scholarly journals Antifungal activity of fibrate-based compounds and substituted pyrroles inhibiting the enzyme 3-hydroxy-methyl-glutaryl-CoA reductase of Candida glabrata (CgHMGR), and decreasing yeast viability and ergosterol synthesis

2021 ◽  
Author(s):  
Damián A. Madrigal-Aguilar ◽  
Adilene Gonzalez-Silva ◽  
Blanca Rosales-Acosta ◽  
Celia Bautista-Crescencio ◽  
Jossué Ortiz-Álvarez ◽  
...  
Keyword(s):  
Candida Glabrata ◽  
Inhibitory Effect ◽  
List Type ◽  
Amino Acid Residues ◽  
Yeast Growth ◽  
Yeast Viability ◽  
Ergosterol Synthesis ◽  
Substituted Pyrroles ◽  
Coa Reductase

ABSTRACTDue to the emergence of multi-drug resistant strains of yeasts belonging to the Candida genus, there is an urgent need to discover antifungal agents directed at alternative molecular targets. The aim of the current study was to evaluate the capacity of synthetic compounds to inhibit the Candida glabrata enzyme denominated 3-hydroxy-methyl-glutaryl-CoA reductase (CgHMGR), and thus affect ergosterol synthesis and yeast viability. One series of synthetic antifungal compounds were analogues to fibrates, a second series had substituted 1,2-dihydroquinolines and the third series included substituted pyrroles. α-asarone-related compounds 1c and 5b with a pyrrolic core were selected as the best antifungal candidates. Both inhibited the growth of fluconazole-resistant C. glabrata 43 and fluconazole-susceptible C. glabrata CBS 138. A yeast growth rescue experiment based on the addition of exogenous ergosterol showed that the compounds act by inhibiting the mevalonate synthesis pathway. A greater recovery of yeast growth occurred for the C. glabrata 43 strain and after the 1c (versus 5b) treatment. Given that the compounds decreased the ergosterol concentration in the yeast strains, they probably target the ergosterol synthesis. According to the docking analysis, the inhibitory effect of the 1c and 5b could possibly be mediated by their interaction with the amino acid residues of the catalytic site of CgHMGR. Since 1c displayed higher binding energy than α-asarone and 5b, it is a good candidate for further research, which should include structural modifications to increase its specificity and potency as well as in vivo studies on its effectiveness at a therapeutic dose.HIGHLIGHTSFibrate-based and pyrrole-containing compounds were tested as C. glabrata inhibitors.The best inhibitor from fibrate was 1c and from pyrroles was 5b.These agents inhibited C. glabrata growth better than the reference antifungals.They also inhibited ergosterol synthesis by the two C. glabrata strains tested. Experimental

scholarly journals Synergistic Activity between Statins and Bisphosphonates against Acute Experimental Toxoplasmosis

2017 ◽  
Vol 61 (8) ◽  
Author(s):  
Zhu-Hong Li ◽  
Catherine Li ◽  
Sergio H. Szajnman ◽  
Juan B. Rodriguez ◽  
Silvia N. J. Moreno
Keyword(s):  
Lethal Dose ◽  
Inhibitory Effect ◽  
Etiologic Agent ◽  
Farnesyl Diphosphate ◽  
Synergistic Activity ◽  
Content Type ◽  
Coa Reductase ◽  
Modest Effect

ABSTRACT Bisphosphonates are widely used for the treatment of bone disorders. These drugs also inhibit the growth of a variety of protozoan parasites, such as Toxoplasma gondii, the etiologic agent of toxoplasmosis. The target of the most potent bisphosphonates is the isoprenoid biosynthesis pathway enzyme farnesyl diphosphate synthase (FPPS). Based on our previous work on the inhibitory effect of sulfur-containing linear bisphosphonates against T. gondii, we investigated the potential synergistic interaction between one of these derivatives, 1-[(n-heptylthio)ethyl]-1,1-bisphosphonate (C7S), and statins, which are potent inhibitors of the host 3-hydroxy-3-methyl glutaryl-coenzyme A reductase (3-HMG-CoA reductase). C7S showed high activity against the T. gondii bifunctional farnesyl diphosphate (FPP)/geranylgeranyl diphosphate (GGPP) synthase (TgFPPS), which catalyzes the formation of FPP and GGPP (50% inhibitory concentration [IC50] = 31 ± 0.01 nM [mean ± standard deviation]), and modest effect against the human FPPS (IC50 = 1.3 ± 0.5 μM). We tested combinations of C7S with statins against the in vitro replication of T. gondii. We also treated mice infected with a lethal dose of T. gondii with similar combinations. We found strong synergistic activities when using low doses of C7S, which were stronger in vivo than when tested in vitro. We also investigated the synergism of several commercially available bisphosphonates with statins both in vitro and in vivo. Our results provide evidence that it is possible to develop drug combinations that act synergistically by inhibiting host and parasite enzymes in vitro and in vivo.

