scholarly journals Cinnamides Target Leishmania amazonensis Arginase Selectively

Molecules ◽  
2020 ◽  
Vol 25 (22) ◽  
pp. 5271
Author(s):  
Edson Roberto da Silva ◽  
Júlio Abel Alfredo dos Santos Simone Come ◽  
Simone Brogi ◽  
Vincenzo Calderone ◽  
Giulia Chemi ◽  
...  
Keyword(s):  
Caffeic Acid ◽  
Selective Inhibition ◽  
Leishmania Amazonensis ◽  
The Other ◽  
Computational Investigation ◽  
Weak Inhibitor ◽  
Starting Point ◽  
Insight Into ◽  
Caffeic Acid Phenethyl Amide

Caffeic acid and related natural compounds were previously described as Leishmania amazonensis arginase (L-ARG) inhibitors, and against the whole parasite in vitro. In this study, we tested cinnamides that were previously synthesized to target human arginase. The compound caffeic acid phenethyl amide (CAPA), a weak inhibitor of human arginase (IC50 = 60.3 ± 7.8 μM) was found to have 9-fold more potency against L-ARG (IC50 = 6.9 ± 0.7 μM). The other compounds that did not inhibit human arginase were characterized as L-ARG, showing an IC50 between 1.3–17.8 μM, and where the most active was compound 15 (IC50 = 1.3 ± 0.1 μM). All compounds were also tested against L. amazonensis promastigotes, and only the compound CAPA showed an inhibitory activity (IC50 = 80 μM). In addition, in an attempt to gain an insight into the mechanism of competitive L-ARG inhibitors, and their selectivity over mammalian enzymes, we performed an extensive computational investigation, to provide the basis for the selective inhibition of L-ARG for this series of compounds. In conclusion, our results indicated that the compounds based on cinnamoyl or 3,4-hydroxy cinnamoyl moiety could be a promising starting point for the design of potential antileishmanial drugs based on selective L-ARG inhibitors.

scholarly journals Relevance and Standardization of In Vitro Antioxidant Assays: ABTS, DPPH, and Folin–Ciocalteu

2018 ◽  
Vol 2018 ◽  
pp. 1-9 ◽  
Author(s):  
Helena Abramovič ◽  
Blaž Grobin ◽  
Nataša Poklar Ulrih ◽  
Blaž Cigić
Keyword(s):  
Ascorbic Acid ◽  
Chlorogenic Acid ◽  
Gallic Acid ◽  
Caffeic Acid ◽  
Sulfonic Acid ◽  
Epigallocatechin Gallate ◽  
The Other ◽  
Oh Groups ◽  
Standard Compound

Trolox, gallic acid, chlorogenic acid, caffeic acid, catechin, epigallocatechin gallate, and ascorbic acid are antioxidants used as standards for reaction with chromogenic radicals, 2,2-diphenyl-1-picrylhydrazyl (DPPH⋅) and 2,2′-azino-bis-3-ethylbenzotiazolin-6-sulfonic acid (ABTS⋅+), and Folin–Ciocalteu (FC) reagent. The number of exchanged electrons has been analyzed as function of method and solvent. A majority of compounds exchange more electrons in FC assay than in ABTS and DPPH assays. In reaction with chromogenic radicals, the largest number of electrons was exchanged in buffer (pH 7.4) and the lowest reactivity was in methanol (DPPH) and water (ABTS). At physiological pH, the number of exchanged electrons of polyphenols exceeded the number of OH groups, pointing to the important contribution of partially oxidized antioxidants, formed in the course of reaction, to the antioxidant potential. For Trolox, small impact on the number of exchanged electrons was observed, confirming that it is more suitable as a standard compound than the other antioxidants.

scholarly journals SARS-CoV-2 Spike triggers barrier dysfunction and vascular leak via integrins and TGF-β signaling

