Статті в журналах: "Inhibitory effects"

1

Senggunprai, Laddawan, Kouichi Yoshinari, and Yasushi Yamazoe. "Inhibitory effects of kynurenic acid, a tryptophan metabolite, and its derivatives on cytosolic sulfotransferases." Biochemical Journal 422, no. 3 (August 27, 2009): 455–62. http://dx.doi.org/10.1042/bj20090168.

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KYNA (kynurenic acid) is an endogenous metabolite of tryptophan in the kynurenine pathway and has been characterized as an antagonist of ionotropic glutamate receptors. In addition, we have reported this endogenous compound as a potent inhibitor of SULTs (cytosolic sulfotransferases). In the present study we characterized the inhibitory effects of KYNA on several human (h) and mouse (m) recombinant SULTs. No sulfate metabolite of KYNA was detected with mouse and human SULTs examined under the conditions used, suggesting that it is a bona fide inhibitor of SULTs. Among the mouse enzymes examined, KYNA exhibited selective inhibitory effects on Sult1b1-mediated sulfation of various compounds with IC50 values in the low micromolar range (2.9–4.9 μM). KYNA also exerted an inhibitory activity towards hSULT1A1 and hSULT1B1. The inhibitory potency of KYNA for mSult1b1 was stronger than that of 2,6-dichloro-4-nitrophenol, a known non-specific SULT inhibitor, whereas the potencies of these two inhibitors for hSULT1B1 were comparable. The inhibitory characteristics of KYNA were clearly distinct from those of mefenamic acid, a selective inhibitor of SULT1A enzymes. The KYNA derivatives 5,7-dichlorokynurenic acid and L689,560 exhibited preferential inhibitory effects on hSULT1A1 and hSULT1B1 respectively. Interestingly, gavestinel, another KYNA derivative, was found to be an extremely potent inhibitor of hSULT1B1. Finally, we have demonstrated that the mechanism underlying the KYNA inhibition varied depending on the enzyme and substrate involved. Taken together, the present results unveil another distinct aspect of KYNA and its derivatives as an inhibitor of SULTs.

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2

Zizzo, Maria Grazia, Flavia Mulè, and Rosa Serio. "Mechanisms underlying the nitric oxide inhibitory effects in mouse ileal longitudinal muscle." Canadian Journal of Physiology and Pharmacology 83, no. 8-9 (August 1, 2005): 805–10. http://dx.doi.org/10.1139/y05-073.

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We investigated the mechanisms involved in the nitric oxide (NO)-induced inhibitory effects on longitudinal smooth muscle of mouse ileum, using organ bath technique. Exogenously applied NO, delivered as sodium nitroprusside (SNP; 0.1–100 µmol/L) induced a concentration-dependent reduction of the ileal spontaneous contractions. 1H-[1,2,4]oxadiazolol[4,3,a]quinoxalin-1-one (ODQ; 1 µmol/L), a guanilyl cyclase inhibitor, reduced the SNP-induced effects. Tetraethylammonium chloride (20 mmol/L), a non-selective K+ channel blocker, and charybdotoxin (0.1 µmol/L), blocker of large conductance Ca2+-dependent K+ channels, significantly reduced SNP-induced inhibitory effects. In contrast, apamin (0.1 µmol/L), blocker of small conductance Ca2+-dependent K+ channels, was not able to affect the response to SNP. Ciclopiazonic acid (10 µmol/L) or thapsigargin (0.1 µmol/L), sarcoplasmatic reticulum Ca2+-ATPase inhibitors, decreased the SNP-inhibitory effects. Ryanodine (10 µmol/L), inhibitor of Ca2+ release from ryanodine-sensitive intracellular stores, significantly reduced the SNP inhibitory effects. The membrane permeable analogue of cGMP, 8-bromoguanosine 3′,5′-cyclic monophosphate (100 µmol/L), also reduced spontaneous mechanical activity, and its effect was antagonized by ryanodine. The present study suggests that NO causes inhibitory effects on longitudinal smooth muscle of mouse ileum through cGMP which in turn would activate the large conductance Ca2+-dependent K+ channels, via localized ryanodine-sensitive Ca2+ release.Key words: nitric oxide, mouse ileum, potassium channels, calcium stores.

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3

Fais, Antonella, Benedetta Era, Amalia Di Petrillo, Sonia Floris, Dario Piano, Paola Montoro, Carlo Ignazio Giovanni Tuberoso, Rosaria Medda, and Francesca Pintus. "Selected Enzyme Inhibitory Effects of Euphorbia characias Extracts." BioMed Research International 2018 (May 29, 2018): 1–9. http://dx.doi.org/10.1155/2018/1219367.

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Extracts of aerial part of Euphorbia characias were examined to check potential inhibitors for three selected enzymes involved in several metabolic disorders. Water and ethanol extracts from leaves and flowers showed in vitro inhibitory activity toward α-amylase, α-glucosidase, and xanthine oxidase. IC50 values were calculated for all the extracts and the ethanolic extracts were found to exert the best effect. In particular, for the α-glucosidase activity, the extracts resulted to be 100-fold more active than the standard inhibitor. The inhibition mode was investigated by Lineweaver-Burk plot analysis. E. characias extracts display different inhibition behaviors toward the three enzymes acting as uncompetitive, noncompetitive, and mixed-type inhibitors. Moreover, ethanolic extracts of E. characias showed no cytotoxic activity and exhibited antioxidant capacity in a cellular model. The LC-DAD metabolic profile was also performed and it showed that leaves and flowers extracts contain high levels of quercetin derivatives. The results suggest that E. characias could be a promising source of natural inhibitors of the enzymes involved in carbohydrate uptake disorders and oxidative stress.

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Sakuda, Shohei, Diyan Prabowo, Keiko Takagi, Kazuro Shiomi, Mihoko Mori, Satoshi Ōmura, and Hiromichi Nagasawa. "Inhibitory Effects of Respiration Inhibitors on Aflatoxin Production." Toxins 6, no. 4 (March 26, 2014): 1193–200. http://dx.doi.org/10.3390/toxins6041193.

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5

Čermák, P., V. Palečková, M. Houška, J. Strohalm, P. Novotná, A. Mikyška, M. Jurková, and M. Sikorová. "Inhibitory effects of fresh hops on Helicobacter pylori strains." Czech Journal of Food Sciences 33, No. 4 (June 3, 2016): 302–7. http://dx.doi.org/10.17221/261/2014-cjfs.

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6

Shi, Yun Feng, Li Li Zhang, Mu Qiu Zhao, and Gang Wang. "Inhibitory Effects of Aqueous Extracts from Leaves of Common Tropical Green Plants on Urea Hydrolysis in Soils." Advanced Materials Research 1010-1012 (August 2014): 614–17. http://dx.doi.org/10.4028/www.scientific.net/amr.1010-1012.614.

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Tropical plants contain a variety of secondary metabolites, and plant aqueous extracts can be used as urease inhibitors to improve nitrogen use efficiency and reduce the negative environmental effects. An incubation experiment was carried out to investigate the effects of aqueous extracts of 32 common tropical green plant species from 24 families on urea hydrolysis. The results indicated that the aqueous extracts from 3 of the common tropical green plants (Pterocarpus indicus, Callistemon rigidus, Terminalia mantaly) belonging to Leguminosae, Myrtaceae and Combretaceae respectively showed better inhibitory effects on urease than hydroquinone as a chemical inhibitor, and had more obvious potential applications. The inhibitory effects of active substances in plants were affected by extract temperature causing by solubility and thermal stability of active substances. T. mantaly had the most potential for development in this study as a fertilizer additive. The inhibitory effects of aqueous extracts of T. mantaly leaves on urea hydrolysis increased with increasing concentration of aqueous extracts, the strongest inhibitory effect on urease occurred after 2-3 d of incubation.

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7

Na, Bon Hyang, Thi Xoan Hoang та Jae Young Kim. "Hsp90 Inhibition Reduces TLR5 Surface Expression and NF-κB Activation in Human Myeloid Leukemia THP-1 Cells". BioMed Research International 2018 (2018): 1–8. http://dx.doi.org/10.1155/2018/4319369.

