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121.
Irene Betancourt-Conde Claudia Avitia-Domínguez Alicia Hernndez-Campos Rafael Castillo Lilin Ypez-Mulia Jesús Oria-Hernndez Sara T. Mndez Erick Sierra-Campos Mnica Valdez-Solana Siseth Martínez-Caballero Juan A. Hermoso Antonio Romo-Mancillas Alfredo Tllez-Valencia 《International journal of molecular sciences》2021,22(24)
Leishmaniasis is a disease caused by parasites of the Leishmania genus that affects 98 countries worldwide, 2 million of new cases occur each year and more than 350 million people are at risk. The use of the actual treatments is limited due to toxicity concerns and the apparition of resistance strains. Therefore, there is an urgent necessity to find new drugs for the treatment of this disease. In this context, enzymes from the polyamine biosynthesis pathway, such as arginase, have been considered a good target. In the present work, a chemical library of benzimidazole derivatives was studied performing computational, enzyme kinetics, biological activity, and cytotoxic effect characterization, as well as in silico ADME-Tox predictions, to find new inhibitors for arginase from Leishmania mexicana (LmARG). The results show that the two most potent inhibitors (compounds 1 and 2) have an I50 values of 52 μM and 82 μM, respectively. Moreover, assays with human arginase 1 (HsARG) show that both compounds are selective for LmARG. According to molecular dynamics simulation studies these inhibitors interact with important residues for enzyme catalysis. Biological activity assays demonstrate that both compounds have activity against promastigote and amastigote, and low cytotoxic effect in murine macrophages. Finally, in silico prediction of their ADME-Tox properties suggest that these inhibitors support the characteristics to be considered drug candidates. Altogether, the results reported in our study suggest that the benzimidazole derivatives are an excellent starting point for design new drugs against leishmanisis. 相似文献
122.
Juan Antonio Mndez-Líter Ivn Ayuso-Fernndez Florian Csarman Laura Isabel de Eugenio Noa Míguez Francisco J. Plou Alicia Prieto Roland Ludwig María Jesús Martínez 《International journal of molecular sciences》2021,22(24)
The first lytic polysaccharide monooxygenase (LPMO) detected in the genome of the widespread ascomycete Talaromyces amestolkiae (TamAA9A) has been successfully expressed in Pichia pastoris and characterized. Molecular modeling of TamAA9A showed a structure similar to those from other AA9 LPMOs. Although fungal LPMOs belonging to the genera Penicillium or Talaromyces have not been analyzed in terms of regioselectivity, phylogenetic analyses suggested C1/C4 oxidation which was confirmed by HPAEC. To ascertain the function of a C-terminal linker-like region present in the wild-type sequence of the LPMO, two variants of the wild-type enzyme, one without this sequence and one with an additional C-terminal carbohydrate binding domain (CBM), were designed. The three enzymes (native, without linker and chimeric variant with a CBM) were purified in two chromatographic steps and were thermostable and active in the presence of H2O2. The transition midpoint temperature of the wild-type LPMO (Tm = 67.7 °C) and its variant with only the catalytic domain (Tm = 67.6 °C) showed the highest thermostability, whereas the presence of a CBM reduced it (Tm = 57.8 °C) and indicates an adverse effect on the enzyme structure. Besides, the potential of the different T. amestolkiae LPMO variants for their application in the saccharification of cellulosic and lignocellulosic materials was corroborated. 相似文献
123.
Bibian M. E. Tullemans Alicia Veninga Delia I. Fernandez Maureen J. B. Aarts Johannes A. Eble Paola E. J. van der Meijden Johan W. M. Heemskerk Marijke J. E. Kuijpers 《International journal of molecular sciences》2021,22(20)
Current antiplatelet drugs for the treatment of arterial thrombosis often coincide with increased bleeding risk. Several tyrosine kinase inhibitors (TKIs) for cancer treatment inhibit platelet function, with minor reported bleeding symptoms. The aim of this study was to compare the antiplatelet properties of eight TKIs to explore their possible repurposing as antiplatelet drugs. Samples of whole blood, platelet-rich plasma (PRP), or isolated platelets from healthy donors were treated with TKI or the vehicle. Measurements of platelet aggregation, activation, intracellular calcium mobilization, and whole-blood thrombus formation under flow were performed. Dasatinib and sunitinib dose-dependently reduced collagen-induced aggregation in PRP and washed platelets; pazopanib, cabozantinib, and vatalanib inhibited this response in washed platelets only; and fostamatinib, axitinib, and lapatinib showed no/limited effects. Fostamatinib reduced thrombus formation by approximately 50% on collagen and other substrates. Pazopanib, sunitinib, dasatinib, axitinib, and vatalanib mildly reduced thrombus formation on collagen by 10–50%. Intracellular calcium responses in isolated platelets were inhibited by dasatinib (>90%), fostamatinib (57%), sunitinib (77%), and pazopanib (82%). Upon glycoprotein-VI receptor stimulation, fostamatinib, cabozantinib, and vatalanib decreased highly activated platelet populations by approximately 15%, while increasing resting populations by 39%. In conclusion, the TKIs with the highest affinities for platelet-expressed molecular targets most strongly inhibited platelet functions. Dasatinib, fostamatinib, sunitinib, and pazopanib interfered in early collagen receptor-induced molecular-signaling compared with cabozantinib and vatalanib. Fostamatinib, sunitinib, pazopanib, and vatalanib may be promising for future evaluation as antiplatelet drugs. 相似文献
124.