2021 ◽  
Author(s):  
Scott B Biering ◽  
Francielle Tramontini Gomes de Sousa ◽  
Laurentia V. Tjang ◽  
Felix Pahmeier ◽  
Richard Ruan ◽  
...  
Keyword(s):  
Transcriptional Response ◽  
Barrier Dysfunction ◽  
Vascular Leak ◽  
Endothelial Barrier Dysfunction ◽  
Mechanistic Insight ◽  
Starting Point ◽  
Signaling Axis ◽  
Insight Into

Severe COVID-19 is associated with epithelial and endothelial barrier dysfunction within the lung as well as in distal organs. While it is appreciated that an exaggerated inflammatory response is associated with barrier dysfunction, the triggers of this pathology are unclear. Here, we report that cell-intrinsic interactions between the Spike (S) glycoprotein of SARS-CoV-2 and epithelial/endothelial cells are sufficient to trigger barrier dysfunction in vitro and vascular leak in vivo, independently of viral replication and the ACE2 receptor. We identify an S-triggered transcriptional response associated with extracellular matrix reorganization and TGF-β signaling. Using genetic knockouts and specific inhibitors, we demonstrate that glycosaminoglycans, integrins, and the TGF-β signaling axis are required for S-mediated barrier dysfunction. Our findings suggest that S interactions with barrier cells are a contributing factor to COVID-19 disease severity and offer mechanistic insight into SARS-CoV-2 triggered vascular leak, providing a starting point for development of therapies targeting COVID-19 pathogenesis.

scholarly journals KBE009: A Bestatin-Like Inhibitor of the Trypanosoma cruzi Acidic M17 Aminopeptidase With In Vitro Anti-Trypanosomal Activity

Life ◽  
2021 ◽  
Vol 11 (10) ◽  
pp. 1037
Author(s):  
Jorge González-Bacerio ◽  
Irina Arocha ◽  
Mirtha Elisa Aguado ◽  
Yanira Méndez ◽  
Sabrina Marsiccobetre ◽  
...  
Keyword(s):  
Trypanosoma Cruzi ◽  
Rational Design ◽  
Specific Effect ◽  
Dermal Fibroblasts ◽  
Aminopeptidase Activity ◽  
Geometrical Shape ◽  
Starting Point ◽  
Insight Into ◽  
Leucyl Aminopeptidase

Chagas disease, caused by the kinetoplastid parasite Trypanosoma cruzi, is a human tropical illness mainly present in Latin America. The therapies available against this disease are far from ideal. Proteases from pathogenic protozoan have been considered as good drug target candidates. T. cruzi acidic M17 leucyl-aminopeptidase (TcLAP) mediates the major parasite’s leucyl-aminopeptidase activity and is expressed in all parasite stages. Here, we report the inhibition of TcLAP (IC50 = 66.0 ± 13.5 µM) by the bestatin-like peptidomimetic KBE009. This molecule also inhibited the proliferation of T. cruzi epimastigotes in vitro (EC50 = 28.1 ± 1.9 µM) and showed selectivity for the parasite over human dermal fibroblasts (selectivity index: 4.9). Further insight into the specific effect of KBE009 on T. cruzi was provided by docking simulation using the crystal structure of TcLAP and a modeled human orthologous, hLAP3. The TcLAP-KBE009 complex is more stable than its hLAP3 counterpart. KBE009 adopted a better geometrical shape to fit into the active site of TcLAP than that of hLAP3. The drug-likeness and lead-likeness in silico parameters of KBE009 are satisfactory. Altogether, our results provide an initial insight into KBE009 as a promising starting point compound for the rational design of drugs through further optimization.