scholarly journals Selective inhibition by antiflamrnin-2 of thromboxane B2release from isolated and perfused guinea-pig lung

1992 ◽  
Vol 1 (4) ◽  
pp. 251-254
Author(s):  
Lidia Sautebin ◽  
Giuseppe Cirino ◽  
Massimo Di Rosa
Keyword(s):  
Guinea Pig ◽  
Histamine Release ◽  
Calcium Ionophore ◽  
Selective Inhibition ◽  
Inhibitory Effect ◽  
Amino Acid Residues ◽  
A 23187 ◽  
Normal Lungs

Antiflammin-2 (AF2) is a nonapeptide corresponding to the amino acid residues 246–254 of lipocortin-1 showing anti-inflammatory activity both in vitro and in vivo. The effect of AF2 on the thromboxane B2(TXB2) and histamine release from isolated and perfused guinea-pig lungs has been studied. AF-2 (10–100 nM) inhibited leukotriene C4- (LTC4) (3 ng) and antigen-induced (ovalbumin, 1 mg) TXB2release in normal and sensitized lungs, respectively. In contrast AF-2 (100 nM) did not modify TXB2release induced by histamine (5 μg) or bradykinin (5 μg) in normal lungs. Antigen-induced histamine release was not affected by 100 nM AF-2 infusion. When tested in chopped lung fragments AF-2 (0.1–25 μM) did not modify the release of histamine and TXB2induced by antigen (ovalbumin, 10 μg ml−1) or calcium ionophore A 23187 (1 μM). Our results show that the inhibitory effect of AF-2 on TXB2release is selective and depends on the stimulus applied. In this respect AF-2 mimics, at least in part, the actions of both glucocorticoids and lipocortin-1.

scholarly journals Calcineurin-dependent growth control in Saccharomyces cerevisiae mutants lacking PMC1, a homolog of plasma membrane Ca2+ ATPases

1994 ◽  
Vol 124 (3) ◽  
pp. 351-363 ◽  
Author(s):  
KW Cunningham ◽  
GR Fink
Keyword(s):  
Saccharomyces Cerevisiae ◽  
Plasma Membrane ◽  
Mammalian Cells ◽  
Growth Control ◽  
Inhibitory Effect ◽  
Yeast Growth ◽  
Recessive Mutations ◽  
Calcineurin A ◽  
Dependent Growth

Ca2+ ATPases deplete the cytosol of Ca2+ ions and are crucial to cellular Ca2+ homeostasis. The PMC1 gene of Saccharomyces cerevisiae encodes a vacuole membrane protein that is 40% identical to the plasma membrane Ca2+ ATPases (PMCAs) of mammalian cells. Mutants lacking PMC1 grow well in standard media, but sequester Ca2+ into the vacuole at 20% of the wild-type levels. pmc1 null mutants fail to grow in media containing high levels of Ca2+, suggesting a role of PMC1 in Ca2+ tolerance. The growth inhibitory effect of added Ca2+ requires activation of calcineurin, a Ca2+ and calmodulin-dependent protein phosphatase. Mutations in calcineurin A or B subunits or the inhibitory compounds FK506 and cyclosporin A restore growth of pmc1 mutants in high Ca2+ media. Also, growth is restored by recessive mutations that inactivate the high-affinity Ca(2+)-binding sites in calmodulin. This mutant calmodulin has apparently lost the ability to activate calcineurin in vivo. These results suggest that activation of calcineurin by Ca2+ and calmodulin can negatively affect yeast growth. A second Ca2+ ATPase homolog encoded by the PMR1 gene acts together with PMC1 to prevent lethal activation of calcineurin even in standard (low Ca2+) conditions. We propose that these Ca2+ ATPase homologs are essential in yeast to deplete the cytosol of Ca2+ ions which, at elevated concentrations, inhibits yeast growth through inappropriate activation of calcineurin.