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Tumors highly express active heat shock protein 90 (Hsp90), which is involved in tumor survival and progression. Enhanced Toll-like receptor (TLR) 5 expression and signaling were reported to be associated with acute myeloid leukemia. In the present study, we investigated the possible modulatory effects of Hsp90 inhibitors on TLR5 expression and signaling in the human myeloid leukemia cell line THP-1. Cells were pretreated with various concentrations of the Hsp90 inhibitor geldanamycin (GA) or the Hsp70 inhibitor VER155008, followed by stimulation with bacterial flagellin. Flagellin-induced nuclear factor-κB (NF-κB) activation was significantly reduced by treatment with GA or VER155008. To elucidate the underlying mechanism of this effect, mRNA and cell surface expression of TLR5 was examined. TLR5 mRNA expression was enhanced by both GA and VER155008, whereas cell surface expression of TLR5 was reduced by three different Hsp90 inhibitors, including GA, 17-(allylamino)-17-demethoxygeldanamycin, and radicicol, and an Hsp70 inhibitor. The inhibitory effect of Hsp90 inhibitors was much higher than that of Hsp70 inhibitor. Our results suggest that Hsp90 inhibitors suppress TLR5 surface expression and activation of NF-κB in THP-1 cells in response to TLR5 ligand, and these inhibitory effects may be associated with the possible mechanisms by which Hsp90 inhibitors suppress myeloid leukemia.

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Rong, Ke Sheng, Xiao Mei Shi, Jia Qin Gong, Qi Bing Wang, Ke Cheng Liu, Yuan Zhi Qu, and Xu Yang Yao. "Effects of Glycine, L-Arginine and their Complexation with Polyvinylpyrrolidone on Tetrahydrofuran Hydrate Formation." Materials Science Forum 1009 (August 2020): 49–53. http://dx.doi.org/10.4028/www.scientific.net/msf.1009.49.

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Hydrophilic amino acids as a new type hydrate inhibitor is a hot topic for scholars. In this paper, the influence of glycine and L-arginine, and their complexation with polyvinylpyrrolidone (PVP) on hydrate formation were clarified by tetrahydrofuran (THF) hydrate formation simulation experiments, and the intrinsic influence mechanism was revealed by many experimental methods. The results show that glycine has a strong inhibitory effect on water molecules because of its strong disturbance to water molecules, and the inhibitory effect is the best when the addition of glycine is 1.0 wt%. Due to the disturbance and binding of hydrophilic amino acids to water molecules, the effect of PVP on the semi-cage structure of water molecules as well as the adsorption and encapsulation of hydrate crystal particles, the combination of glycine and L-arginine and PVP has synergistic inhibitory effect on the formation of THF hydrate. When the total amount of hydrate inhibitor is 1.0 wt%, the synergistic inhibition ability of glycine and PVP is stronger. The results obtained in this paper provide an experimental and theoretical basis for the research and development of new hydrate inhibitors.

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9

RICHTSMEIER, WILLIAM J., and SIDNEY E. GROSSBERG. "Inhibitory Effects of Mitochondrial Metabolic Inhibitors on Interferon Action." Journal of Interferon Research 9, no. 1 (February 1989): 87–96. http://dx.doi.org/10.1089/jir.1989.9.87.

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10

Augustsson, Cecilia, Ida Hilden, and Lars C. Petersen. "Inhibitory effects of LDL-associated tissue factor pathway inhibitor." Thrombosis Research 134, no. 1 (July 2014): 132–37. http://dx.doi.org/10.1016/j.thromres.2014.03.043.

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11

Sasaki-Tanaka, Reina, Kalyan C. Nagulapalli Venkata, Hiroaki Okamoto, Mitsuhiko Moriyama, and Tatsuo Kanda. "Evaluation of Potential Anti-Hepatitis A Virus 3C Protease Inhibitors Using Molecular Docking." International Journal of Molecular Sciences 23, no. 11 (May 27, 2022): 6044. http://dx.doi.org/10.3390/ijms23116044.

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Hepatitis A virus (HAV) infection is a major cause of acute hepatitis worldwide and occasionally causes acute liver failure and can lead to death in the absence of liver transplantation. Although HAV vaccination is available, the prevalence of HAV vaccination is not adequate in some countries. Additionally, the improvements in public health reduced our immunity to HAV infection. These situations motivated us to develop potentially new anti-HAV therapeutic options. We carried out the in silico screening of anti-HAV compounds targeting the 3C protease enzyme using the Schrodinger Modeling software from the antiviral library of 25,000 compounds to evaluate anti-HAV 3C protease inhibitors. Additionally, in vitro studies were introduced to examine the inhibitory effects of HAV subgenomic replicon replication and HAV HA11-1299 genotype IIIA replication in hepatoma cell lines using luciferase assays and real-time RT-PCR. In silico studies enabled us to identify five lead candidates with optimal binding interactions in the active site of the target HAV 3C protease using the Schrodinger Glide program. In vitro studies substantiated our hypothesis from in silico findings. One of our lead compounds, Z10325150, showed 47% inhibitory effects on HAV genotype IB subgenomic replicon replication and 36% inhibitory effects on HAV genotype IIIA HA11-1299 replication in human hepatoma cell lines, with no cytotoxic effects at concentrations of 100 μg/mL. The effects of the combination therapy of Z10325150 and RNA-dependent RNA polymerase inhibitor, favipiravir on HAV genotype IB HM175 subgenomic replicon replication and HAV genotype IIIA HA11-1299 replication showed 64% and 48% inhibitory effects of HAV subgenomic replicon and HAV replication, respectively. We identified the HAV 3C protease inhibitor Z10325150 through in silico screening and confirmed the HAV replication inhibitory activity in human hepatocytes. Z10325150 may offer the potential for a useful HAV inhibitor in severe hepatitis A.

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12

Bilan, Philip J., Jonathan B. Weitzman, Tracey Pflieger, C. Roy D. Lancaster, Alan Stafford, and Richard M. Epand. "Potent inhibitors of glucagon-stimulated adenylate cyclase associated with serum lipoprotein particles." Biochemistry and Cell Biology 67, no. 11-12 (November 1, 1989): 759–62. http://dx.doi.org/10.1139/o89-114.

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Lipoprotein fractions from some individuals have inhibitory effects on rat liver adenylate cyclase. Precipitation of the lipoprotein fractions with acetone released an inhibitory factor, which was soluble in acetone–H2O (3:1, v/v). The inhibition was greater against glucagon-stimulated activity than against basal activity. Acetone extraction increased the potency of inhibition. All three lipoprotein fractions, i.e., very low, low, and high density lipoproteins, released some inhibitory component after acetone extraction. The inhibitor was concentrated in the lipoprotein fractions, since acetone extraction of plasma did not release an inhibitor. The acetone extract from the very low density liproprotein was the most inhibitory. This material was further purified and partially characterized. The inhibitor had a molecular mass of about 500. It was inhibitory at micromolar concentrations. The material was sufficiently hydrophobic to migrate in normal-phase thin-layer chromatography (TLC). Nuclear magnetic resonance results indicated that it was not a polar lipid. There were several different inhibitory factors that were separable by TLC. The sequestration of these inhibitors into lipoproteins reduced their effectiveness in inhibiting the action of counter-regulatory hormones, such as glucagon.Key words: glucagon, adenylate cyclase, lipoprotein, diabetes mellitus.

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13

Rødland, Gro Elise, Sissel Hauge, Grete Hasvold, Lilli T. E. Bay, Tine T. H. Raabe, Mrinal Joel, and Randi G. Syljuåsen. "Differential Effects of Combined ATR/WEE1 Inhibition in Cancer Cells." Cancers 13, no. 15 (July 28, 2021): 3790. http://dx.doi.org/10.3390/cancers13153790.

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Inhibitors of WEE1 and ATR kinases are considered promising for cancer treatment, either as monotherapy or in combination with chemo- or radiotherapy. Here, we addressed whether simultaneous inhibition of WEE1 and ATR might be advantageous. Effects of the WEE1 inhibitor MK1775 and ATR inhibitor VE822 were investigated in U2OS osteosarcoma cells and in four lung cancer cell lines, H460, A549, H1975, and SW900, with different sensitivities to the WEE1 inhibitor. Despite the differences in cytotoxic effects, the WEE1 inhibitor reduced the inhibitory phosphorylation of CDK, leading to increased CDK activity accompanied by ATR activation in all cell lines. However, combining ATR inhibition with WEE1 inhibition could not fully compensate for cell resistance to the WEE1 inhibitor and reduced cell viability to a variable extent. The decreased cell viability upon the combined treatment correlated with a synergistic induction of DNA damage in S-phase in U2OS cells but not in the lung cancer cells. Moreover, less synergy was found between ATR and WEE1 inhibitors upon co-treatment with radiation, suggesting that single inhibitors may be preferable together with radiotherapy. Altogether, our results support that combining WEE1 and ATR inhibitors may be beneficial for cancer treatment in some cases, but also highlight that the effects vary between cancer cell lines.

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14

Jasim, Haider Hadi, Read Abd Al-Hussain, and Ahmed Shawqi Sadeq. "Evaluation the Efficiency of Various Types of Corrosion Inhibitors Used for Basrah Water Storage Tanks." Al-Nahrain Journal for Engineering Sciences 23, no. 3 (November 21, 2020): 267–76. http://dx.doi.org/10.29194/njes.23030267.

