ; Lipase ; Pancreas ; Pancreatic Fistula ; Prospective Studies ; Protease Inhibitors*

PURPOSE: We investigated the effect of ceramide on keratocyte apoptosis and pathway of ceramide-induced keratocyte apoptosis. METHODS: Cultured Newzealand White Rabbit keratocytes were exposed to various concentrations of ceramide type II, VI and phytoceramide type II, VI. LDH level was measured for the evaluation of time and concentration related apoptosis. Keratocytes were preincubated in various concentrations of CPP32-like protease inhibitor (Z-VAD-FMK, diffuse caspase inhibitor), specific caspase-8 inhibitor (IETD-CHO) and specific caspase-9 inhibitor (Z-LEHD-FMK), then were exposed to 20 micro M of 4 types of ceramide. Cytochome C immune stainining was done after exposure of keratocyte to 4 types of ceramide. RESULTS: The lower effective dose of 4 types of ceramide was 20 micro M. Apoptosis of keratocytes was dependent on ceramide exposure time. Ceramide induced keratocyte apoptosis was inhibited by CPP32-like protease inhibitor, specific caspase-8 inhibitor and specific caspase-9 inhibitor. Apoptotic keratocytes induced by ceramide were immune-stained with cytochrome C antibody. CONCLUSIONS: Ceramide induced apoptosis in cultured corneal keratocytes. This apoptosis developed according caspase cascade, especially via mitochondria.
Apoptosis* ; Caspase 8 ; Caspase 9 ; Corneal Keratocytes ; Cytochromes c ; Mitochondria ; Protease Inhibitors

BACKGROUND/AIMS: Gabexate, a protease inhibitor, has been known to prevent pancreatic damage following ERCP. We conducted a prospective and randomized study to assess the preventive effect of gabexate. Methods: Of the 96 patients enrolled, 46 were treated with gabexate and 50 with placebo. The groups were similar with regard to sex, age, body-mass index, and the final diagnosis of ERCP. RESULTS: 24 patients (25.0%) had elevated pancreatic-enzyme levels; the frequency was similar in the two groups (P=0.48). Mean serum amylase value at 4 hours after ERCP was similar in patients with elevated basal level (220.5+/-43.2 U/L) and those with normal basal level (170.4+/-31.2 U/L). After the procedures, serum amylase values were lower in the gabexate group (137.1+/-19.8 U/L) than in the placebo group (212.0+/-50.4 U/L). The differences were not significant in the mean levels of amylase between the groups for any of imaging of the pancreatic ducts (pancreatic-duct imaging, 201.5+/-49.4 U/L, bile-duct imaging, 153.7+/-30.0 U/L). But in the patients with pancreatic duct imaging, serum amylase values were significantly higher in the placebo group (295.0+/-97.6 U/L) than in the gabexate group (112.0+/-10.6 U/L)(p<0.05). CONCLUSIONS: Prophylactic treatment with gabexate does not reduce pancreatic damage related to ERCP, but only in the patients with pancreatic duct imaging there were the significant differences between in the gabexate group and in the placebo group.
Amylases ; Cholangiopancreatography, Endoscopic Retrograde* ; Diagnosis ; Gabexate* ; Humans ; Pancreatic Ducts ; Pancreatitis ; Prospective Studies ; Protease Inhibitors