scholarly journals Inhibition of 3-Hydroxy-3-methylglutaryl Coenzyme A Reductase (Ex Vivo) by Morus indica (Mulberry)

2014 ◽  
Vol 2014 ◽  
pp. 1-5 ◽  
Author(s):  
Vanitha Reddy Palvai ◽  
Asna Urooj
Keyword(s):  
Coenzyme A ◽  
Cholesterol Metabolism ◽  
Ex Vivo ◽  
Plasma Cholesterol ◽  
Effective Means ◽  
Inhibitory Effect ◽  
Hmg Coa Reductase ◽  
Standard Drug ◽  
Coa Reductase

Phytochemicals are the bioactive components that contribute to the prevention of cardiovascular and other degenerative diseases. Inhibition of 3-hydroxy-3-methylglutaryl coenzyme A (HMG CoA) reductase would be an effective means of lowering plasma cholesterol in humans. The present study explores the HMG CoA reductase inhibitory effect of extracts from leaves of Morus indica varieties, M5, V1, and S36, compared with the statin, using an ex vivo method. The assay is based on the stoichiometric formation of coenzyme A during the reduction of microsomal HMG CoA to mevalonate. Dechlorophyllised extract of three varieties was studied at 300 µg. The coenzyme A released at the end of assay in control (100.31 nmoles) and statins (94.46 nm) was higher than the dechlorphyllised extracts of the samples. The coenzyme A released during the reduction of HMG CoA to mevalonate in dechlorophyllised extracts of the samples was as follows: S36 < M5 < V1. The results indicated that the samples were highly effective in inhibiting the enzyme compared to statins (standard drug). The results indicate the role of Morus varieties extracts in modulating the cholesterol metabolism by inhibiting the activity of HMG CoA reductase. These results provide scope for designing in vivo animal studies to confirm their effect.

A somatostatin analogue inhibits chondrosarcoma and insulinoma tumour growth

1985 ◽  
Vol 109 (1) ◽  
pp. 108-114 ◽  
Author(s):  
J. C. Reubi
Keyword(s):  
Tumour Growth ◽  
Direct Action ◽  
Somatostatin Receptors ◽  
Tumour Volume ◽  
Inhibitory Effect ◽  
Somatostatin Analogue ◽  
List Type ◽  
Experimental Conditions ◽  
Tumour Growth Inhibition

Abstract. The in vivo effects on tumour growth of a potent somatostatin analogue, SMS 201-995 [H-(D)Phe-Cys-Phe-(D)Trp-Lys-Thr-Cys-Thr-(ol)], were measured in two characterised transplantable tumours: the Swarm rat chondrosarcoma, known to be insulin-, growth hormone (GH)-, somatomedin- and corticosteroid-dependent, a hamster insulinoma, bearing specific high affinity somatostatin receptors. SMS 201-995 (1.25 mg/kg/day) given for 25 days to rats bearing freshly transplanted chondrosarcomas inhibited tumour volume by 48%. A significant tumour growth inhibition was measured also in well developed tumours treated with high doses of SMS 201-995 (1.25 mg/kg/day) for 7 days. In the treated animals, GH was significantly inhibited. In hamsters bearing a freshly transplanted insulinoma, the daily application of SMS 201-995 (200 μg/kg/day, sc) for 33 days could significantly inhibit the growth (as measured by tumour volume) of the tumour. A moderate inhibitory effect of SMS 201-995 on the growth of well grown insulinomas could also be observed. This study shows that SMS 201-995 under the present experimental conditions has a moderate but significant growth inhibitory effect in two different transplantable tumour models. In the rat chondrosarcoma, the effect of SMS 201-995 is probably indirect, due to inhibition of GH, somatomedin and insulin. In the hamster insulinoma, the effect is possibly due to a more direct action of SMS 201-995 on specific somatostatin receptors present in this tumor.