Anionic and cationic exchange mechanisms in the skin of anurans, with special reference to Leptodactylidae in vivo

1971 ◽  
Vol 262 (842) ◽  
pp. 163-174 ◽  
Keyword(s):  
Transport Mechanism ◽  
Selective Inhibition ◽  
The Other ◽  
Sodium Absorption ◽  
Experimental Conditions ◽  
Net Flux ◽  
Cationic Exchange

In several species of anurans, the in vivo skin has been shown to absorb Na + and Cl - independently from dilute external solutions. That the mechanism for sodium absorption is different from that of chloride absroption is born out by the following: (1) Either of these ions is absorbed without an accompanying ion when this latter is impermeant. (2) From NaCl solutions there can be an unequal absorption of sodium and chloride. (3) A selective inhibition of the absorption of one of the ions can be produced experimentally, while the net flux of the other remains unchanged. In all these situations, the absorbed ion has to be exchanged against an endogenous ion of the same charge. In Calyptocephalella gayi , H + and HCO - 3 are exchanged against sodium and chloride respectively. A comparison of the relationships between H + excretion and Na + absorption in vivo skins and shortcircuited in vitro skins shows that in the latter no H + excretion occurs, only the Na + transport being maintained under these experimental conditions. From this, one must conclude that the active Na + transport is the motive factor of the transport mechanism. H + excretion by the in vivo skin plays the role of physiologically short-circuiting the Na + transport.

scholarly journals Immunoregulation of murine myeloma in vitro. II. Suppression of MOPC-315 immunoglobulin secretion and synthesis by idiotype-specific suppressor T cells.

1982 ◽  
Vol 155 (3) ◽  
pp. 852-862 ◽  
Author(s):  
G L Milburn ◽  
R G Lynch
Keyword(s):  
T Cells ◽  
Surface Membrane ◽  
Selective Inhibition ◽  
Myeloma Cell ◽  
Membrane Expression ◽  
Dose Dependent ◽  
Specific Suppressor T Cells ◽  
Insight Into

In previous studies, BALB/c mice immunized with trinitrophenyl-specific IgA protein (M315) produced by MOPC-315 developed idiotype (Id315)-specific T cells that suppressed M315 secretion in vivo. In the present in vitro studies, we show that inhibition of M315 secretion is mediated by a theta,Lyt-1-2+ cell that expresses a surface membrane receptor for Id315. The suppressor signal is a diffusable product that acts directly on M315-secreting myeloma cells. Inhibition of M315 secretion is T cell dose-dependent, Id315-specific, reversible, and occurs without any effect on MOPC-315 growth, viability, or surface membrane expression of M315. Inhibition of M315 secretion results from a selective inhibition of M315 synthesis in the myeloma cell. These studies provide new insight into the mechanisms of direct B cell regulation by idiotype-specific T cells.

Biotransformation of caffeic acid by Momordica charantia peroxidase

2008 ◽  
Vol 86 (8) ◽  
pp. 821-830 ◽  
Author(s):  
Xiang Wan ◽  
Haili Liu ◽  
Xuefeng Huang ◽  
Jianguang Luo ◽  
Lingyi Kong
Keyword(s):  
Antioxidant Activity ◽  
Caffeic Acid ◽  
2D Nmr ◽  
Momordica Charantia ◽  
The Other ◽  
Oxidative Activity ◽  
Nmr Techniques ◽  
New Compounds ◽  
First Time

Biotransformation of caffeic acid with H2O2/Momordica charantia peroxidase at pH 5.0, 25 °C in the presence of acetone has resulted in the isolation of three caffeic acid trimers 1–3, five caffeic acid dimers 4–8, and one monomer 9. Among them, seven (1–7) are new compounds, and two (8 and 9) are known compounds, including one compound (9), which was obtained by biotransformation for the first time. The structures were established by 2D NMR techniques, such as HSQC, HMBC, and NOESY measurements. The possible mechanism for the formation of the products is also discussed. This is the first time that caffeic acid trimers have been obtained through the biotransformation of catalyzed by peroxidase in vitro. Compound 5 has shown much stronger anti-oxidative activity than the other caffeic acid polymers obtained.Key words: Momordica charantia peroxidase, caffeic acid, polymers of caffeic acid, biotransformation, antioxidant activity.

scholarly journals Kinase Function of Brassinosteroid Receptor Specified by Two Allosterically Regulated Subdomains