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In this paper, the efficiency of six different types of corrosion inhibitors used in Basrah drinking water tanks was assessed using a potentiostatic test method. The mechanism of adsorption of silicate and phosphate inhibitors in AISI 316 stainless steel surfaces and the effects of different water components in inhibitors are discussed in detail. The values of corrosion rate obtained from the Potentiostatic test showed that the protection against corrosion in the presence of inhibitors is better compared to the case of absence of inhibitors. The results of the six types of corrosion inhibitors tested showed that the inhibitory efficacy is higher below the temperatures 45oC, but when raise the temperature above 45oC the inhibitory efficiency becomes to decrease. Also, the test results indicated that the corrosion inhibitor involves silicate products provided more inhibited efficiency compared to the phosphate inhibitor alone or used the combined silicate/phosphate corrosion inhibitor. The inspection of the surface of the tested samples using optical methods shows that the pitting corrosion is demonstrated on the specimen surfaces after testing with or without inhibitors.

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Weisberg, Ellen, Lolita Banerji, Renee D. Wright, Rosemary Barrett, Arghya Ray, Daisy Moreno, Laurence Catley, et al. "Potentiation of antileukemic therapies by the dual PI3K/PDK-1 inhibitor, BAG956: effects on BCR-ABL– and mutant FLT3-expressing cells." Blood 111, no. 7 (April 1, 2008): 3723–34. http://dx.doi.org/10.1182/blood-2007-09-114454.

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AbstractMediators of PI3K/AKT signaling have been implicated in chronic myeloid leukemia (CML) and acute myeloid leukemia (AML). Studies have shown that inhibitors of PI3K/AKT signaling, such as wortmannin and LY294002, are able to inhibit CML and AML cell proliferation and synergize with targeted tyrosine kinase inhi-bitors. We investigated the ability of BAG956, a dual PI3K/PDK-1 inhibitor, to be used in combination with inhibitors of BCR-ABL and mutant FLT3, as well as with the mTOR inhibitor, rapamycin, and the rapamycin derivative, RAD001. BAG956 was shown to block AKT phosphorylation induced by BCR-ABL–, and induce apoptosis of BCR-ABL–expressing cell lines and patient bone marrow cells at concentrations that also inhibit PI3K signaling. Enhancement of the inhibitory effects of the tyrosine kinase inhibitors, imatinib and nilotinib, by BAG956 was demonstrated against BCR-ABL expressing cells both in vitro and in vivo. We have also shown that BAG956 is effective against mutant FLT3-expressing cell lines and AML patient bone marrow cells. Enhancement of the inhibitory effects of the tyrosine kinase inhibitor, PKC412, by BAG956 was demonstrated against mutant FLT3-expressing cells. Finally, BAG956 and rapamycin/RAD001 were shown to combine in a nonantagonistic fashion against BCR-ABL– and mutant FLT3-expressing cells both in vitro and in vivo.

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Umezawa, Koji, and Isao Kii. "Druggable Transient Pockets in Protein Kinases." Molecules 26, no. 3 (January 27, 2021): 651. http://dx.doi.org/10.3390/molecules26030651.

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Drug discovery using small molecule inhibitors is reaching a stalemate due to low selectivity, adverse off-target effects and inevitable failures in clinical trials. Conventional chemical screening methods may miss potent small molecules because of their use of simple but outdated kits composed of recombinant enzyme proteins. Non-canonical inhibitors targeting a hidden pocket in a protein have received considerable research attention. Kii and colleagues identified an inhibitor targeting a transient pocket in the kinase DYRK1A during its folding process and termed it FINDY. FINDY exhibits a unique inhibitory profile; that is, FINDY does not inhibit the fully folded form of DYRK1A, indicating that the FINDY-binding pocket is hidden in the folded form. This intriguing pocket opens during the folding process and then closes upon completion of folding. In this review, we discuss previously established kinase inhibitors and their inhibitory mechanisms in comparison with FINDY. We also compare the inhibitory mechanisms with the growing concept of “cryptic inhibitor-binding sites.” These sites are buried on the inhibitor-unbound surface but become apparent when the inhibitor is bound. In addition, an alternative method based on cell-free protein synthesis of protein kinases may allow the discovery of small molecules that occupy these mysterious binding sites. Transitional folding intermediates would become alternative targets in drug discovery, enabling the efficient development of potent kinase inhibitors.

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17

Cheng, Liwei, Limin Wang, Zhi Li, Bei Liu, and Guangjin Chen. "Inhibition Effect of Kinetic Hydrate Inhibitors on the Growth of Methane Hydrate in Gas–Liquid Phase Separation State." Energies 12, no. 23 (November 25, 2019): 4482. http://dx.doi.org/10.3390/en12234482.

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The effect of kinetic hydrate inhibitors (KHIs) on the growth of methane hydrate in the gas–liquid phase separation state is studied at the molecular level. The simulation results show that the kinetic inhibitors, named PVP and PVP-A, show good inhibitory effects on the growth of methane hydrate under the gas–liquid phase separation state, and the initial position of the kinetic hydrate inhibitors has a major effect on the growth of methane hydrates. In addition, inhibitors at different locations exhibit different inhibition performances. When the inhibitor molecules are located at the gas–liquid phase interface, increasing the contact area between the groups of the inhibitor molecules and methane is beneficial to enhance the inhibitory performance of the inhibitors. When inhibitor molecules are located at the solid–liquid phase interface, the inhibitor molecules adsorbed on the surface of the hydrate nucleus and decreased the direct contact of hydrate nucleus with the surrounding water and methane molecules, which would delay the growth of hydrate nucleus. Moreover, the increase of hydrate surface curvature and the Gibbs–Thomson effect caused by inhibitors can also reduce the growth rate of methane hydrate.

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Schaller, Martin, Nikola Krnjaic, Markus Niewerth, Gerald Hamm, Bernhard Hube, and Hans C. Korting. "Effect of antimycotic agents on the activity of aspartyl proteinases secreted by Candida albicans." Journal of Medical Microbiology 52, no. 3 (March 1, 2003): 247–49. http://dx.doi.org/10.1099/jmm.0.05048-0.

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The inhibitory effect of human immunodeficiency virus (HIV) proteinase inhibitors amprenavir and saquinavir and antifungal agents terbinafine, ketoconazole, amphotericin B and ciclopiroxolamine on aspartyl proteinases (Saps) secreted by Candida albicans was tested in an in vitro spectophotometric assay. As expected, both HIV proteinase inhibitors showed a significant inhibitory effect on Sap activity, which was comparable to that of the classical aspartyl proteinase inhibitor pepstatin A (P < 0.001). Antifungal drugs such as ketoconazole, terbinafine and amphotericin B had no, or only minor, inhibitory effects on proteolytic activity. In contrast, a significant reduction in Sap activity could be demonstrated during treatment with the antifungal agent ciclopiroxolamine (P < 0.001). These results point to a multiple effect of this antimycotic agent and might explain the reduced adherence of C. albicans to human epithelial cells at subinhibitory doses.

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Ptasinska-Wnuk, Dorota, Hanna Lawnicka, Slawomir Mucha, Jolanta Kunert-Radek, Marek Pawlikowski, and Henryk Stepien. "Angiotensins Inhibit Cell Growth in GH3 Lactosomatotroph Pituitary Tumor Cell Culture: A Possible Involvement of the p44/42 and p38 MAPK Pathways." Scientific World Journal 2012 (2012): 1–10. http://dx.doi.org/10.1100/2012/189290.

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The local renin-angiotensin system is present in the pituitary. We investigated the effects of angiotensins on GH3 lactosomatotroph cells proliferation in vitro and the involvement of p44/42 and p38 MAPK inhibitors in the growth-regulatory effects of angiotensins.Materials and Methods. Cell viability using the Mosmann method and proliferation by the measurement of BrdU incorporation during DNA synthesis were estimated.Results. Ang II and ang IV decreased the viability and proliferation of GH3 cells. Inhibitor of p44/42 MAPK attenuated the effects of ang II on cell viability and proliferation but did not affect the ang 5-8-dependent actions. Inhibitor of p38 MAPK prevented the decrease in the number of GH3 cells in ang-II- and ang-IV-treated groups.Conclusions. The growth-inhibitory effect of ang II is possibly mediated by the p44/42 MAPK. The p38 MAPK appears to mediate the inhibitory effects of both ang II and ang 5–8 upon cell survival.

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Bilodeau-Goeseels, Sylvie, Nora Magyara, and Coralie Collignon. "Characterization of the effects of metformin on porcine oocyte meiosis and on AMP-activated protein kinase activation in oocytes and cumulus cells." Zygote 22, no. 2 (April 12, 2013): 275–85. http://dx.doi.org/10.1017/s0967199413000075.

