Inhibitory effects of 1-O-hexyl-2,3,5-trimethylhydroquinone (HTHQ), green tea catechins and other antioxidants on 2-amino-6-methyldipyrido[l,2-a: 3′ ,2′ -d]imidazole (Glu-P-1)-induced rat hepatocarcinogenesis and dose-dependent inhibition by HTHQ of lesion induction by Glu-P-1 or 2-amino-3,8-dimethylimidazo[4,5-f]quinoxaline (MeIQx)

1995 ◽  
Vol 16 (12) ◽  
pp. 3049-3055 ◽  
Author(s):  
Masao Hirose ◽  
Ryohei Hasegawa ◽  
Juki Kimura ◽  
Keisuke Akagi ◽  
Yasunori Yoshida ◽  
...  
Keyword(s):  
Green Tea ◽  
Inhibitory Effects ◽  
Tea Catechins ◽  
Green Tea Catechins ◽  
Dependent Inhibition ◽  
Dose Dependent Inhibition ◽  
Dose Dependent

scholarly journals Discovery of five HIV nucleoside analog reverse-transcriptase inhibitors (NRTIs) as potent inhibitors against the RNA-dependent RNA polymerase (RdRp) of SARS-CoV and 2019-nCoV

2020 ◽  
Author(s):  
Jialei Sun
Keyword(s):  
Rna Polymerase ◽  
Polymerase Activity ◽  
Inhibitory Effects ◽  
Rna Dependent Rna Polymerase ◽  
Nucleotide Analogs ◽  
Dependent Inhibition ◽  
Catalytic Metal ◽  
Dose Dependent Inhibition ◽  
Dose Dependent ◽  
Low Activity

AbstractThe outbreak of SARS in 2002-2003 caused by SARS-CoV, and the pandemic of COVID-19 in 2020 caused by 2019-nCoV (SARS-CoV-2), have threatened human health globally and raised the urgency to develop effective antivirals against the viruses. In this study, we expressed and purified the RNA-dependent RNA polymerase (RdRp) nsp12 of SARS-CoV and developed a primer extension assay for the evaluation of nsp12 activity. We found that nsp12 could efficiently extend single-stranded RNA, while having low activity towards double-stranded RNA. Nsp12 required a catalytic metal (Mg2+ or Mn2+) for polymerase activity and the activity was also K+-dependent, while Na+ promoted pyrophosphorylation, the reverse process of polymerization. To identify antivirals against nsp12, a competitive assay was developed containing 4 natural rNTPs and a nucleotide analog, and the inhibitory effects of 24 FDA-approved nucleotide analogs were evaluated in their corresponding active triphosphate forms. Ten of the analogs, including 2 HIV NRTIs, could inhibit the RNA extension of nsp12 by more than 40%. The 10 hits were verified which showed dose-dependent inhibition. In addition, the 24 nucleotide analogs were screened on SARS-CoV primase nsp8 which revealed stavudine and remdesivir were specific inhibitors to nsp12. Furthermore, the 2 HIV NRTIs were evaluated on 2019-nCoV nsp12 which showed inhibition as well. Then we expanded the evaluation to all 8 FDA-approved HIV NRTIs and discovered 5 of them, tenofovir, stavudine, abacavir, zidovudine and zalcitabine, could inhibit the RNA extension by nsp12 of SARS-CoV and 2019-nCoV. In conclusion, 5 FDA-approved HIV NRTIs inhibited the RNA extension by nsp12 and were promising candidates for the treatment of SARS and COVID-19.

scholarly journals Effects of cigarette smoke and its constituents on the adherence of polymorphonuclear leukocytes

1980 ◽  
Vol 29 (3) ◽  
pp. 1096-1101
Author(s):  
R B Bridges ◽  
L Hsieh ◽  
D G Haack
Keyword(s):  
Cigarette Smoke ◽  
Water Soluble ◽  
Inhibitory Effects ◽  
Partial Protection ◽  
Nylon Fiber ◽  
Dependent Inhibition ◽  
Dose Dependent Inhibition ◽  
In Vitro Effects ◽  
Dose Dependent

The in vitro effects of the water-soluble fraction of whole cigarette smoke (WSF) and two alpha, beta-unsaturated aldehydes of cigarette smoke (acrolein and crotonaldehyde) on polymorphonuclear leukocyte (PMNL) adherence were determined with nylon fiber columns. Each of these cigarette smoke constituents caused a dose-dependent inhibition of PMNL adherence. However, at least fivefold higher concentrations of these agents were necessary to inhibit adherence as compared with those necessary to achieve the same level of inhibition of PMNL chemotaxis. Furthermore, inhibition of adherence by WSF could be differentiated from its effects on chemotaxis in that reduced glutathione completely protected chemotaxis from the effects of WSF but only afforded partial protection to PMNL adherence. These data suggest that the inhibitory effects of WSF, acrolein, and crotonaldehyde on PMNL chemotaxis are not due to their inhibition of adherence. Finally, although PMNL adherence is considered to be an integral part of the chemotactic mechanism, differentiation between these two PMNL functions may be possible, since some inhibitors of chemotaxis do not have corresponding inhibitory effects on adherence.

