Cardiac and renal diseases(CRDs) are characterized by extensive remodeling of the extracellular matrix(ECM)architecture of the cardiorenal system. Among the many extracellular proteolytic enzymes present in cardiorena...Cardiac and renal diseases(CRDs) are characterized by extensive remodeling of the extracellular matrix(ECM)architecture of the cardiorenal system. Among the many extracellular proteolytic enzymes present in cardiorenal cells and involved in ECM remodeling, members of the matrix metalloproteinase family and serine protease family have received the most attention. However, recent findings from laboratory and clinical studies have indicated that cysteine protease cathepsins also participate in pathogenesis of the heart and kidney.Deficiency and pharmacological inhibition of cathepsins have allowed their in vivo evaluation in the setting of pathological conditions. Furthermore, recent studiesevaluating the feasibility of cathepsins as a diagnostic tool have suggested that the serum levels of cathepsins L, S and K and their endogenous inhibitor cystatin C have predictive value as biomarkers in patients with coronary artery disease and heart and renal failure. The goal of this review is to highlight recent discoveries regarding the contributions of cathepsins in CRDs, particularly hypertensive heart failure and proteinuric kidney disease.展开更多
A series of N1-substituted-3-aryl-4-alkyl-4, 5-dihydro-1H-1-pyrazolethiocarboxamide were prepared from the Mannich bases of aryl ketones in good yields. Some derivatives were found to be active against the cysteine p...A series of N1-substituted-3-aryl-4-alkyl-4, 5-dihydro-1H-1-pyrazolethiocarboxamide were prepared from the Mannich bases of aryl ketones in good yields. Some derivatives were found to be active against the cysteine protease of T.cruzi..展开更多
There are evidences indicating that cysteine proteases play an essential role in malaria parasites;therefore, an obvious area of investigation is the inhibition of these enzymes to treat malaria. Small cysteine protea...There are evidences indicating that cysteine proteases play an essential role in malaria parasites;therefore, an obvious area of investigation is the inhibition of these enzymes to treat malaria. Small cysteine protease inhibitors of malaria are well studied, but macromolecular nature of inhibitor is a new field to explore. In malarial cysteine proteases, there are macromolecular endogenous inhibitors playing important roles in regulation of the cysteine protease activity of parasite and host. Recent studies suggested that there are known and characterized endogenous inhibitors like falstatin present in P. falciparum, PbICP (inhibitor of cysteine protease in P. berghei), PyICP (inhibitor of cysteine protease in P. yoelli), and other macromolecular inhibitors which are the prodomain of enzyme itself regulating the activity of the mature enzyme. All the known macromolecular endogenous inhibitors are using specific loop-like structure to interact with malarial cysteine proteases. The majority of macromolecular inhibitors are competitive in nature, and block access to the active site of their target protease, but do not bind in a strictly substrate-like manner. They rather interact with the protease subsites and catalytic residues in a non-catalytically competent manner. In future, designing inhibitors based on these protein-protein interactions will be a new approach in the field of malaria. Since macromolecular inhibitors can gain potency through the burial of a large surface area and specificity through contacts with secondary binding sites critical for inhibition, and could be less prone to drug resistant mutation.展开更多
The oral pathogen Porphyromonas gingivalis is recognized as one of the major aetiological agents of chronic periodontitis. The gingipains, which are the principal virulence factors of P. gingivalis, are multi-domain p...The oral pathogen Porphyromonas gingivalis is recognized as one of the major aetiological agents of chronic periodontitis. The gingipains, which are the principal virulence factors of P. gingivalis, are multi-domain proteins containing an N-terminal C25 cysteine protease domain. We have conducted a bio-informatics study of the C25 cysteine protease domains and have identified related domains in over two thousand proteins from 739 organisms in 35 distinct phyla. Proteins having significant similarity to the gingipain C25 cysteine protease domain are also found in Gram +ve bacteria, Archaea, algae, higher fungi, and a wide variety of Eukaryotic species.展开更多