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SummaryThe adenosine monophosphate-activated protein kinase (AMPK) activators 5-aminoimidazole-4-carboxamide 1-β-d-ribofuranoside (AICAR) and metformin (MET) inhibit resumption of meiosis in porcine cumulus-enclosed oocytes. The objective of this study was to characterize the inhibitory effect of MET on porcine oocyte meiosis by: (1) determining the effects of an AMPK inhibitor and of inhibitors of signalling pathways involved in MET-induced AMPK activation in other cell types on MET-mediated meiotic arrest in porcine cumulus-enclosed oocytes; (2) determining whether MET and AICAR treatments lead to increased activation of porcine oocyte and/or cumulus cell AMPK as measured by phosphorylation of its substrate acetyl-CoA carboxylase; and (3) determining the effects of inhibition of the AMPK kinase, Ca2+/calmodulin-dependent protein kinase kinase (CaMKK), and Ca2+ chelation on oocyte meiotic maturation and AMPK activation in porcine oocytes and cumulus cells. The AMPK inhibitor compound C (CC; 1 μM) did not reverse the inhibitory effect of AICAR (1 mM) and MET (2 mM) on porcine oocyte meiosis. Additionally, CC had a significant inhibitory effect on its own. eNOS, c-Src and PI-3 kinase pathway inhibitors did not reverse the effect of metformin on porcine oocyte meiosis. The level of acetyl-CoA carboxylase (ACC) phosphorylation in oocytes and cumulus cells did not change in response to culture in the presence of MET, AICAR, CC, the CaMKK inhibitor STO-609 or the Ca2+ chelator BAPTA-AM for 3 h, but STO-609 increased the percentage of porcine cumulus-enclosed oocytes (CEO) that remained at the germinal vesicle (GV) stage after 24 h of culture. These results indicate that the inhibitory effect of MET and AICAR on porcine oocyte meiosis was probably not mediated through activation of AMPK.

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Balzarini, J., and E. De Clercq. "The Thiocarboxanilides UC-10 and UC-781 Have an Additive Inhibitory Effect against Human Immunodeficiency Virus Type 1 Reverse Transcriptase and Replication in Cell Culture When Combined with other Antiretroviral Drugs." Antiviral Chemistry and Chemotherapy 8, no. 3 (June 1997): 197–204. http://dx.doi.org/10.1177/095632029700800303.

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The thiocarboxanilides represent a structural class of potent and selective human immunodeficiency virus type 1 (HIV-1)-specific reverse transcriptase (RT) inhibitors. Combinations of the clinical candidate thiocarboxanilides UC-10 (oxime ether derivative) and UC-781 (pentenyloxy ether derivative) with a variety of nucleoside RT inhibitors (NRTIs) and non-nucleoside RT inhibitors (NNRTIs), two HIV protease inhibitors and one fusion/uncoating inhibitor were evaluated for their inhibitory effects on HIV-1 RT activity and HIV-1 replication in CEM cell cultures. The inhibitory activity of the NNRTIs including UC-10, UC-781, nevirapine, BHAR α-APA, 8-chloro-TIBO, MKC-442 and the quinoxaline HBY 097 against HIV-1 RT was highly dependent on the nature of the template/primer used in the HIV-1 RT reaction. However, fractionary inhibitory concentration (FIC) indexes for all drug concentrations evaluated in the combination experiments of UC-781 and the other NNRTIs fell within the range 0.5–1.5. This points to a predominantly additive effect of the thiocarboxanilides and other NNRTIs in the inhibition of HIV-1 RT. Similar FIC indexes were observed for the combination of UC-781 with the NRTI triphosphates AZT-TP, d4T-TP, ddCTP, ddATP and 3TC-TP and the NRTI diphosphate PMEApp against HIV-1 RT. All these drug combinations showed similar additive inhibitory effects on HIV-1 replication in cell culture. Also, the combinations of UC-10 or UC-781 with the protease inhibitors Ro31–8959/008 and ABT 84538.0 and the fusion/uncoating inhibitor bicyclam JM 3100 showed an additive effect (FIC within the 0.5–1.5 range). Thus, irrespective of the nature of the drugs, their combination with the thiocarboxanilides proved merely additive. In no case were antagonistic anti-HIV activity or increased cytotoxicity observed. In conclusion, thiocarboxanilides combined with a variety of clinically used anti-HIV agents result in additive anti-HIV activity.

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Buzzelli, Mark D., Murali Nagarajan, John F. Radtka, Margaret L. Shumate, Maithili Navaratnarajah, Charles H. Lang та Robert N. Cooney. "Nuclear Factor-κB Mediates the Inhibitory Effects of Tumor Necrosis Factor-α on Growth Hormone-Inducible Gene Expression in Liver". Endocrinology 149, № 12 (21 серпня 2008): 6378–88. http://dx.doi.org/10.1210/en.2007-1574.

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TNF inhibits serine protease inhibitor 2.1 (Spi 2.1) and IGF-I gene expression by GH in CWSV-1 hepatocytes. The current study describes construction of a GH-inducible IGF-I promoter construct and investigates mechanisms by which TNF and nuclear factor-κB (NFκB) inhibit GH-inducible gene expression. CWSV-1 cells were transfected with GH-inducible Spi 2.1 or IGF-I promoter luciferase constructs, incubated with TNF signaling inhibitors (fumonisin B1 for sphingomyelinase and SP600125 for c-Jun N-terminal kinase), treated with or without TNF, and then stimulated with recombinant human GH. The 5- to 6-fold induction of Spi 2.1 and IGF-I promoter activity by GH was inhibited by TNF. Neither fumonisin B1 nor SP600125 prevented the inhibitory effects of TNF on GH-inducible promoter activity. Dominant-negative inhibitor-κBα (IκBα) expression vectors (IκBαS/A or IκBαTrunc), p65 and p50 expression vectors, and p65 deletion constructs were used to investigate the NFκB pathway. IκBαS/A and IκBαTrunc ameliorated the inhibitory effects of TNF on GH-inducible Spi 2.1 and IGF-I promoter activity. Cotransfection of CWSV-1 cells with expression vectors for p65 alone or p50 and p65 together inhibited GH-inducible Spi 2.1 and IGF-I promoter activity. Cotransfection with a C-terminal p65 deletion (1–450) enhanced GH-inducible promoter activity, whereas the N-terminal deletion (31–551) was inhibitory for IGF-I but not Spi 2.1. Cycloheximide did not antagonize the inhibitory effects of TNF on GH-inducible IGF-I expression. We conclude the inhibitory effects of TNF on GH-inducible promoter activity are mediated by NFκB, especially p65, by a mechanism that does not require protein synthesis.

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23

NAKAMURA, K., N. YOKOYAMA, and I. IGARASHI. "Cyclin-dependent kinase inhibitors block erythrocyte invasion and intraerythrocytic development of Babesia bovis in vitro." Parasitology 134, no. 10 (July 18, 2007): 1347–53. http://dx.doi.org/10.1017/s0031182007002831.

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SUMMARYCyclin-dependent kinases (CDKs) are essential for the regulation of the eukaryotic cell cycle. A number of chemicals, which selectively inhibit the CDK activities, have been synthesized for the development of anti-cancer drugs. This report describes the inhibitory effect of purine derivatives known to be CDK inhibitors on the asexual growth of Babesia bovis. The 4 compounds, roscovitine, purvalanol A, CGP74514A, and CDK2 Inhibitor II, showed significantly suppressive effects on the in vitro growth of B. bovis. Three (roscovitine, purvalanol A, and CDK2 Inhibitor II) showed an inhibitory effect on the early stages of intraerythrocytic development of B. bovis. CGP74514A (CDK1-specific inhibitor) blocked the erythrocyte invasion by merozoites. Our data suggest the chemotherapeutic potential of the CDK inhibitors for babesiosis, and the target molecules of the compounds would participate in the process of successful erythrocyte invasion or intraerythrocytic development of B. bovis.

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24

NAKAMURA, KAZUO, KOICHI YAMAGUCHI, TOSHIRO MOTOYA, SHUJI HASHIMOTO, and MARUO ISHIBASHI. "Inhibitory effects of various protease inhibitors on complement-mediated hemolysis." Japanese Journal of Hospital Pharmacy 14, no. 5 (1988): 339–46. http://dx.doi.org/10.5649/jjphcs1975.14.339.

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25

Tang, Cuiping, and Deqing Liang. "Inhibitory effects of novel green inhibitors on gas hydrate formation." Chinese Journal of Chemical Engineering 27, no. 9 (September 2019): 2107–17. http://dx.doi.org/10.1016/j.cjche.2019.02.016.

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26

Sidwell, Robert W., Donald F. Smee, John H. Huffman, Dale L. Barnard, Kevin W. Bailey, John D. Morrey, and Y. S. Babu. "In Vivo Influenza Virus-Inhibitory Effects of the Cyclopentane Neuraminidase Inhibitor RWJ-270201." Antimicrobial Agents and Chemotherapy 45, no. 3 (March 1, 2001): 749–57. http://dx.doi.org/10.1128/aac.45.3.749-757.2001.

