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1.
Briolat J Wu SD Mahata SK Gonthier B Bagnard D Chasserot-Golaz S Helle KB Aunis D Metz-Boutigue MH 《Cellular and molecular life sciences : CMLS》2005,62(3):377-385
Catestatin (bCGA344–364), an endogenous peptide of bovine chromogranin A, was initially characterized for its effect on the inhibition of catecholamine release from chromaffin cells. Catestatin and its active domain (bCGA344–358) were identified in chromaffin cells and in secretion medium. The present study identified a potent antimicrobial activity of bCGA344–358 in the lowmicromolar range against bacteria, fungi and yeasts, without showing any haemolytic activity. Confocal laser microscopy demonstrated penetration of the rhodaminated peptide into the cell membranes of fungi and yeasts and its intracellular accumulation. Time-lapse videomicroscopy showed arrest of fungal growth upon penetration of the labelled peptide into a fungal filament. We identified several catestatin-containing fragments in the stimulated secretion medium of human polymorphonuclear neutrophils, suggesting the N-terminal sequence of catestatin (bCGA344–358) (named cateslytin) as a novel component of innate immunity.Received 21 October 2004; received after revision 6 December 2004; accepted 7 December 2004 相似文献
2.
Computational inhibitor design against malaria plasmepsins 总被引:1,自引:1,他引:0
Bjelic S Nervall M Gutiérrez-de-Terán H Ersmark K Hallberg A Aqvist J 《Cellular and molecular life sciences : CMLS》2007,64(17):2285-2305
Plasmepsins are aspartic proteases involved in the degradation of the host cell hemoglobin that is used as a food source by
the malaria parasite. Plasmepsins are highly promising as drug targets, especially when combined with the inhibition of falcipains
that are also involved in hemoglobin catabolism. In this review, we discuss the mechanism of plasmepsins I–IV in view of the
interest in transition state mimetics as potential compounds for lead development. Inhibitor development against plasmepsin
II as well as relevant crystal structures are summarized in order to give an overview of the field. Application of computational
techniques, especially binding affinity prediction by the linear interaction energy method, in the development of malarial
plasmepsin inhibitors has been highly successful and is discussed in detail. Homology modeling and molecular docking have
been useful in the current inhibitor design project, and the combination of such methods with binding free energy calculations
is analyzed.
S. Bjelic, M. Nervall: These authors contributed equally to this work.
Received 27 February 2007; received after revision 17 April 2007; accepted 26 April 2007 相似文献
3.
Despite the absence of classical tyrosine kinases encrypted in the kinome of Plasmodium falciparum, biochemical analyses have detected significant tyrosine phosphorylation in its cell lysates. Supporting such phosphorylation
is critical for parasite development. These observations have thus raised queries regarding the plasmodial enzymes accountable
for tyrosine kinase activities in vivo. In the current investigation, immunoblot analysis intriguingly demonstrated that Pfnek3,
a plasmodial mitogen-activated protein kinase kinase (MAPKK), displayed both serine/threonine and tyrosine kinase activities
in autophosphorylation reactions as well as in phosphorylation of the exogenous myelin basic protein substrate. The results
obtained strongly support Pfnek3 as a novel dual-specificity kinase of the malarial parasite, even though it displays a HGDLKSTN
motif in the catalytic loop that resembles the consensus HRDLKxxN signature found in the serine/threonine kinases. Notably,
its serine/threonine and tyrosine kinase activities were found to be distinctly influenced by Mg2+ and Mn2+ cofactors. Further probing into the regulatory mechanism of Pfnek3 also revealed tyrosine phosphorylation to be a crucial
factor that stimulates its kinase activity. Through biocomputational analyses and functional assays, tyrosine residues Y117,
Y122, Y172, and Y238 were proposed as phosphorylation sites essential for mediating the catalytic activities of Pfnek3. The
discovery of Pfnek3’s dual role in phosphorylation marks its importance in closing the loop for cellular regulation in P. falciparum, which remains elusive to date. 相似文献
4.