目的:分析外周血核苷酸结合寡聚化结构域样受体蛋白3(nucleotide binding oligomerization domain like receptor protein 3,NLRP3)-半胱氨酸蛋白酶1(cysteine-aspartic acid protease 1,Caspase-1)-白细胞介素(interleukin,IL)-1β信...目的:分析外周血核苷酸结合寡聚化结构域样受体蛋白3(nucleotide binding oligomerization domain like receptor protein 3,NLRP3)-半胱氨酸蛋白酶1(cysteine-aspartic acid protease 1,Caspase-1)-白细胞介素(interleukin,IL)-1β信号轴与肺癌的相关性。方法:选取2021年6月—2023年8月江苏省连云港市赣榆区人民医院收治的肺癌住院患者72例初诊患者(肺癌组)和72例健康体检者(健康对照组)。比较两组外周血单核细胞、NLRP3、Caspase-1、IL-1β水平及肺功能[1秒用力呼气量(forced expiratory volume in one second,FEV_(1))、用力肺活量(forced vital capacity,FVC)、FEV_(1)/FVC],并分析肺癌组外周血中NLRP3、IL-1β水平与FEV_(1)、FVC、FEV_(1)/FVC的相关性。结果:肺癌组患者FEV_(1)、FVC、FEV_(1)/FVC水平均显著低于健康对照组,差异有统计学意义(P均<0.05);外周血中Nlrp3、Caspase-1、Il-1βmRNA相对表达水平和Caspase-1和IL-1β分泌水平均高于健康对照组,差异有统计学意义(P均<0.05);Spearman相关分析显示,肺癌组患者外周血单核细胞Nlrp3基因mRNA相对表达量与FEV_(1)、FEV_(1)/FVC水平呈负相关(P<0.05);而外周血IL-1β分泌水平与FEV_(1)/FVC水平呈正相关(P<0.05)。结论:外周血单核细胞中NLRP3 mRNA相对表达水平及外周血IL-1β分泌水平与肺癌进展呈负相关,可反映肺癌进展程度,对肺癌的筛查和诊断具有潜在的参考价值。展开更多
Cysteine proteases continue to provide validated targets for treatment of human diseases.In neurodegenerative disorders,multiple cysteine proteases provide targets for enzyme inhibitors,notably caspases,calpains,and c...Cysteine proteases continue to provide validated targets for treatment of human diseases.In neurodegenerative disorders,multiple cysteine proteases provide targets for enzyme inhibitors,notably caspases,calpains,and cathepsins.The reactive,active-site cysteine provides specificity for many inhibitor designs over other families of proteases,such as aspartate and serine;however,a)inhibitor strategies often use covalent enzyme modification,and b)obtaining selectivity within families of cysteine proteases and their isozymes is problematic.This review provides a general update on strategies for cysteine protease inhibitor design and a focus on cathepsin B and calpain 1 as drug targets for neurodegenerative disorders;the latter focus providing an interesting query for the contemporary assumptions that irreversible,covalent protein modification and low selectivity are anathema to therapeutic safety and efficacy.展开更多
A gene encoding a cysteine proteinase was iso- lated from senescent leave of cotton (Gossypium hirsutum) cv liaomian No. 9 by utilizing rapid amplification of cDNA ends polymerase chain reaction (RACE-PCR), and a set ...A gene encoding a cysteine proteinase was iso- lated from senescent leave of cotton (Gossypium hirsutum) cv liaomian No. 9 by utilizing rapid amplification of cDNA ends polymerase chain reaction (RACE-PCR), and a set of con- sensus oligonucleotide primers was designed to anneal the conserved sequences of plant cysteine protease genes. The cDNA, which designated Ghcysp gene, contained 1368 bp terminating in a poly(A)+ trail, and included a putative 5 (98 bp) and a 3 (235 bp) non-coding region. The opening reading frame (ORF) encodes polypeptide 344 amino acids with the predicted molecular mass of 37.88 kD and theoretical pI of 4.80. A comparison of the deduced amino acid sequence with the sequence in the GenBank database has shown consider- able sequence similarity to a novel family of plant cysteine proteases. This putative cotton Ghcysp protein shows from 67% to 82% identity to the other plants. All of them share catalytic triad of residues, which are highly conserved in three regions. Hydropaths analysis of the amino acid se- quence shows that the Ghcysp is a potential membrane pro- tein and localizes to the vacuole, which has a transmembrane helix between resides 7 —25. A characteristic feature of Ghcysp is the presence of a putative vacuole-targeting signal peptide of 19-amino acid residues at the N-terminal region. The expression of Ghcysp gene was determined using north- ern blot analysis. The Ghcysp mRNA levels are high in de- velopment senescent leaf but below the limit of detection in senescent root, hypocotyl, faded flower, 6 d post anthesis ovule, and young leaf.展开更多