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ABSTRACT The cyclopentane influenza virus neuraminidase inhibitor RWJ-270201 was evaluated against influenza A/NWS/33 (H1N1), A/Shangdong/09/93 (H3N2), A/Victoria/3/75 (H3N2), and B/Hong Kong/05/72 virus infections in mice. Treatment was by oral gavage twice daily for 5 days beginning 4 h pre-virus exposure. The influenza virus inhibitor oseltamivir was run in parallel, and ribavirin was included in studies with the A/Shangdong and B/Hong Kong viruses. RWJ-270201 was inhibitory to all infections using doses as low as 1 mg/kg/day. Oseltamivir was generally up to 10-fold less effective than RWJ-270201. Ribavirin was also inhibitory but was less tolerated by the mice at the 75-mg/kg/day dose used. Disease-inhibitory effects included prevention of death, lessening of decline of arterial oxygen saturation, inhibition of lung consolidation, and reduction in lung virus titers. RWJ-270201 and oseltamivir, at doses of 10 and 1 mg/kg/day each, were compared with regard to their effects on daily lung parameters in influenza A/Shangdong/09/93 virus-infected mice. Maximum virus titer inhibition was seen on day 1, with RWJ-270201 exhibiting the greater inhibitory effect, a titer reduction of >104 cell culture 50% infective doses (CCID50)/g. By day 8, the lung virus titers in mice treated with RWJ-270201 had declined to 101.2 CCID50/g, whereas titers from oseltamivir-treated animals were >103CCID50/g. Mean lung consolidation was also higher in the oseltamivir-treated animals on day 8. Both neuraminidase inhibitors were well tolerated by the mice. RWJ-270201 was nontoxic at doses as high as 1,000 mg/kg/day. These data indicate potential for the oral use of RWJ-270201 in the treatment of influenza virus infections in humans.

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27

Ercan-Fang, Nacide, Miriam R. Taylor, Judith L. Treadway, Carolyn B. Levy, Paul E. Genereux, E. Michael Gibbs, Virginia L. Rath, Younggil Kwon, Mary C. Gannon, and Frank Q. Nuttall. "Endogenous effectors of human liver glycogen phosphorylase modulate effects of indole-site inhibitors." American Journal of Physiology-Endocrinology and Metabolism 289, no. 3 (September 2005): E366—E372. http://dx.doi.org/10.1152/ajpendo.00264.2004.

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Phosphorylase is regulated by a number of small-molecular-weight effectors that bind to three sites on the enzyme. Recently, a fourth site referred to as the indole-inhibitor site has been identified. Synthetic compounds bind to the site and inhibit activity. However, the effects of these compounds in the presence of other endogenous effectors are unknown. We have determined the effects of four indole derivative glycogen phosphorylase inhibitors (GPI) on recombinant human liver glycogen phosphorylase a activity. The GPIs tested were all potent inhibitors. However, the endogenous inhibitors (glucose, ADP, ATP, fructose 1-phosphate, glucose 6-phosphate, UDP-glucose) and the activator (AMP) markedly reduced the inhibitory effect of GPIs. Consistent with these in vitro findings, the IC50 for the inhibition of glycogenolysis in cells and the liver drug concentration associated with glucose-lowering activity in diabetic ob/ ob mice in vivo were also significantly higher than those determined in in vitro enzyme assays. The inhibitory effect of indole-site effectors is modulated by endogenous small-molecular-weight effectors of phosphorylase a activity. However, at higher concentrations (10–30 μM), the GPI effect was dominant and resulted in inhibition of phosphorylase a activity irrespective of the presence or absence of the other modulators of the enzyme.

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28

Sun, Xuemei, Judith E. Layton, Andrew Elefanty, and Graham J. Lieschke. "Comparison of effects of the tyrosine kinase inhibitors AG957, AG490, and STI571 on BCR-ABL–expressing cells, demonstrating synergy between AG490 and STI571." Blood 97, no. 7 (April 1, 2001): 2008–15. http://dx.doi.org/10.1182/blood.v97.7.2008.

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Abstract STI571 (formerly CGP57148) and AG957 are small molecule inhibitors of the protein tyrosine kinase (PTK) p145abland its oncogenic derivative p210bcr-abl. AG490 is an inhibitor of the PTK Janus kinase 2 (JAK2). No direct comparison of these inhibitors has previously been reported, so this study compared their effects on factor-dependent FDC-P1, 32D, and MO7e cells and their p210bcr-abl-expressing factor-independent derivatives. STI571 was a more potent inhibitor of3H-thymidine incorporation in p210bcr-abl-expressing cells than was AG957, and it showed superior discrimination between inhibitory effects on parental cell lines and effects on their p210bcr-abl-expressing derivatives. Assays performed with and without growth factor demonstrated that STI571 but not AG957 reversed the p210bcr-abl-driven factor independence of cell lines. p210bcr-abl-expressing cells were less sensitive to AG490 than to AG957 or STI571. However, for p210bcr-abl-expressing clones from all 3 cell lines, synergistic inhibition was demonstrated between STI571 and concentrations of AG490 with no independent inhibitory effect. Inhibition of nucleic acid synthesis with AG957 treatment was associated with reduced cell numbers, reduced viability, and small pyknotic apoptotic cells. At concentrations of STI571 that reversed the p210bcr-abl factor-independent phenotype, STI571 treatment and growth factor deprivation together were sufficient to induce apoptosis. This study concludes that, for the cell lines studied, (1) STI571 is a more potent and more selective inhibitor of a p210bcr-abl-dependent phenotype than AG957; (2) AG490 synergizes with STI571 to enhance its inhibitory effect on p210bcr-abl-driven proliferation; and (3) the combination of p210bcr-abl-tyrosine kinase inhibition and growth factor signal withdrawal can be sufficient to induce apoptotic death of transformed cells.

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Hatton, C. J., and C. Peers. "Effects of cytochrome P-450 inhibitors on ionic currents in isolated rat type I carotid body cells." American Journal of Physiology-Cell Physiology 271, no. 1 (July 1, 1996): C85—C92. http://dx.doi.org/10.1152/ajpcell.1996.271.1.c85.

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Hypoxic chemoreception in the carotid body involves selective inhibition of K+ channels in type I cells. We have investigated whether cytochrome P-450 may act as an O2 sensor coupling hypoxia to K+ channel inhibition, by investigating the actions of P-450 inhibitors to modulate channel activity (recorded using patch-clamp techniques) in type I cells isolated from 8-to 12-day-old rat pups. The imidazole antimycotic P-450 inhibitors miconazole and clotrimazole (1-10 microM) inhibited the Ca(2+)-activated (KCa) and voltage-gated K+ (Kv) currents in isolated type I cells. Single-channel recordings indicated that the KCa channels could be inhibited directly by miconazole. Miconazole also irreversibly inhibited Ca2+ channel currents. By contrast, acute application of the suicide substrate P-450 inhibitor, 1-aminobenzotriazole (1-ABT; 3 mM) was without effect on K+ or Ca2+ currents. Hypoxia (16-23 mmHg) reversibly inhibited K+ currents and prevented the inhibitory actions of miconazole. Furthermore, the inhibitory actions of miconazole could be partially reversed by hypoxia. Pretreatment of cells for 60 min with 3 mM 1-ABT substantially reduced the inhibitory actions of hypoxia on K+ currents. Our results indicate that imidazole antimycotic P-450 inhibitors can directly and nonselectively inhibit ionic channels in type I cells but, more importantly, provide evidence to suggest that hypoxic inhibition of K+ currents in type I cells is mediated in part at least by cytochrome P-450.

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30

Yan, Daojing, Jiakun Xu, Xiang Wang, Jiaxing Zhang, Gang Zhao, Yingwu Lin, and Xiangshi Tan. "Spiro-Oxindole Skeleton Compounds Are Efficient Inhibitors for Indoleamine 2,3-Dioxygenase 1: An Attractive Target for Tumor Immunotherapy." International Journal of Molecular Sciences 23, no. 9 (April 23, 2022): 4668. http://dx.doi.org/10.3390/ijms23094668.

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Indoleamine 2,3-dioxygenase 1 (IDO1) is an attractive heme enzyme for its significant function in cancer immunotherapy. Potent IDO1 inhibitors have been discovered for decades, whereas no clinical drugs are used for cancer treatment up to now. With the goal of developing medically valuable IDO inhibitors, we performed a systematic study of SAR405838 analogs with a spiro-oxindole skeleton in this study. Based on the expression and purification of human IDO1, the inhibitory activity of spiro-oxindole skeleton compounds to IDO1 was evaluated by IC50 and Ki values. The results demonstrated that inhibitor 3 exhibited the highest IDO1 inhibitory activity with IC50 at 7.9 μM among all inhibitors, which is ~six-fold of the positive control (4−PI). Moreover, inhibitor 3 was found to have the most effective inhibition of IDO1 in MCF-7 cancer cells without toxic effects. Molecular docking analysis revealed that the hydrophobic interaction stabilized the binding of inhibitor 3 to the IDO1 active site and made an explanation for the uncompetitive mode of inhibitors. Therefore, this study provides valuable insights into the screen of more potent IDO1 inhibitors for cancer immunotherapy.