Abdirahman Abdi Sylvain Eschenlauer Luc Reininger Christian Doerig 《Cellular and molecular life sciences : CMLS》2010,67(19):3355-3369
Over the last decade, several protein kinases inhibitors have reached the market for cancer chemotherapy. The kinomes of pathogens
represent potentially attractive targets in infectious diseases. The functions of the majority of protein kinases of Plasmodium falciparum, the parasitic protist responsible for the most virulent form of human malaria, remain unknown. Here we present a thorough
characterisation of PfTKL3 (PF13_0258), an enzyme that belongs to the tyrosine kinase-like kinase (TKL) group. We demonstrate
by reverse genetics that PfTKL3 is essential for asexual parasite proliferation in human erythrocytes. PfTKL3 is expressed
in both asexual and gametocytes stages, and in the latter the protein co-localises with cytoskeleton microtubules. Recombinant
PfTKL3 displays in vitro autophosphorylation activity and is able to phosphorylate exogenous substrates, and both activities
are dramatically dependent on the presence of an N-terminal “sterile α-motif” domain. This study identifies PfTKL3 as a validated
drug target amenable to high-throughput screening. 相似文献
5.
Bhavani S. Sahu Parshuram J. Sonawane Nitish R. Mahapatra 《Cellular and molecular life sciences : CMLS》2010,67(6):861-874
Chromogranin A (CHGA) is ubiquitously expressed in secretory cells of the endocrine, neuroendocrine, and neuronal tissues.
Although this protein has long been known as a marker for neuroendocrine tumors, its role in cardiovascular disease states
including essential hypertension (EH) has only recently been recognized. It acts as a prohormone giving rise to bioactive
peptides such as vasostatin-I (human CHGA1–76) and catestatin (human CHGA352–372) that exhibit several cardiovascular regulatory functions. CHGA is over-expressed but catestatin is diminished in EH. Moreover,
genetic variants in the promoter, catestatin, and 3′-untranslated regions of the human CHGA gene alter autonomic activity and blood pressure. Consistent with these findings, targeted ablation of this gene causes severe
arterial hypertension and ventricular hypertrophy in mice. Transgenic expression of the human CHGA gene or exogenous administration of catestatin restores blood pressure in these mice. Thus, the accumulated evidence establishes
CHGA as a novel susceptibility gene for EH. 相似文献
6.
S. G. Goijman J. F. Turrens G. B. Marini-Bettolo A. O. M. Stoppani 《Cellular and molecular life sciences : CMLS》1985,41(5):646-648
Summary Tingenone and horminone, two natural quinonoid substances, inhibited the in vitro growth ofTrypanosoma cruzi, 30 M drug concentration producing total inhibition of growth. Tingenone inhibited total uptake and incorporation of [3H]thymidine, [3H]uridine, L-[3H]leucine into parasite macromolecules. Other quinonoids assayed were either less effective (abruquinone A) or even quite inactive (visminone B and ferruginin B). Investigation of several mechanisms for the cytotoxic action of tingenone pointed to the interaction with DNA as the most likely factor involved. Tingenone also inhibited the growth ofCrithidia fasciculata, but the drug was significantly less active on this organism than onT. cruzi.This work was supported by grants of UNDP/World Bank/World Health Organization Special Programme for Research and Training in Tropical Diseases, Organization of American States (Multinational Programme of Biochemistry) and Programa Nacional de Enfermedades Endémicas (SECYT), República Argentina. A preliminary account was given at the Workshop on Oxidative Damage and Related Enzymes, Frascatti (Italy), 1983. 相似文献
7.
Malaria results in up to 2.5 million deaths annually, with young children and pregnant women at greatest risk. The great
majority of severe disease is caused by Plasmodium falciparum. A characteristic feature of infection with P. falciparum is the accumulation or sequestration of parasite-infected red blood cells (RBCs) in various organs, such as the brain, lung
and placenta, and together with other factors is important in the pathogenesis of severe forms of malaria. Sequestration results
from adhesive interactions between parasite-derived proteins expressed on the surface of infected RBCs and a number of host
molecules on the surface of endothelial cells, placental cells and uninfected RBCs. Some receptors for parasite adhesion have
been implicated in particular malaria syndromes, such as intercellular adhesion molecule 1 in cerebral malaria and chondroitin
sulfate A and hyaluronic acid in placental infection. The principal parasite ligand and antigen on the RBC surface, P. falciparum erythrocyte membrane protein 1 encoded by a multigene family termed var, is clonally variant, enabling evasion of specific immune responses. An understanding of these host-parasite interactions
in the context of clinical disease and immunity may reveal potential targets to prevent or treat severe forms of malaria.