Leishmania is associated with a broad spectrum of diseases, ranging from simple cutaneous to invasive visceral leishmaniasis. Here, the sequences of ten cysteine proteases of types A, B and C of Leishmania major were ...Leishmania is associated with a broad spectrum of diseases, ranging from simple cutaneous to invasive visceral leishmaniasis. Here, the sequences of ten cysteine proteases of types A, B and C of Leishmania major were obtained from GeneDB database. Prediction of MHC class I epitopes of these cysteine proteases was performed by NetCTL program version 1.2. In addition, by using BcePred server, different structural properties of the proteins were predicted to find out their potential B cell epitopes. According to this computational analysis, nine regions were predicted as B cell epitopes. The results provide useful information for designing peptide-based vaccines.展开更多
基金Supported by Grants from the Japan Heart Foundation/Novartis Research Award on Molecular and Cellular Cardiology,No.26-007523The Scientific Research Fund of the Chinese Ministry of Education,No.30960128
文摘Cardiac and renal diseases(CRDs) are characterized by extensive remodeling of the extracellular matrix(ECM)architecture of the cardiorenal system. Among the many extracellular proteolytic enzymes present in cardiorenal cells and involved in ECM remodeling, members of the matrix metalloproteinase family and serine protease family have received the most attention. However, recent findings from laboratory and clinical studies have indicated that cysteine protease cathepsins also participate in pathogenesis of the heart and kidney.Deficiency and pharmacological inhibition of cathepsins have allowed their in vivo evaluation in the setting of pathological conditions. Furthermore, recent studiesevaluating the feasibility of cathepsins as a diagnostic tool have suggested that the serum levels of cathepsins L, S and K and their endogenous inhibitor cystatin C have predictive value as biomarkers in patients with coronary artery disease and heart and renal failure. The goal of this review is to highlight recent discoveries regarding the contributions of cathepsins in CRDs, particularly hypertensive heart failure and proteinuric kidney disease.
文摘A series of N1-substituted-3-aryl-4-alkyl-4, 5-dihydro-1H-1-pyrazolethiocarboxamide were prepared from the Mannich bases of aryl ketones in good yields. Some derivatives were found to be active against the cysteine protease of T.cruzi..
文摘There are evidences indicating that cysteine proteases play an essential role in malaria parasites;therefore, an obvious area of investigation is the inhibition of these enzymes to treat malaria. Small cysteine protease inhibitors of malaria are well studied, but macromolecular nature of inhibitor is a new field to explore. In malarial cysteine proteases, there are macromolecular endogenous inhibitors playing important roles in regulation of the cysteine protease activity of parasite and host. Recent studies suggested that there are known and characterized endogenous inhibitors like falstatin present in P. falciparum, PbICP (inhibitor of cysteine protease in P. berghei), PyICP (inhibitor of cysteine protease in P. yoelli), and other macromolecular inhibitors which are the prodomain of enzyme itself regulating the activity of the mature enzyme. All the known macromolecular endogenous inhibitors are using specific loop-like structure to interact with malarial cysteine proteases. The majority of macromolecular inhibitors are competitive in nature, and block access to the active site of their target protease, but do not bind in a strictly substrate-like manner. They rather interact with the protease subsites and catalytic residues in a non-catalytically competent manner. In future, designing inhibitors based on these protein-protein interactions will be a new approach in the field of malaria. Since macromolecular inhibitors can gain potency through the burial of a large surface area and specificity through contacts with secondary binding sites critical for inhibition, and could be less prone to drug resistant mutation.
文摘The oral pathogen Porphyromonas gingivalis is recognized as one of the major aetiological agents of chronic periodontitis. The gingipains, which are the principal virulence factors of P. gingivalis, are multi-domain proteins containing an N-terminal C25 cysteine protease domain. We have conducted a bio-informatics study of the C25 cysteine protease domains and have identified related domains in over two thousand proteins from 739 organisms in 35 distinct phyla. Proteins having significant similarity to the gingipain C25 cysteine protease domain are also found in Gram +ve bacteria, Archaea, algae, higher fungi, and a wide variety of Eukaryotic species.