scholarly journals Inhibitory Effects of Eight Green Tea Catechins on Cytochrome P450 1A2, 2C9, 2D6, and 3A4 Activities

2016 ◽  
Vol 19 (2) ◽  
pp. 188 ◽  
Author(s):  
Takashi Satoh ◽  
Haruka Fujisawa ◽  
Ami Nakamura ◽  
Natsuko Takahashi ◽  
Kazuhiro Watanabe
Keyword(s):  
Cytochrome P450 ◽  
Green Tea ◽  
Competitive Inhibition ◽  
Liver Microsomes ◽  
Inhibitory Effect ◽  
Dietary Habit ◽  
Inhibitory Effects ◽  
Tea Catechins ◽  
Green Tea Catechins ◽  
High Concentrations

PURPOSE: Green tea is a traditional beverage that has been enjoyed by the Japanese to this day. Recently, there has been an increase in the consumption of green tea beverage having high concentrations of catechins, such as (-)-epigallocatechin-3-O-gallate (EGCG). Many people tend to ingest large amounts of catechins through the frequent consumption of green tea beverage, and this dietary habit may lead to unwanted interactions between the catechins in green tea and medicinal drug. METHODS: The inhibitory effects of eight green tea catechins on drug metabolizing enzymes, cytochrome P450 (CYP) 1A2, 2C9, 2D6, and 3A4, were investigated in human liver microsomes. Incubation was initiated by the addition of cocktail probe drugs that served as specific substrates for each CYP, and the resulting metabolites were analyzed by LC-MS. RESULTS: From a comparison of the fifty percent inhibitory concentration (IC50) values of the eight green tea catechins, it was found that non-gallated catechins did not inhibit CYPs, whereas gallated catechins inhibited all CYPs except CYP2D6. Among them, CYP2C9 was most strongly inhibited by (-)-catechin-3-O-gallate (CG) (7.60 µM), and CYP1A2 was most strongly inhibited by EGCG (8.93 µM). Catechin gallate exhibited non-competitive inhibition of CYP2C9, and its Ki value was 9.76 ± 0.47µM. The present study is the first to report the inhibitory effect of CG on CYP2C9. In contrast, EGCG showed competitive inhibition of CYP1A2, and its Ki value was 14.3 ± 0.09 µM. CONCLUSION: Previous reports had predicted that plasma EGCG concentration reached 7.4 µM after ingesting green tea having high concentrations of catechins. That concentration of EGCG is equivalent to one-half to one-third of its Ki value for CYP1A2 and CYP3A4 in this study. The ingestion of beverages containing large amounts of green tea catechins together with drugs that are metabolized by CYP1A2, CYP2C9, and CYP3A4 should be avoided. This article is open to POST-PUBLICATION REVIEW. Registered readers (see “For Readers”) may comment by clicking on ABSTRACT on the issue’s contents page.

Comparison of the inhibitory effects of PYY(3-36) and PYY(1-36) on gastric emptying in rats

2004 ◽  
Vol 287 (5) ◽  
pp. R1064-R1070 ◽  
Author(s):  
Prasanth K. Chelikani ◽  
Alvin C. Haver ◽  
Roger D. Reidelberger
Keyword(s):  
Gastric Emptying ◽  
Intravenous Infusion ◽  
Peptide Yy ◽  
Molecular Forms ◽  
Inhibitory Effects ◽  
Dependent Inhibition ◽  
Order Of Magnitude ◽  
Dose Dependent Inhibition ◽  
Dose Dependent ◽  
The Brain

We compared the effects of the two molecular forms of the brain-gut peptide YY (PYY), PYY(1-36) and PYY(3-36), on gastric emptying. Unanesthetized rats received 20-min intravenous infusions of rat PYY(1-36) (0, 1.7, 5, 17, 50, 100, 170 pmol·kg−1·min−1) and rat PYY(3-36) (0, 0.5, 1.7, 5, 17, 50, 100, 170 pmol·kg−1·min−1), either alone or combined, and gastric emptying of saline was measured during the last 10 min of infusion. For comparison, human PYY(3-36) was administered at 0, 17, and 50 pmol·kg−1·min−1. Gastric emptying was decreased by 11, 24, 26 and 38% in response to 17, 50, 100, and 170 pmol·kg−1·min−1 of rat PYY(1-36); by 10, 26, 41, 53, and 57% in response to 5, 17, 50, 100, and 170 pmol·kg−1·min−1 of rat PYY(3-36); and by 35 and 53% in response to 17 and 50 pmol·kg−1·min−1 of human PYY(3-36), respectively. Estimated ED50s were 470 and 37 pmol·kg−1·min−1 for rat PYY(1-36) and PYY(3-36), respectively. In general, within an experiment, coadministration of PYY(1-36) and PYY(3-36) inhibited gastric emptying by an amount that was comparable to that produced when either peptide was given alone. We conclude that 1) intravenous infusion of PYY(1-36) and PYY(3-36) each produces a dose-dependent inhibition of gastric emptying in rats, 2) PYY(3-36) is an order of magnitude more potent than PYY(1-36) in inhibiting gastric emptying, 3) human PYY(3-36) and rat PYY(3-36) inhibit gastric emptying similarly, and 4) PYY(1-36) and PYY(3-36) do not appear to interact in an additive or synergistic manner to inhibit gastric emptying.