Received 25 June 2001; received after revision 22 August 2001; accepted 24 August 2001 相似文献
8.
Tingenone and horminone, two natural quinonoid substances, inhibited the in vitro growth of Trypanosoma cruzi, 30 microM drug concentration producing total inhibition of growth. Tingenone inhibited total uptake and incorporation of [3H]thymidine, [3H]uridine, L-[3H]leucine into parasite macromolecules. Other quinonoids assayed were either less effective (abruquinone A) or even quite inactive (visminone B and ferruginin B). Investigation of several mechanisms for the cytotoxic action of tingenone pointed to the interaction with DNA as the most likely factor involved. Tingenone also inhibited the growth of Crithidia fasciculata, but the drug was significantly less active on this organism than on T. cruzi. 相似文献
9.
E. F. Roth Jr J. C. McKitrick F. Herz 《Cellular and molecular life sciences : CMLS》1989,45(5):478-480
Summary In vitro culture systems are often contaminated by bacteria and fungi. It is therefore often necessary to supplement culture media with agents such as penicillin/streptomycin, gentamycin or amphotericin B. The latter cannot be used in the in vitro culture of erythrocytic stages ofP. falciparum, and thus anti-fungal agents have not been regularly used in this system. We describe the prophylactic use of 5-fluorocytosine (5-FC) and ketoconazole (KTZ) in tissue cultures at concentrations up to 300 and 10 g/ml respectively which have no effect on the growth ofP. falciparum (FCR-3 strain). A melanoma cell line (C32) and a line of uterine carcinoma (C41) were also unaffected by similar concentrations of 5-FC and KTZ. When dissolved in complete culture medium (RPMI 1640) with 10% human plasma, the minimum inhibitory concentration of 5-FC for a susceptible strain ofCandida remained below 2 g/ml. These experiments suggest that 5-FC (at 50 g/ml) alone or in combination with KTZ (at 1 g/ml) is a useful addition to the armamentarium of antimicrobials available to the tissue culture biologist for a variety of cell culture systems. 相似文献
10.
Semisynthesis and biological properties of the [B24-leucine]-, [B25-leucine]- and [B24-leucine,B25-leucine]-analogues of human insulin 总被引:2,自引:0,他引:2
K. Inouye K. Watanabe Y. Tochino T. Kanaya M. Kobayashi Y. Shigeta 《Cellular and molecular life sciences : CMLS》1981,37(8):811-813
Summary Trypsin-catalyzed coupling of porcine desoctapeptide-insulin with synthetic octapeptides produced the [LeuB24]-(I), [LeuB25]- (II) and [LeuB24, LeuB25]- (III)analogues of human insulin. I, II and III displayed respectively 20–30%, 1–2% and 0.5% of the receptor binding activity of the normal hormone. Biological activities of these analogues seemed to be proportional to their binding potencies when assayed in vitro, while in an in vivo assay analogue I was fully active and II exhibited 10–20% of normal activity. III was less active than II in all assays tested. 相似文献
11.
Chun-Song Chua Huiyu Low Kian-Sim Goo T. S. Sim 《Cellular and molecular life sciences : CMLS》2010,67(10):1675-1686
It is well known that the co-chaperone p23 regulates Hsp90 chaperone activity in protein folding. In Plasmodium falciparum, a putative p23 (Pfp23) has been identified through genome analysis, but its authenticity has remained unconfirmed since
co-immunoprecipitation experiments failed to show its interaction with P. falciparum Hsp90 (PfHsp90). Thus, recombinant Pfp23 and PfHsp90 proteins purified from expressed clones were used in this study. It
was clear that Pfp23 exhibited chaperone activity by virtue of its ability to suppress citrate synthase aggregation at 45°C.
Pfp23 was also shown to interact with PfHsp90 and to suppress its ATPase activity. Analyses of modeled Pfp23-PfHsp90 protein
complex and site-directed mutagenesis further revealed strategically placed amino acid residues, K91, H93, W94 and K96, in
Pfp23 to be crucial for binding PfHsp90. Collectively, this study has provided experimental evidence for the inherent chaperone
function of Pfp23 and its interaction with PfHsp90, a sequel widely required for client protein activation. 相似文献
12.