文摘目的:分析外周血核苷酸结合寡聚化结构域样受体蛋白3(nucleotide binding oligomerization domain like receptor protein 3,NLRP3)-半胱氨酸蛋白酶1(cysteine-aspartic acid protease 1,Caspase-1)-白细胞介素(interleukin,IL)-1β信号轴与肺癌的相关性。方法:选取2021年6月—2023年8月江苏省连云港市赣榆区人民医院收治的肺癌住院患者72例初诊患者(肺癌组)和72例健康体检者(健康对照组)。比较两组外周血单核细胞、NLRP3、Caspase-1、IL-1β水平及肺功能[1秒用力呼气量(forced expiratory volume in one second,FEV_(1))、用力肺活量(forced vital capacity,FVC)、FEV_(1)/FVC],并分析肺癌组外周血中NLRP3、IL-1β水平与FEV_(1)、FVC、FEV_(1)/FVC的相关性。结果:肺癌组患者FEV_(1)、FVC、FEV_(1)/FVC水平均显著低于健康对照组,差异有统计学意义(P均<0.05);外周血中Nlrp3、Caspase-1、Il-1βmRNA相对表达水平和Caspase-1和IL-1β分泌水平均高于健康对照组,差异有统计学意义(P均<0.05);Spearman相关分析显示,肺癌组患者外周血单核细胞Nlrp3基因mRNA相对表达量与FEV_(1)、FEV_(1)/FVC水平呈负相关(P<0.05);而外周血IL-1β分泌水平与FEV_(1)/FVC水平呈正相关(P<0.05)。结论:外周血单核细胞中NLRP3 mRNA相对表达水平及外周血IL-1β分泌水平与肺癌进展呈负相关,可反映肺癌进展程度,对肺癌的筛查和诊断具有潜在的参考价值。
文摘Cysteine proteases continue to provide validated targets for treatment of human diseases.In neurodegenerative disorders,multiple cysteine proteases provide targets for enzyme inhibitors,notably caspases,calpains,and cathepsins.The reactive,active-site cysteine provides specificity for many inhibitor designs over other families of proteases,such as aspartate and serine;however,a)inhibitor strategies often use covalent enzyme modification,and b)obtaining selectivity within families of cysteine proteases and their isozymes is problematic.This review provides a general update on strategies for cysteine protease inhibitor design and a focus on cathepsin B and calpain 1 as drug targets for neurodegenerative disorders;the latter focus providing an interesting query for the contemporary assumptions that irreversible,covalent protein modification and low selectivity are anathema to therapeutic safety and efficacy.
文摘A gene encoding a cysteine proteinase was iso- lated from senescent leave of cotton (Gossypium hirsutum) cv liaomian No. 9 by utilizing rapid amplification of cDNA ends polymerase chain reaction (RACE-PCR), and a set of con- sensus oligonucleotide primers was designed to anneal the conserved sequences of plant cysteine protease genes. The cDNA, which designated Ghcysp gene, contained 1368 bp terminating in a poly(A)+ trail, and included a putative 5 (98 bp) and a 3 (235 bp) non-coding region. The opening reading frame (ORF) encodes polypeptide 344 amino acids with the predicted molecular mass of 37.88 kD and theoretical pI of 4.80. A comparison of the deduced amino acid sequence with the sequence in the GenBank database has shown consider- able sequence similarity to a novel family of plant cysteine proteases. This putative cotton Ghcysp protein shows from 67% to 82% identity to the other plants. All of them share catalytic triad of residues, which are highly conserved in three regions. Hydropaths analysis of the amino acid se- quence shows that the Ghcysp is a potential membrane pro- tein and localizes to the vacuole, which has a transmembrane helix between resides 7 —25. A characteristic feature of Ghcysp is the presence of a putative vacuole-targeting signal peptide of 19-amino acid residues at the N-terminal region. The expression of Ghcysp gene was determined using north- ern blot analysis. The Ghcysp mRNA levels are high in de- velopment senescent leaf but below the limit of detection in senescent root, hypocotyl, faded flower, 6 d post anthesis ovule, and young leaf.
基金supported by a grant (No. 88-GR-SC-47) from Shiraz University
文摘Leishmania is associated with a broad spectrum of diseases, ranging from simple cutaneous to invasive visceral leishmaniasis. Here, the sequences of ten cysteine proteases of types A, B and C of Leishmania major were obtained from GeneDB database. Prediction of MHC class I epitopes of these cysteine proteases was performed by NetCTL program version 1.2. In addition, by using BcePred server, different structural properties of the proteins were predicted to find out their potential B cell epitopes. According to this computational analysis, nine regions were predicted as B cell epitopes. The results provide useful information for designing peptide-based vaccines.