The Inhibition of Platelet Aggregation by an Aorta Intima Extract

1974 ◽  
Vol 32 (02/03) ◽  
pp. 417-431 ◽  
Author(s):  
A. du P Heyns ◽  
D. J van den Berg ◽  
G. M Potgieter ◽  
F. P Retief
Keyword(s):  
Platelet Aggregation ◽  
Degradation Products ◽  
Adenosine Diphosphate ◽  
Inhibitory Effect ◽  
Protective Role ◽  
Vascular Trauma ◽  
Wear And Tear ◽  
Sequential Addition ◽  
Aggregation Activity

SummaryThe platelet aggregating activity of extracts of different layers of the arterial wall was compared to that of Achilles tendon. Arterial media and tendon extracts, adjusted to equivalent protein content as an index of concentration, aggregated platelets to the same extent but an arterial intima extract did not aggregate platelets. Platelet aggregation induced by collagen could be inhibited by mixing with intima extract, but only to a maximum of about 80%. Pre-mixing adenosine diphosphate (ADP) with intima extracts diminished the platelet aggregation activity of the ADP. Depending on the relationship between ADP and intima extract concentrations aggregating activity could either be completely inhibited or inhibition abolished. Incubation of ADP with intima extract and subsequent separation of degradation products by paper chromatography, demonstrated a time-dependent breakdown of ADP with AMP, adenosine, inosine and hypoxanthine as metabolic products; ADP removal was complete. Collagen, thrombin and adrenaline aggregate platelets mainly by endogenous ADP of the release reaction. Results of experiments comparing inhibition of aggregation caused by premixing aggregating agent with intima extract, before exposure to platelets, and the sequential addition of first the intima extract and then aggregating agent to platelets, suggest that the inhibitory effect of intima extract results from ADP breakdown. It is suggested that this ADP degradation by intima extract may play a protective role in vivo by limiting the size of platelet aggregates forming at the site of minimal “wear and tear” vascular trauma.

Measurement of the Platelet Response to Laser- induced Microvascular Injury

1974 ◽  
Vol 32 (02/03) ◽  
pp. 704-713 ◽  
Author(s):  
F. N McKenzie ◽  
K.-E Arfors ◽  
N. A Matheson
Keyword(s):  
Inhibitory Effect ◽  
Microvascular Blood Flow ◽  
Platelet Response ◽  
High Concentration ◽  
Platelet Activity ◽  
Microvascular Injury ◽  
Arterial Blood ◽  
Proximal Site ◽  
Adenosine Phosphates

SummaryA study has been made of the biochemical factors underlying the platelet response to laser-induced microvascular injury. A platelet aggregating substance is produced at sites of laser-induced injury which markedly stimulates platelet activity at a site of injury inflicted a short distance downstream. Distal sites of injury are not similarly influenced if the distance between the injuries is increased or if the proximal site no longer shows platelet-stimulating activity. The stimulating effect of an adjacent proximal injury on platelet activity at a distal site is inhibited by local intra-arterial infusion of adenosine. Measurements of arterial blood pressure and microvascular blood flow velocity during adenosine infusion showed that its inhibitory effect on platelet activity is largely independent of its vasodilator properties. The effect of infusion of different adenosine phosphates (AMP, ADP, ATP) was also studied. Very small amounts of ADP markedly stimulated platelet activity and the emboli formed were similar to those normally produced at sites of laser injury. At high concentration AMP inhibited while ATP stimulated platelet activity in vivo. The results emphasise the fundamental role of ADP as a mediator of the platelet response at sites of laser- induced microvascular injury.

The Effects of Heparin and Annexin V on Fibrin Accretion after Injury in the Jugular Veins of Rabbits

1993 ◽  
Vol 69 (03) ◽  
pp. 227-230 ◽  
Author(s):  
J Van Ryn-McKenna ◽  
H Merk ◽  
T H Müller ◽  
M R Buchanan ◽  
W G Eisert
Keyword(s):  
Vessel Wall ◽  
Thrombin Generation ◽  
Antithrombin Iii ◽  
Specific Effect ◽  
Annexin V ◽  
Inhibitory Effect ◽  
Jugular Veins ◽  
Prothrombinase Complex ◽  
Wall Injury