Ana Lechuga Cdric Lood Mnica Berjn-Otero Alicia del Prado Jeroen Wagemans Vera van Noort Rob Lavigne Margarita Salas Modesto Redrejo-Rodríguez 《International journal of molecular sciences》2021,22(20)
Bacillus virus Bam35 is the model Betatectivirus and member of the family Tectiviridae, which is composed of tailless, icosahedral, and membrane-containing bacteriophages. Interest in these viruses has greatly increased in recent years as they are thought to be an evolutionary link between diverse groups of prokaryotic and eukaryotic viruses. Additionally, betatectiviruses infect bacteria of the Bacillus cereus group, which are known for their applications in industry and notorious since it contains many pathogens. Here, we present the first protein–protein interactions (PPIs) network for a tectivirus–host system by studying the Bam35–Bacillus thuringiensis model using a novel approach that integrates the traditional yeast two-hybrid system and high-throughput sequencing (Y2H-HTS). We generated and thoroughly analyzed a genomic library of Bam35′s host B. thuringiensis HER1410 and screened interactions with all the viral proteins using different combinations of bait–prey couples. Initial analysis of the raw data enabled the identification of over 4000 candidate interactions, which were sequentially filtered to produce 182 high-confidence interactions that were defined as part of the core virus–host interactome. Overall, host metabolism proteins and peptidases were particularly enriched within the detected interactions, distinguishing this host–phage system from the other reported host–phage PPIs. Our approach also suggested biological roles for several Bam35 proteins of unknown function, including the membrane structural protein P25, which may be a viral hub with a role in host membrane modification during viral particle morphogenesis. This work resulted in a better understanding of the Bam35–B. thuringiensis interaction at the molecular level and holds great potential for the generalization of the Y2H-HTS approach for other virus–host models. 相似文献
125.
126.
The objective of this research was to determine the kinetics of water loss and oil uptake during frying of pre-treated potato slices under vacuum and atmospheric pressure. Potato slices (diameter: 30 mm; width: 3 mm) were pre-treated in the following ways: (i) raw potato slices “control”; (ii) control slices were blanched in hot water at 85 °C for 3.5 min; (iii) blanched slices were dried in hot air until reaching a moisture content of ∼0.6 g water/g dry basis. The slices were fried under vacuum (5.37 kPa, absolute pressure, at 120, 130 and 140 °C) and atmospheric conditions (at 180 °C). Two models based on the Fick's law were used to describe water loss: (i) with a constant effective diffusive coefficient; and (ii) with a variable effective diffusive coefficient. Oil uptake data were fitted to an empirical model, with a linear behavior for short times whereas the model was time independent for long times. The variable diffusivity model better fitted experimental water loss, giving values of effective diffusivity between 4.73 × 10−9 and 1.80 × 10−8 m2/s. The proposed model for the study of the kinetics of oil uptake fitted the experimental data properly. Control and blanched vacuum fried potato chips increased their final oil contents to 57.1% and 75.4% respectively, when compared with those fried at atmospheric pressure. However, the oil absorption of dried vacuum fried potato chips diminished by ∼30%. 相似文献
127.