Yesica R. Nievas Veronica M. Coceres Victor Midlej Wanderley de Souza Marlene Benchimol Antonio Pereira-Neves Ajay A. Vashisht James A. Wohlschlegel Patricia J. Johnson Natalia de Miguel 《Cellular and molecular life sciences : CMLS》2018,75(12):2211-2226
Trichomonas vaginalis is a common sexually transmitted parasite that colonizes the human urogenital tract, where it remains extracellular and adheres to epithelial cells. Infections range from asymptomatic to highly inflammatory, depending on the host and the parasite strain. Despite the serious consequences associated with trichomoniasis disease, little is known about parasite or host factors involved in attachment of the parasite-to-host epithelial cells. Here, we report the identification of microvesicle-like structures (MVs) released by T. vaginalis. MVs are considered universal transport vehicles for intercellular communication as they can incorporate peptides, proteins, lipids, miRNA, and mRNA, all of which can be transferred to target cells through receptor–ligand interactions, fusion with the cell membrane, and delivery of a functional cargo to the cytoplasm of the target cell. In the present study, we demonstrated that T. vaginalis release MVs from the plasma and the flagellar membranes of the parasite. We performed proteomic profiling of these structures demonstrating that they possess physical characteristics similar to mammalian extracellular vesicles and might be selectively charged with specific protein content. In addition, we demonstrated that viable T. vaginalis parasites release large vesicles (LVs), membrane structures larger than 1 µm that are able to interact with other parasites and with the host cell. Finally, we show that both populations of vesicles present on the surface of T vaginalis are induced in the presence of host cells, consistent with a role in modulating cell interactions. 相似文献
13.
K. A. I. Siddiqui A. K. Gupta A. K. Paul A. K. Banerjee 《Cellular and molecular life sciences : CMLS》1979,35(9):1222-1223
Summary A partially purified preparation of a water-soluble, heat-resistant, nonspecific exotoxin produced by a strain ofMacrophomina phaseolina, isolated fromPhaseolus mungo L. could reduce Cu++ ions and produced a red colour with 2,4-dinitrophenyl hydrazine reagent. It caused inhibition of seed germination, wilting of cut seedlings, stunted growth of young seedlings and loss of permeability of the cell membrane. Seedlings ofP. mungo, grown in presence of the toxin showed a slight increase in the contents of protein and total RNA over control, but a significant increase in the specific activities of F-1, 6-BP aldolase and G-6-P isomerase. 相似文献
14.
To evaluate how chloroquine kills malaria parasites, hemoglobin catabolism was studied at the various stages of intraerythrocytic parasite development. We found that hemoglobin catabolism is switched off whenPlasmodium falciparum parasites mature to the late trophozoite or early schizont stages and is switched on again during the ring stage. When hemoglobin catabolism is switched off, the parasites are resistant to the morphologic effects of chloroquine. Although the ring stage parasites failed to mature in the presence of chloroquine, some of them switched on hemoglobin ingestion and became stuffed with hemoglobin-filled vesicles, indicating a distal block in catabolism. In fact, we demonstrated a high-grade block in hemozoin production during a 22 h incubation of synchronized ring forms; ferriprotoporphyrin IX (FP) incorporation into the β-hematin of hemozoin decreased from 900 to 50 pmol/106 parasitized erythrocytes. We propose that the primary effect of chloroquine on hemoglobin catabolism is to block FP polymerization to β-hematin. Secondarily, toxic FP and FP-chloroquine complexes accumulate and are available to exert their several toxicities, which include inhibition of hemoglobindegrading proteases and membrane damage. As a consequence, maturation is arrested and eventually the parasites die and lyse. 相似文献
15.
The deep-sea clams Calyptogena nautilei and C. tsubasa, which live in the cold-seep area at a depth of 3570 m in the Nankai Trough, Japan, have abundant hemoglobins (Hbs) in erythrocytes, similar to other Calyptogena species. We determined the cDNA-derived amino acid sequences of Hbs from two Calyptogena species. C. tsubasa was found to contain two dimeric Hbs, Hb I consisting of 145 amino acid residues and Hb II with 137 residues, similar to known Hbs from C. soyoae and C. kaikoi. Sequence identity was over 90% among the orthologous chains of Calyptogena Hbs. On the other hand, surprisingly, C. nautilei contained two monomeric Hbs, Hb III containing 141 residues and Hb IV with 134 residues. In addition, Hbs III and IV showed only 33–42% sequence identity with Hbs I and II from other Calyptogena species. The distal (E7) histidine, one of the functionally important residues of the heme protein, is replaced by glutamine in all Hb chains of Calyptogena species. A phylogenetic analysis indicated that C. nautilei Hb III is closer to Hb I from other Calyptogena species. We suppose that a Hb gene was duplicated at least three times in an immediate ancestor of Calyptogena and, presumably depending on physiological conditions different Hb sets are being expressed: dimeric Hbs I and II in C. soyoae, C. kaikoi and C. tsubasa, and monomeric Hbs III and IV in C. nautilei.