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31

Degtjarjov, F. "Evaluation of mineral and organic inhibitor effects on bentonite clay." Georesursy 20, no. 4 (November 30, 2018): 355–58. http://dx.doi.org/10.18599/grs.2018.4.355-358.

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The supra-salt complex of the oilfield of the Republic of Belarus is represented by high-colloidal multicolored clay deposits with layers of unstable sandstones and aleurolites evenly distributed throughout the section. Drilling of intervals which are represented by clay sediments is accompanied by complications caused by swelling of clays – stuck, tightening, sticking clay on the drilling tool. Swelling occurs during drilling of high-colloidal clays. As a result of the action of the drilling mud and its filtrate, the clay swells, narrowing the trunk and reducing the stability of the walls of well. For the prevention or maximum reduction of the intensity of the swelling the drilling mud must have a high inhibitory ability. Such properties are attached by special reagents-inhibitors, which are the main component of the inhibiting drilling fluid. The creation of such drilling fluid is advisable to start with the choice of the reagent-inhibitor. This article provides a comparison of the inhibitory effect of the two reagents specific to organic (Polyekol) and inorganic (potassium chloride) compounds. To assess the effectiveness of these reagents, the indicator of moisturizing ability was used. In the experiment, the highest efficiency demonstrated organic reagent-inhibitor Polyekol at a concentration of 2%, and the inorganic reagent-inhibitor potassium chloride resulted in cracking of samples. The results obtained during the comparison of these reagents will form the basis for the development of an inhibiting drilling mud for drilling of the supra-salt deposits of the Pripyat trough.

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Macková, Anna, Pavel Mučaji, Ute Widowitz, and Rudolf Bauer. "In vitro Anti-inflammatory Activity of Ligustrum vulgare Extracts and Their Analytical Characterization." Natural Product Communications 8, no. 11 (November 2013): 1934578X1300801. http://dx.doi.org/10.1177/1934578x1300801102.

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Interest in the anti-inflammatory effects of Ligustrum vulgare L., which has been used traditionally in China and Japan prompted us to determine anti-inflammatory effects of the plant's compounds in leukocytes. The leaves of L. vulgare were used to prepare a decoction which was successively extracted with organic solvents (dichloromethane (DCM), n-butanol, ethyl acetate) using liquid-liquid partition. Extracts were tested for inhibition of LTB4, resp. PGE2 biosynthesis. Each extract was evaluated for its in vitro cyclooxygenase-1/2 (COX-1/2) inhibitory activity using assays with purified COX-1 and COX-2 enzymes, as well as for their LTB4 formation inhibitory activity using an assay with activated human neutrophil granulocytes. All extracts reported inhibitory actions against COXs in comparison with the synthetic inhibitors NS-398 (IC50 = 2.6 μM) and indomethacin (IC50 = 0.9 μM). The dichloromethane extract of privet leaves showed a considerable inhibitory effect against COX-1 and COX-2 enzyme activity. The DCM extract revealed 2.7 times higher inhibitory activity against LTB4 formation in comparison with the known specific LT inhibitor zileuton (IC50 = 5.0 μM). Additionally, oleuropein and echinacoside were detected by HPLC-DAD and LC-MS in the Ligustrum vulgare leaves. Both compounds exhibited weak inhibitory activity on cyclooxygenases and leukotriene formation.

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33

Tan, Shixiong, Yvonne Ng, and David E. James. "Next-generation Akt inhibitors provide greater specificity: effects on glucose metabolism in adipocytes." Biochemical Journal 435, no. 2 (March 29, 2011): 539–44. http://dx.doi.org/10.1042/bj20110040.

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Many human tumours exhibit activation of the PI3K (phosphoinositide 3-kinase)/Akt pathway, and inhibition of this pathway slows tumour growth. This led to the development of specific Akt inhibitors for in vivo use. However, activation of Akt is also necessary for processes including glucose metabolism. Therefore a potential complication of such anticancer drugs is insulin resistance and/or diabetes. In the process of characterizing the metabolic effects of early-phase Akt inhibitors, we discovered an off-target inhibitory effect on mammalian facilitative glucose transporters. In view of the crucial role of glucose transport for all mammalian cells, such an off-target effect would have major implications for further development of this family of compounds. In the present study, we have characterized a next-generation Akt inhibitor, MK-2206. MK-2206 is an orally active allosteric Akt inhibitor under development for treating solid tumours. We report that MK-2206 potently inhibits Thr308Akt and Ser473Akt phosphorylation in 3T3-L1 adipocytes (IC50 0.11 and 0.18 μM respectively) as well as downstream effects of insulin on GLUT4 (glucose transporter 4) translocation (IC50 0.47 μM) and glucose transport (IC50 0.14 μM). Notably, the potency of MK-2206 is approximately 1 log higher than previous inhibitors and its specificity is significantly improved with modest inhibitory effects on glucose transport in GLUT4-expressing adipocytes and GLUT1-rich human erythrocytes, independently of Akt. Nevertheless, MK-2206 clearly has potent effects on Akt2, the principal isoform involved in peripheral insulin action, in which case insulin resistance will probably be a major complication following in vivo administration. We conclude that MK-2206 provides an optimal tool for studying the effects of Akt in vitro.

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34

Lei, Xia, Fujun Shi, Debapriya Basu, Afroza Huq, Sophie Routhier, Robert Day, and Weijun Jin. "Proteolytic Processing of Angiopoietin-like Protein 4 by Proprotein Convertases Modulates Its Inhibitory Effects on Lipoprotein Lipase Activity." Journal of Biological Chemistry 286, no. 18 (March 12, 2011): 15747–56. http://dx.doi.org/10.1074/jbc.m110.217638.

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Angiopoietin-like protein 4 (ANGPTL4) has been associated with a variety of diseases. It is known as an endogenous inhibitor of lipoprotein lipase (LPL), and it modulates lipid deposition and energy homeostasis. ANGPTL4 is cleaved by unidentified protease(s), and the biological importance of this cleavage event is not fully understood with respect to its inhibitory effect on LPL activity. Here, we show that ANGPTL4 appears on the cell surface as the full-length form, where it can be released by heparin treatment in culture and in vivo. ANGPTL4 protein is then proteolytically cleaved into several forms by proprotein convertases (PCs). Several PCs, including furin, PC5/6, paired basic amino acid-cleaving enzyme 4, and PC7, are able to cleave human ANGPTL4 at a consensus site. PC-specific inhibitors block the processing of ANGPTL4. Blockage of ANGPTL4 cleavage reduces its inhibitory effects on LPL activity and decreases its ability to raise plasma triglyceride levels. In summary, the cleavage of ANGPTL4 by these PCs modulates its inhibitory effect on LPL activity.

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Tado, Motoki, Takayuki Abe, Toshifumi Hatta, Masahide Ishikawa, Susumu Nakada, Tomoyuki Yokota, and Hiroshi Takaku. "Inhibitory Effect of Modified 5′-Capped Short RNA Fragments on Influenza Virus RNA Polymerase Gene Expression." Antiviral Chemistry and Chemotherapy 12, no. 6 (December 2001): 353–58. http://dx.doi.org/10.1177/095632020101200605.

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We have shown previously that the 5′-capped short phosphodiester RNA fragments, Cap decoy, (Gm 12 nt) are potent inhibitors of influenza virus RNA polymerase gene expression. Here we investigate the modified capped RNA derivative containing phosphorothioate oligonucleotides (Cap decoy) as a potential influenza virus RNA polymerase inhibitor. The modified 5′-capped short phosphorothioate RNA fragments (Gms 12–15 nt) with the 5′-capped structure (m7GpppGm) were synthesized by T7 RNA polymerase. The 5′-capped short RNA fragments (Gms 12–15 nt) were encapsulated in liposome particulates and tested for their inhibitory effects on influenza virus RNA polymerase gene expression in the clone 76 cells. The 12–15 nt long Gms RNA fragments showed highly inhibitory effects. By contrast, the inhibitory effects of the 13 nt long short RNA fragments (Gm 13 nt) were considerably less in comparison with the 5′-capped short phosphorothioate RNA fragments (Gms 12–15 nt). In particular, the various Gms RNA chain lengths showed no significant differences in the inhibition of influenza virus RNA polymerase gene expression. Furthermore, the capped RNA with a phosphorothioate backbone was resistant to nuclease activity. These phosphorothioate RNA fragments exhibited higher inhibitory activity than the 5′-capped short RNA fragments (Gm 12 nt). These decoys may prove to be useful in anti-influenza virus therapeutics.