scholarly journals Effects of adenosine, 2-deoxyadenosine and N6-phenylisopropyladenosine on rat islet function and metabolism

1982 ◽  
Vol 204 (3) ◽  
pp. 689-696 ◽  
Author(s):  
Iain L. Campbell ◽  
Keith W. Taylor
Keyword(s):  
Cyclic Amp ◽  
Insulin Release ◽  
Biological Effects ◽  
Insulin Biosynthesis ◽  
Inhibitory Effects ◽  
Marked Inhibition ◽  
Cyclic Amp Accumulation ◽  
Dependent Inhibition ◽  
Dose Dependent Inhibition ◽  
Dose Dependent

Adenosine (1.0–100 μm). N6-phenylisopropyladenosine (0.1–10 μm) and 2-deoxyadenosine (10 mm) all produced a dose-dependent inhibition of glucose-stimulated insulin release. The inhibition of glucose-stimulated insulin release by adenosine and N6-phenylisopropyladenosine was abolished by 3-isobutyl-1-methylxanthine (0.1 mm), whereas 2-deoxyadenosine inhibited insulin release even in the presence of 3-isobutyl-1-methylxanthine. These adenosine nucleosides also inhibited the release of insulin induced by 4-methyl-2-oxopentanoate (20 mm), dl-glyceraldehyde (30 mm) and l-leucine (20 mm). Adenosine (10 μm). N6-phenylisopropyladenosine (10 μm) and 2-deoxyadenosine (10 mm) did not inhibit insulin biosynthesis or [U-14C]glucose oxidation at concentrations of the nucleosides that gave maximal inhibition of insulin release. However, adenosine, 2-deoxyadenosine and N6-phenylisopropyladenosine produced marked inhibition of the glucose-stimulated increases seen in islet cyclic AMP accumulation. Similar to its effects on insulin release, 3-isobutyl-1-methylxanthine (0.1 mm) antagonized the inhibitory effects of cyclic AMP accumulation produced by adenosine and N6-phenylisopropyladenosine, but had no effect on the inhibition of cyclic AMP accumulation seen with 2-deoxyadenosine. These results show that adenosine and its specifically modified analogues, 2-deoxyadenosine and N6-phenylisopropyladenosine, are strong inhibitors of insulin release from rat islets, a function that appears to be the consequence of their ability to inhibit the accumulation of cyclic AMP. It is proposed that the B cells, in common with many other tissues, may possess two different sites at which adenosine nucleosides interact to produce their biological effects; these are the so-called ‘P’ and ‘R’ sites first described by Londos & Wolff [(1977) Proc. Natl. Acad. Sci. U.S.A.74, 5482–5486].

Effects of leukotriene C4 on pancreatic secretion and circulation in dogs

1988 ◽  
Vol 254 (6) ◽  
pp. G849-G855
Author(s):  
S. J. Konturek ◽  
W. Pawlik ◽  
K. Czarnobilski ◽  
P. Gustaw ◽  
J. Jaworek ◽  
...  
Keyword(s):  
Pancreatic Secretion ◽  
Pancreatic Tissue ◽  
Leukotriene C4 ◽  
Inhibitory Effects ◽  
Maximal Inhibition ◽  
Control Value ◽  
Dependent Inhibition ◽  
Dose Dependent Inhibition ◽  
Protein Output ◽  
Dose Dependent

In the present study the effects of leukotriene C4 (LTC4) on exocrine pancreatic secretion and pancreatic blood flow were determined. LTC4 given intravenously in various doses ranging from 0.35 to 2.8 nmol.kg-1.h-1 in conscious dogs caused a dose-dependent inhibition of pancreatic HCO-3 and protein responses to exogenous hormones such as secretin, cholecystokinin octapeptide (CCK-8), and bombesin and to endogenous stimulants including meat feeding and duodenal perfusion with oleate. In tests with pancreatic secretion induced by secretin plus CCK, maximal inhibition by LTC4 occurred at a dose of 1.4 nmol.kg-1.h-1 and reached approximately 70% of the control value for HCO-3 output and 45% for protein output. In tests with separate secretin- or CCK-induced secretion, maximal inhibition occurred at a dose of 1.4 nmol.kg-1.h-1 and reached 38 and 66% of the control HCO-3 and protein secretion, respectively. The same dose of LTC4 reduced the postprandial HCO-3 secretion by approximately 80% and protein output by approximately 70%. After administration of indomethacin, the pancreatic secretion declined, but the inhibitory effects of LTC4 remained unchanged. Pancreatic tissue generated two to three times more LTC4 than the gastrointestinal mucosa, and indomethacin caused further increase in this generation, suggesting that LTC4 may contribute to indomethacin-induced pancreatic inhibition. (ABSTRACT TRUNCATED AT 250 WORDS)

Sign in / Sign up

Export Citation Format

Share Document