Received 13 May 2003; received after revision 5 June 2003; accepted 12 June 2003 相似文献
16.
E. S. Güner 《Cellular and molecular life sciences : CMLS》1994,50(1):54-59
In vitro cultivation ofB. burgdorferi in BSK medium results in the loss of infectivity and pathogenicity after repeated passages. To prevent this loss, a feeder layer of tibio-tarsal joint tissue derived from newborn LEW/N rats was grown on Cytodex 3 microcarriers in ESG (formerly BSKE), a novel medium developed to support the growth of both the feeder layer andB. burgdorferi. A new pathogenic isolate (FNJ) and a high passage, non-pathogenic strain (TNJ) grew well in this co-culture system with high yields of viable organism. FNJ caused no growth inhibition or visible damage to the cells in the feeder layer. FNJ remained arthritogenic for newborn LEW/N rats after 22 passages in the co-culture system, but lost its arthritogenicity after 7 passages when cultured in BSK medium. This borrelia-mammalian tissue co-culture technique presents an experimental system to study the long term interactions ofB. burgdorferi with the infected host tissues in vitro, as well as facilitate diagnostic tests and vaccine development. 相似文献
17.
18.
We have examined the effects of seven protein kinase inhibitors (staurosporine, genistein, methyl 2,5-dihydroxycinnamate, tyrphostins B44 and B46, lavendustin A and R03) on the erythrocytic cycle of the malaria parasite,Plasmodium falciparum. One (staurosporine) strongly inhibits serine/threonine kinases, but the remainder all exhibit a strong preference for tyrosine kinases. We have been able to discriminate between effects on invasion and on intraerythrocytic development. All reagents impeded development of intraerythrocytic parasites, though at widely differing concentrations, from the sub-micromolar to the millimolar. Several inhibitors, including staurosporine, also reduced invasion. The phosphatase inhibitor, okadaic acid, had a strong inhibitory effect both on invasion and development. The regulation of malaria development by phosphorylation or dephosphorylation reactions at several points in the blood-stage cycle is implied. 相似文献
19.
Summary The administration of ethionin to tissue cultures of fibroblastsin vitro causes a rapid and total inhibition of the growth of the transplanted tissues.It was observed that equimolar quantities of methionin are, on the contrary, well tolerated. The inhibition is therefore seen to be due to the dismetabolic activity of the antagonist.The contemporary administration of cholin is not able to restore the growth capacity of ethionin inhibited tissue cultures.In conclusion, ethionin produces a direct action on fibroblastsin vitro, probably intervening in the process of protein synthesis of the transplanted elements. 相似文献
20.
Qian Han Tao Cai Danilo A. Tagle Jianyong Li 《Cellular and molecular life sciences : CMLS》2010,67(3):353-368
Kynurenine aminotransferases (KATs) catalyze the synthesis of kynurenic acid (KYNA), an endogenous antagonist of N-methyl-d-aspartate and alpha 7-nicotinic acetylcholine receptors. Abnormal KYNA levels in human brains are implicated in the pathophysiology
of schizophrenia, Alzheimer’s disease, and other neurological disorders. Four KATs have been reported in mammalian brains,
KAT I/glutamine transaminase K/cysteine conjugate beta-lyase 1, KAT II/aminoadipate aminotransferase, KAT III/cysteine conjugate
beta-lyase 2, and KAT IV/glutamic-oxaloacetic transaminase 2/mitochondrial aspartate aminotransferase. KAT II has a striking
tertiary structure in N-terminal part and forms a new subgroup in fold type I aminotransferases, which has been classified
as subgroup Iε. Knowledge regarding KATs is vast and complex; therefore, this review is focused on recent important progress
of their gene characterization, physiological and biochemical function, and structural properties. The biochemical differences
of four KATs, specific enzyme activity assays, and the structural insights into the mechanism of catalysis and inhibition
of these enzymes are discussed. 相似文献