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36

Poncet, Delphine, Anne-Laure Pauleau, Gyorgy Szabadkai, Angelo Vozza, Sebastian R. Scholz, Morgane Le Bras, Jean-Jacques Brière, et al. "Cytopathic effects of the cytomegalovirus-encoded apoptosis inhibitory protein vMIA." Journal of Cell Biology 174, no. 7 (September 18, 2006): 985–96. http://dx.doi.org/10.1083/jcb.200604069.

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Replication of human cytomegalovirus (CMV) requires the expression of the viral mitochondria–localized inhibitor of apoptosis (vMIA). vMIA inhibits apoptosis by recruiting Bax to mitochondria, resulting in its neutralization. We show that vMIA decreases cell size, reduces actin polymerization, and induces cell rounding. As compared with vMIA-expressing CMV, vMIA-deficient CMV, which replicates in fibroblasts expressing the adenoviral apoptosis suppressor E1B19K, induces less cytopathic effects. These vMIA effects can be separated from its cell death–inhibitory function because vMIA modulates cellular morphology in Bax-deficient cells. Expression of vMIA coincided with a reduction in the cellular adenosine triphosphate (ATP) level. vMIA selectively inhibited one component of the ATP synthasome, namely, the mitochondrial phosphate carrier. Exposure of cells to inhibitors of oxidative phosphorylation produced similar effects, such as an ATP level reduced by 30%, smaller cell size, and deficient actin polymerization. Similarly, knockdown of the phosphate carrier reduced cell size. Our data suggest that the cytopathic effect of CMV can be explained by vMIA effects on mitochondrial bioenergetics.

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37

Wilson, J. A., D. Johnston, J. Penston, and K. G. Wormsley. "Gastric inhibitory effects of CM57755." European Journal of Clinical Pharmacology 30, no. 1 (1986): 33–36. http://dx.doi.org/10.1007/bf00614192.

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38

Asin-Milan, Odalis, Mohamed Sylla, Mohamed El-Far, Geneviève Belanger-Jasmin, Alpha Haidara, Julie Blackburn, Annie Chamberland, and Cécile L. Tremblay. "Synergistic Combinations of the CCR5 Inhibitor VCH-286 with Other Classes of HIV-1 Inhibitors." Antimicrobial Agents and Chemotherapy 58, no. 12 (September 29, 2014): 7565–69. http://dx.doi.org/10.1128/aac.03630-14.

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ABSTRACTHere, we evaluated thein vitroanti-HIV-1 activity of the experimental CCR5 inhibitor VCH-286 as a single agent or in combination with various classes of HIV-1 inhibitors. Although VCH-286 used alone had highly inhibitory activity, paired combinations with different drug classes led to synergistic or additive interactions. However, combinations with other CCR5 inhibitors led to effects ranging from synergy to antagonism. We suggest that caution should be exercised when combining CCR5 inhibitorsin vivo.

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39

Chen, Xianxian, Chenyi Wang, Jiajia Fu, Zhaowei Huang, and Shaoqi Wang. "Research Status and Progress of Inhibitory Effects and Inhibitory Mechanism of Complex-Type Urease Inhibitors - A Review." Communications in Soil Science and Plant Analysis 50, no. 6 (March 5, 2019): 772–81. http://dx.doi.org/10.1080/00103624.2019.1579826.

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40

F. F. Liu, A.H. Zhang, F. J. Lei, J. Zhang, Y.H. Xu, M. J. Yin, and L.X. Zhang. "Inhibitory effects of Panax ginseng stem and leaf ginsenosides against Fusarium solani." Allelopathy Journal 40, no. 2 (March 2017): 163–72. http://dx.doi.org/10.26651/2017-40-1-1075.

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41

F. F. Liu, A.H. Zhang, F. J. Lei, J. Zhang, Y.H. Xu, M. J. Yin, and L.X. Zhang. "Inhibitory effects of Panax ginseng stem and leaf ginsenosides against Fusarium solani." Allelopathy Journal 40, no. 2 (March 2017): 163–72. http://dx.doi.org/10.26651/2017-40-2-1075.

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Quiroz, Sara, Isabel C. Henao Castañeda, Johan Granados, Arley Camilo Patiño, Lina María Preciado, and Jaime Andrés Pereañez. "Inhibitory Effects of Varespladib, CP471474, and Their Potential Synergistic Activity on Bothrops asper and Crotalus durissus cumanensis Venoms." Molecules 27, no. 23 (December 6, 2022): 8588. http://dx.doi.org/10.3390/molecules27238588.

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Snakebite is a neglected tropical disease that causes extensive mortality and morbidity in rural communities. Antivenim sera are the currently approved therapy for snake bites; however, they have some therapeutic limitations that have been extensively documented. Recently, small molecule toxin inhibitors have received significant attention as potential alternatives or co-adjuvant to immunoglobulin-based snakebite therapies. Thus, in this study, we evaluated the inhibitory effects of the phospholipase A2 inhibitor varespladib and the metalloproteinase inhibitor CP471474 and their synergistic effects on the lethal, edema-forming, hemorrhagic, and myotoxic activities of Bothrops asper and Crotalus durissus cumanensis venoms from Colombia. Except for the preincubation assay of the lethal activity with B. asper venom, the mixture showed the best inhibitory activity. Nevertheless, the mix did not display statistically significant differences to varespladib and CP471474 used separately in all assays. In preincubation assays, varespladib showed the best inhibitory activity against the lethal effect induced by B. asper venom. However, in independent injection assays, the mix of the compounds partially inhibited the lethal activity of both venoms (50%). In addition, in the assays to test the inhibition of edema-forming activity, the mixture exhibited the best inhibitory activity, followed by Varespladib, but without statistically significant differences (p > 0.05). The combination also decreased the myotoxic activity of evaluated venoms. In these assays, the mix showed statistical differences regarding CP471474 (p < 0.05). The mixture also abolished the hemorrhagic activity of B. asper venom in preincubation assays, with no statistical differences to CP471474. Finally, the mixture showed inhibition in studies with independent administration in a time-dependent manner. To propose a mode of action of varespladib and CP471474, molecular docking was performed. PLA2s and SVMPs from tested venoms were used as targets. In all cases, our molecular modeling results suggested that inhibitors may occupy the substrate-binding cleft of the enzymes, which was supported by specific interaction with amino acids from the active site, such as His48 for PLA2s and Glu143 for the metalloproteinase. In addition, varespladib and CP471474 also showed interaction with residues from the hydrophobic channel in PLA2s and substrate binding subsites in the SVMP. Our results suggest a synergistic action of the mixed inhibitors and show the potential of varespladib, CP471474, and their mixture to generate new treatments for snakebite envenoming with application in the field or as antivenom co-adjuvants.

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Chang, Yan-xu, Ai-hua Ge, Yan Jiang, John Teye Azietaku, Jin Li, and Xiu-mei Gao. "A Bioactivity-Based Method for Screening, Identification of Lipase Inhibitors, and Clarifying the Effects of Processing Time on Lipase Inhibitory Activity of Polygonum Multiflorum." Evidence-Based Complementary and Alternative Medicine 2016 (2016): 1–10. http://dx.doi.org/10.1155/2016/5965067.

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Traditional Chinese medicine (TCM) has been used for the treatment of many complex diseases. However, the bioactive components are always undefined. In this study, a bioactivity-based method was developed and validated to screen lipase inhibitors and evaluate the effects of processing on the lipase inhibitory activity of TCM by ultrahigh performance liquid chromatography coupled with quadrupole-time-of-flight mass spectrometry and fraction collector (UHPLC/Q-TOF-MS-FC). The results showed that bothPolygonum multiflorumand processedP. multiflorumextracts had inhibitory effect against lipase with IC50values of 38.84 μg/mL and 190.6 μg/mL, respectively. Stilbenes, phenolic acid, flavonoids, and anthraquinones were considered to be the potential lipase inhibitors. Eleven potential lipase inhibitors were simultaneously determined by UHPLC. Principal component analysis (PCA) was employed in exploring the effects of processing time on lipase inhibitory activity ofP. multiflorum. Compared with conventional methods, a bioactivity-based method could quantitatively analyze lipase inhibitory activity of individual constituent and provide the total lipase inhibitory activity of the samples. The results demonstrated that the activity integrated UHPLC/Q-TOF-MS-FC method was an effective and powerful tool for screening and identifying lipase inhibitors from traditional Chinese medicines.