2022 ◽  
Vol 12 ◽  
Author(s):  
Khawar Ali ◽  
Wenjuan Li ◽  
Yaopeng Qin ◽  
Shanshan Wang ◽  
Lijie Feng ◽  
...  
Keyword(s):  
Signaling Pathway ◽  
Kinase Activity ◽  
The Other ◽  
Activation Loop ◽  
Biological Functions ◽  
Kinase Activation ◽  
Downstream Signaling ◽  
Signaling Function ◽  
Insight Into

Plants acquire the ability to adapt to the environment using transmembrane receptor-like kinases (RLKs) to sense the challenges from their surroundings and respond appropriately. RLKs perceive a variety of ligands through their variable extracellular domains (ECDs) that activate the highly conserved intracellular kinase domains (KDs) to control distinct biological functions through a well-developed downstream signaling cascade. A new study has emerged that brassinosteroid-insensitive 1 (BRI1) family and excess microsporocytes 1 (EMS1) but not GASSHO1 (GSO1) and other RLKs control distinct biological functions through the same signaling pathway, raising a question how the signaling pathway represented by BRI1 is specified. Here, we confirm that BRI1-KD is not functionally replaceable by GSO1-KD since the chimeric BRI1-GSO1 cannot rescue bri1 mutants. We then identify two subdomains S1 and S2. BRI1 with its S1 and S2 substituted by that of GSO1 cannot rescue bri1 mutants. Conversely, chimeric BRI1-GSO1 with its S1 and S2 substituted by that of BRI1 can rescue bri1 mutants, suggesting that S1 and S2 are the sufficient requirements to specify the signaling function of BRI1. Consequently, all the other subdomains in the KD of BRI1 are functionally replaceable by that of GSO1 although the in vitro kinase activities vary after replacements, suggesting their functional robustness and mutational plasticity with diverse kinase activity. Interestingly, S1 contains αC-β4 loop as an allosteric hotspot and S2 includes kinase activation loop, proposedly regulating kinase activities. Further analysis reveals that this specific function requires β4 and β5 in addition to αC-β4 loop in S1. We, therefore, suggest that BRI1 specifies its kinase function through an allosteric regulation of these two subdomains to control its distinct biological functions, providing a new insight into the kinase evolution.

scholarly journals The Arab World and the Occident: Toward the Construction of an Occidentalist Discourse

2021 ◽  
Vol 39 (2) ◽  
pp. 205-222
Author(s):  
Zahia Smail Salhi
Keyword(s):  
Arab World ◽  
The Self ◽  
The Other ◽  
Starting Point ◽  
Reverse Relationship ◽  
Style Of Thought ◽  
Definition Of ◽  
Insight Into ◽  
East West

Purpose: This article aims to engage in a meaningful discussion of Occidentalism as a discourse that draws its roots from Orientalism. It scrutinizes the limitations of Occidentalism in investigating the East-West encounter from the perspective of Orientals (Arab intellectuals) and the multifarious ways the latter relate to and imagine the Occident. It will cast a critical eye on the multiple and diverse constructions of Occidentalism as a discourse, arguing that unlike Orientalism, which homogenizes the Orient, Occidentalism does not Occidentalize/homogenize the Occident. Methodology: We take as a starting point Edward Said’s definition of Orientalism as a style of thought based upon an ontological and epistemological distinction made between ‘the Orient’ and ‘the Occident’, and we explore the limitations and the possibilities of Occidentalism as a method to construe the colonial mechanisms of misrepresentation of the Other as everything different from the Self. This article compares and contrasts a plethora of existing definitions of Occidentalism as formulated by scholars from both the Arab world and the Occident. Findings: This paper concludes that the Oriental’s encounter with the Occident cannot, and should not, be projected as a reverse relationship, or, as some claim, as an ‘Orientalism in reverse’. Instead, it should be projected as a diverse set of relationships of Orientals who have experienced the Occident in a variety of manners. Furthermore, while Orientalism derives from a particular closeness experienced between the Occident and its Orient, often through real or imagined encounters, Occidentalism is also the outcome of a long cultural relationship between the Orient and its Occident. What differs between the Orient and Occident, however, is the position of power and hegemony, which characterizes the Occident’s encounter with the Orient. Originality: This article takes an all-inclusive view to discuss the term Occidentalism from the perspectives of both the Orient and the Occident. It teases out the limitations of this term. It challenges Orientalist methods of misrepresentation, which continues to blemish the Arab world and its discourse of Occidentalism as a discourse of hatred of the Occident. Furthermore, through the discussion of Alloula’s Oriental Harem, it offers insight into the suggested Occidentalism method, which emphasizes the disfigurations of the Orient while tactfully writing back to the Occident.