SummaryWe compared the relative abilities of unfractionated heparin and annexin V to prevent fibrin accretion onto injured jugular veins in vivo. Heparin was used to accelerate the inhibition of thrombin by antithrombin III, and annexin V was used to inhibit the assembly of the prothrombinase complex on phospholipid surfaces, thereby blocking thrombin generation. Rabbit jugular veins were isolated in situ, a 2 cm segment was injured by perfusing it with air, and then blood flow was re-established. Five minutes later, each rabbit was injected with heparin (20 U/kg) or annexin V (0.3 mg/kg) and then with 125I-fibrinogen. The amount of 125I-fibrin accumulation onto each injured vessel wall segment was measured 4 h later. Each injured vessel was completely deendothelialized as a result of the air perfusion as demonstrated by electron microscopy. 125I-fibrin accretion onto the injured jugular veins was enhanced 2.4-fold as compared to the uninjured veins in sham-operated animals. Heparin treatment did not reduce fibrin accretion, whereas, annexin V treatment decreased fibrin accretion by 60%, p <0.05. This latter effect was achieved without sustained circulating anticoagulation. Additional experiments confirmed that the inhibitory effect of annexin V on fibrin accretion was associated with a surface specific effect, since more annexin V bound to the injured jugular vein segments as compared to the non-injured jugular veins. We conclude that, i) mild vessel wall injury (selective de-endothelialization) in veins results in a thrombogenic vessel wall; ii) the thrombogenecity of which is not inhibited by prophylactic doses of heparin; but iii) is inhibited by annexin V, which binds to injured vessel wall surface, and inhibits thrombin generation independently of antithrombin III.

The Effect of Barbituric Acid Derivatives on Platelet Function in Vitro and in Vivo

1973 ◽  
Vol 30 (02) ◽  
pp. 315-326
Author(s):  
J. Heinz Joist ◽  
Jean-Pierre Cazenave ◽  
J. Fraser Mustard
Keyword(s):  
Platelet Aggregation ◽  
Platelet Function ◽  
Barbituric Acid ◽  
Platelet Rich Plasma ◽  
Inhibitory Effect ◽  
Primary Response ◽  
Sodium Pentobarbital ◽  
Barbituric Acid Derivatives

SummarySodium pentobarbital (SPB) and three other barbituric acid derivatives were found to inhibit platelet function in vitro. SPB had no effect on the primary response to ADP of platelets in platelet-rich plasma (PRP) or washed platelets but inhibited secondary aggregation induced by ADP in human PRP. The drug inhibited both phases of aggregation induced by epinephrine. SPB suppressed aggregation and the release reaction induced by collagen or low concentrations of thrombin, and platelet adherence to collagen-coated glass tubes. The inhibition by SPB of platelet aggregation was readily reversible and isotopically labeled SPB did not become firmly bound to platelets. No inhibitory effect on platelet aggregation induced by ADP, collagen, or thrombin could be detected in PRP obtained from rabbits after induction of SPB-anesthesia.

Inhibition of Human and Animal Platelet Adhesiveness to Glass Bead Columns by Adenosine, Dipyridamole, Chlorpromazine and Acetylsalicylic Acid

1976 ◽  
Vol 36 (02) ◽  
pp. 401-410 ◽  
Author(s):  
Buichi Fujttani ◽  
Toshimichi Tsuboi ◽  
Kazuko Takeno ◽  
Kouichi Yoshida ◽  
Masanao Shimizu
Keyword(s):  
Guinea Pig ◽  
Acetylsalicylic Acid ◽  
Guinea Pigs ◽  
Glass Bead ◽  
Animal Species ◽  
Inhibitory Effect ◽  
Rabbit Platelet ◽  
Platelet Adhesiveness

SummaryThe differences among human, rabbit and guinea-pig platelet adhesiveness as for inhibitions by adenosine, dipyridamole, chlorpromazine and acetylsalicylic acid are described, and the influence of measurement conditions on platelet adhesiveness is also reported. Platelet adhesiveness of human and animal species decreased with an increase of heparin concentrations and an increase of flow rate of blood passing through a glass bead column. Human and rabbit platelet adhesiveness was inhibited in vitro by adenosine, dipyridamole and chlorpromazine, but not by acetylsalicylic acid. On the other hand, guinea-pig platelet adhesiveness was inhibited by the four drugs including acetylsalicylic acid. In in vivo study, adenosine, dipyridamole and chlorpromazine inhibited platelet adhesiveness in rabbits and guinea-pigs. Acetylsalicylic acid showed the inhibitory effect in guinea-pigs, but not in rabbits.

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