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HODOHARA, Keiko, Yoshihide FUJIYAMA, Shiro HOSODA, and Kohjiro YASUNAGA. "Mechanism of inhibitory effects of serine protease inhibitors of platelet aggregation." Blood & Vessel 18, no. 3 (1987): 229–31. http://dx.doi.org/10.2491/jjsth1970.18.229.

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Kim, Chang, Sang Noh, Yujin Park, Dongwan Kang, Pusoon Chun, Hae Chung, Hee Jung та Hyung Moon. "A Potent Tyrosinase Inhibitor, (E)-3-(2,4-Dihydroxyphenyl)-1-(thiophen-2-yl)prop-2-en-1-one, with Anti-Melanogenesis Properties in α-MSH and IBMX-Induced B16F10 Melanoma Cells". Molecules 23, № 10 (22 жовтня 2018): 2725. http://dx.doi.org/10.3390/molecules23102725.

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In this study, we designed and synthesized eight thiophene chalcone derivatives (1a–h) as tyrosinase inhibitors and evaluated their mushroom tyrosinase inhibitory activities. Of these eight compounds, (E)-3-(2,4-dihydroxyphenyl)-1-(thiophen-2-yl)prop-2-en-1-one (1c) showed strong competitive inhibition activity against mushroom tyrosinase with IC50 values of 0.013 μM for tyrosine hydroxylase and 0.93 μM for dopa oxidase. In addition, we used enzyme kinetics study and docking program to further evaluate the inhibitory mechanism of 1c toward tyrosinase. As an underlying mechanism of 1c mediated anti-melanogenic effect, we investigated the inhibitory activity against melanin contents and cellular tyrosinase in B16F10 melanoma cells. As the results, the enzyme kinetics and docking results supports that 1c highly interacts with tyrosinase residues in the tyrosinase active site and it can directly inhibit tyrosinase as competitive inhibitor. In addition, 1c exhibited dose-dependent inhibitory effects in melanin contents and intracellular tyrosinase on α-MSH and IBMX-induced B16F10 cells. Overall, our results suggested that 1c might be considered potent tyrosinase inhibitor for use in the development of therapeutic agents for diseases associated with hyperpigment disorders.

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Wang, Fan, and Sheng-Jun Wang. "Effects of Inhibitory Signal on Criticality in Excitatory-Inhibitory Networks." Communications in Theoretical Physics 71, no. 6 (June 2019): 746. http://dx.doi.org/10.1088/0253-6102/71/6/746.

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Goto, Akira, Yoshihiro Matsui, Kunio Ohyama, Motoo Arai та Sawao Murao. "Inhibitory Effects of the Proteinaceousα-Amylase Inhibitor Haim on Animalα-Amylase". Agricultural and Biological Chemistry 49, № 2 (лютий 1985): 435–39. http://dx.doi.org/10.1080/00021369.1985.10866734.

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Tang, Liang, Clark Pan, Harpartap Atwal, Jennifer Nixon, Thomas Barnett, John E. Murphy, Baisong Mei, and Michael Fournel. "PEGylation of Factor VIII Reduces the Inhibitory Effects of Human Antibody Inhibitors on the Factor VIII Molecule." Blood 108, no. 11 (November 16, 2006): 4017. http://dx.doi.org/10.1182/blood.v108.11.4017.4017.

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Abstract Replacement therapy with plasma-derived or recombinant Factor VIII (FVIII) has successfully reduced mortality and morbidity and improved the quality of life for patients with hemophilia A. However, up to 30% of patients develop antibody inhibitors to the FVIII molecule. Inhibitors reduce the efficacy of FVIII, increase the cost of treatment, and greatly increase the risk for life-threatening bleeding events in these patients. In the hopes of developing a more efficacious FVIII therapeutic for hemophilia A patients with inhibitors, we initiated studies on the PEGylation of B-region deleted FVIII (FVIII-BDD) with different sizes of polyethylene glycol (PEG) and investigated the inhibitory effects of anti-FVIII inhibitors on the activity of PEGylated FVIII-BDDs. Applying a site-specific mutagenesis technique to the FVIII-BDD molecule, an amino-acid residue at the inhibitor binding site was changed to cysteine. Mutated FVIII-BDD was purified and PEG molecules of different sizes were added at the mutation sites through a chemical reaction with the maleimide group on the activated PEG. PEGylated FVIII-BDD molecules were further purified and tested for FVIII activity using the chromogenic assay. To investigate the effects of antibody inhibitors on the PEGylated FVIII-BDD, studies were carried out utilizing inhibitory plasmas collected from 8 hemophilia A patients with confirmed inhibitors and different monoclonal antibodies as controls. Of the 8 patient plasmas tested, 43 kD PEGylated FVIII-BDD was more resistant to antibody inhibitors in 4 patient plasma samples than unmodified FVIII-BDD. In one sample, pre-incubation of FVIII-BDD with inhibitor patient plasma (1:15 dilution) reduced FVIII activity to 5% of the originally activity added, according to the chromogenic assay. By contrast, approximately 20% of original activity was retained for monoPEGylated FVIII-BDD and >40% activity was retained for diPEGylated FVIII-BDD. Overall, the results suggest that PEGylated FVIII-BDDs may retain more FVIII activity in the presence of some FVIII antibody inhibitors compared to FVIII-BDD. It is important to note that there was a positive correlation between the size of PEG added to FVIII-BDD and the amount of FVIII activity retained. This study indicates that the addition of PEG to FVIII molecules through site-specific PEGylation has the potential to increase the resistance of FVIII to the effects of some antibody inhibitors in patients with hemophilia A.

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Lance, Richard F., and Xin Guan. "Variation in inhibitor effects on qPCR assays and implications for eDNA surveys." Canadian Journal of Fisheries and Aquatic Sciences 77, no. 1 (January 2020): 23–33. http://dx.doi.org/10.1139/cjfas-2018-0263.

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Aquatic environmental DNA (eDNA) surveys are sometimes impacted by polymerase chain reaction (PCR) inhibitors. We tested varying concentrations of different inhibitors (humic, phytic, and tannic acids; crude leaf extracts) for impacts on quantitative PCR (qPCR) assays designed for eDNA surveys of bighead and silver carp (Hypophthalmichthys nobilis and Hypophthalmichthys molitrix). We also tested for inhibition by high concentrations of exogenous DNA, hypothesizing that DNA from increasingly closely related species would be increasingly inhibitory. All tested inhibitors impacted qPCR, though only at very high concentrations — likely a function, in part, of having used an inhibitor-resistant qPCR solution. Closer phylogenetic relatedness resulted in inhibition at lower exogenous DNA concentrations, but not at relatively close phylogenetic scales. Inhibition was also influenced by the qPCR reporter dye used. Importantly, different qPCR assays responded differently to the same inhibitor concentrations. Implications of these results are that the inclusion of more than one assay for the same target taxa in an eDNA survey may be an important countermeasure against false negatives and that internal positive controls may not, in the absence of efforts to maximize inhibition compatibility, provide useful information about the inhibition of an eDNA assay.

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Cao, Jiangying, Wei Zhao, Chunlong Zhao, Qian Liu, Shunda Li, Guozhen Zhang, C. James Chou, and Yingjie Zhang. "Development of a Bestatin-SAHA Hybrid with Dual Inhibitory Activity against APN and HDAC." Molecules 25, no. 21 (October 28, 2020): 4991. http://dx.doi.org/10.3390/molecules25214991.

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With five histone deacetylase (HDAC) inhibitors approved for cancer treatment, proteolysis-targeting chimeras (PROTACs) for degradation of HDAC are emerging as an alternative strategy for HDAC-targeted therapeutic intervention. Herein, three bestatin-based hydroxamic acids (P1, P2 and P3) were designed, synthesized and biologically evaluated to see if they could work as HDAC degrader by recruiting cellular inhibitor of apoptosis protein 1 (cIAP1) E3 ubiquitin ligase. Among the three compounds, the bestatin-SAHA hybrid P1 exhibited comparable even more potent inhibitory activity against HDAC1, HDAC6 and HDAC8 relative to the approved HDAC inhibitor SAHA. It is worth noting that although P1 could not lead to intracellular HDAC degradation after 6 h of treatment, it could dramatically decrease the intracellular levels of HDAC1, HDAC6 and HDAC8 after 24 h of treatment. Intriguingly, the similar phenomenon was also observed in the HDAC inhibitor SAHA. Cotreatment with proteasome inhibitor bortezomib could not reverse the HDAC decreasing effects of P1 and SAHA, confirming that their HDAC decreasing effects were not due to protein degradation. Moreover, all three bestatin-based hydroxamic acids P1, P2 and P3 exhibited more potent aminopeptidase N (APN, CD13) inhibitory activities than the approved APN inhibitor bestatin, which translated to their superior anti-angiogenic activities. Taken together, a novel bestatin-SAHA hybrid was developed, which worked as a potent APN and HDAC dual inhibitor instead of a PROTAC.

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