Melania Gonzalez-Rodriguez Veronica Astillero-Lopez Patricia Villanueva-Anguita M. Eugenia Paya-Rodriguez Alicia Flores-Cuadrado Sandra Villar-Conde Isabel Ubeda-Banon Alino Martinez-Marcos Daniel Saiz-Sanchez 《International journal of molecular sciences》2021,22(16)
Alzheimer’s disease (AD) is the most prevalent neurodegenerative disease in the elderly. Progressive accumulation of insoluble isoforms of amyloid-β peptide (Aβ) and tau protein are the major neuropathologic hallmarks, and the loss of cholinergic pathways underlies cognitive deficits in patients. Recently, glial involvement has gained interest regarding its effect on preservation and impairment of brain integrity. The limbic system, including temporal lobe regions and the olfactory bulb, is particularly affected in the early stages. In the early 1980s, the reduced expression of the somatostatin neuropeptide was described in AD. However, over the last three decades, research on somatostatin in Alzheimer’s disease has been scarce in humans. Therefore, the aim of this study was to stereologically quantify the expression of somatostatin in the human hippocampus and olfactory bulb and analyze its spatial distribution with respect to that of Aβ and au neuropathologic proteins and astroglia. The results indicate that somatostatin-expressing cells are reduced by 50% in the hippocampus but are preserved in the olfactory bulb. Interestingly, the coexpression of somatostatin with the Aβ peptide is very common but not with the tau protein. Finally, the coexpression of somatostatin with astrocytes is rare, although their spatial distribution is very similar. Altogether, we can conclude that somatostatin expression is highly reduced in the human hippocampus, but not the olfactory bulb, and may play a role in Alzheimer’s disease pathogenesis. 相似文献
128.
Data on the ability of chemical poultry decontaminants to induce an acid stress response in pathogenic bacteria are lacking. This study was undertaken in order to compare the survival rates in acid broths of Listeria monocytogenes and Salmonella enterica strains, both exposed to and not exposed to decontaminants. The contribution of the glutamate decarboxylase (GAD) acid resistance system to the survival of bacteria in acid media was also examined. Four strains (L. monocytogenes serovar 1/2, L. monocytogenes serovar 4b, S. enterica serotype Typhymurium and S. enterica serotype Enteritidis) were tested before (control) and after exposure to trisodium phosphate, acidified sodium chlorite, citric acid, chlorine dioxide and peroxyacids (strains were repeatedly passed through media containing increasing concentrations of a compound). Stationary-phase cells (108 cfu/ml) were inoculated into tryptic soy broth (TSB) acidified with citric acid (pH 2.7 and 5.0) with or without glutamate (10 mM) added, and incubated at 37 °C for 15 min. Survival percentages (calculated from viable colonies) varied from 2.47 ± 0.67% to 91.93 ± 5.83%. L. monocytogenes cells previously exposed to acid decontaminants (citric acid and peroxyacids) showed, when placed in acid TSB, a higher (P < 0.05) percentage of survival (average 38.80 ± 30.52%) than control and pre-exposed to non-acidic decontaminants strains (22.82 ± 23.80%). Similar (P > 0.05) survival percentages were observed in previously exposed to different decontaminants and control Salmonella strains. The GAD acid resistance system did not apparently play any role in the survival of L. monocytogenes or S. enterica at a low pH. This study demonstrates for the first time that prior exposure to acidic poultry decontaminants increases the percentage of survival of L. monocytogenes exposed to severe acid stress. These results have important implications for the meat industry when considering which decontaminant treatment to adopt. 相似文献
129.
Establishment of the contribution of volatile compounds to the aroma of fermented sausages at different stages of processing and storage 总被引:1,自引:0,他引:1
The generation of aroma compounds through the curing process of dry fermented sausages was studied. The most important aroma compounds were determined using their odour-activity values (OAVs). The compound quantification in the headspace (HS) was carried out by solid phase microextraction (SPME) and the total concentration in the sausage by multiple headspace SPME (multiple HS-SPME) using gas chromatography and mass spectrometry. The main compounds that contributed to the aroma of dry fermented sausages were those with the highest oil OAVs such as 3-methyl butanal, 2-methyl butanal, octanal, diacetyl and ethyl 2-methyl butanoate that were important from the beginning of the process. Other compounds were important contributors as they were generated at the end of process, including propanal, pentanal, hexanal, ethyl 3-methyl butanoate, 1-octen-3-ol, 3-methyl butanoic acid, 2-methyl propanoic acid, ethyl hexanoate and nonanal. However, the aroma perceived in the HS was due to compounds with the highest air OAVs such as 3-methyl butanoic acid, ethyl 2-methyl butanoate, nonanal and octanal. In many cases, the percentage of the aroma compound released to the HS was around 10–20% of the total concentration in the sausage. 相似文献
130.