scholarly journals ACTIVIDAD ANTIBACTERIANA DE NANOPARTÍCULAS DE PLATA INMOVILIZADAS EN CEMENTO DE ÓXIDO DE ZINC-EUGENOL CONTRA EL ENTEROCOCCUS FAECALIS: ESTUDIO IN VITRO

2019 ◽  
Vol 30 (2) ◽  
Author(s):  
Juan Camilo Duque-Aristizabal ◽  
Liza Maria Isaza-Areiza ◽  
Diego Tobon-Calle ◽  
Martha Elena Londoño Lopez
Keyword(s):  
Silver Nanoparticles ◽  
Enterococcus Faecalis ◽  
In Vitro Study ◽  
The Other ◽  
Future Research ◽  
Visible Spectroscopy ◽  
Starting Point ◽  
Significant Difference ◽  
Uv Visible

Introduction: the aim of this study is to evaluate the antimicrobial capacity of silver nanoparticles immobilized in a zinc oxide-eugenol (ZOE) cement against Enterococcus faecalis for potential use in endodontic treatments. Method: experimental in vitro study, performing synthesis of silver nanoparticles (AgNPs) and UV-visible spectroscopy to confirm presence of AgNPs in the prepared solutions. The ZOE mixture was standardized, producing the integrated AgNPs/ZOE material. Scanning electron microscopy (SEM) and Fourier-Transform Infrared Spectroscopy (FTIR) were used to characterize the integrated material; a KirbyBauer assay was finally run to measure the inhibition halos produced by the compound-microorganism interaction. Results: the UV-visible spectroscopy showed presence of AgNPs in the created solution; both SEM and FTIR show that the AgNPs are integrated into the ZOE system, not altering their properties when performed under conditions like those found in the mouth. The Kirby-Bauer assay shows that all samples had inhibition halos. The AgNPs in guava extract had statistically significant differences with the halos of the other samples (p < 0.05). Conclusions: the obtained AgNPs show bactericidal activity against Enterococcus faecalis, as a statistically significant difference was found between the AgNPs suspended in guava extract and the other groups; this will be the starting point for future research

scholarly journals Highly selective inhibition of myosin motors provides the basis of potential therapeutic application

2016 ◽  
Vol 113 (47) ◽  
pp. E7448-E7455 ◽  
Author(s):  
Serena Sirigu ◽  
James J. Hartman ◽  
Vicente José Planelles-Herrero ◽  
Virginie Ropars ◽  
Sheila Clancy ◽  
...  
Keyword(s):  
Smooth Muscle ◽  
Muscle Relaxation ◽  
Selective Inhibition ◽  
Pharmacological Agents ◽  
Skeletal Muscle Myosin ◽  
Starting Point ◽  
Myosin Motors ◽  
Muscle Myosin

Direct inhibition of smooth muscle myosin (SMM) is a potential means to treat hypercontractile smooth muscle diseases. The selective inhibitor CK-2018571 prevents strong binding to actin and promotes muscle relaxation in vitro and in vivo. The crystal structure of the SMM/drug complex reveals that CK-2018571 binds to a novel allosteric pocket that opens up during the “recovery stroke” transition necessary to reprime the motor. Trapped in an intermediate of this fast transition, SMM is inhibited with high selectivity compared with skeletal muscle myosin (IC50 = 9 nM and 11,300 nM, respectively), although all of the binding site residues are identical in these motors. This structure provides a starting point from which to design highly specific myosin modulators to treat several human diseases. It further illustrates the potential of targeting transition intermediates of molecular machines to develop exquisitely selective pharmacological agents.

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