scholarly journals Inhibitory effects of pentamidine analogues on protein biosynthesis in vitro.

2000 ◽  
Vol 47 (1) ◽  
pp. 113-120 ◽  
Author(s):  
K Bielawski ◽  
A Galicka ◽  
A Bielawska ◽  
K Sredzińska
Keyword(s):  
Protein Biosynthesis ◽  
Elongation Factor ◽  
Inhibitory Effect ◽  
New Drugs ◽  
Clinical Use ◽  
Inhibitory Effects ◽  
Inhibit Protein Synthesis ◽  
Primary Target ◽  
Eukaryotic Elongation Factor

Pentamidine despite its rather high toxicity, is currently in clinical use. For development of new drugs of this type it is important to know the mechanism of their action. Two new amidines (I and II) and 4',6-diamidino-2-phenylindole (DAPI) were found in preliminary experiments to inhibit protein synthesis in vitro in the cell-free rat liver system. The three compounds differed in the precise mode of action. The inhibitory effect of I on the activity of the eukaryotic elongation factor eEF-2 and ribosomes seems to suggest that the binding site of eEF-2 on the ribosome was blocked by this compound. eEF-2 has been identified as the primary target of II and eEF-1 as the primary target of DAPI in the system studied.

In Vitro Effects of Ethanol on Rabbit Platelet Aggregation, Secretion of Granule Contents, and Cyclic AMP Levels in the Presence of Prostacyclin

1989 ◽  
Vol 61 (02) ◽  
pp. 254-258 ◽  
Author(s):  
Margaret L Rand ◽  
Peter L Gross ◽  
Donna M Jakowec ◽  
Marian A Packham ◽  
J Fraser Mustard
Keyword(s):  
Cyclic Amp ◽  
Inhibitory Effect ◽  
Rabbit Platelet ◽  
Inhibitory Effects ◽  
Low Concentrations ◽  
Rabbit Platelets ◽  
High Concentrations ◽  
In Vitro Effects ◽  
Aggregation Of Platelets

SummaryEthanol, at physiologically tolerable concentrations, inhibits platelet responses to low concentrations of collagen or thrombin, but does not inhibit responses of washed rabbit platelets stimulated with high concentrations of ADP, collagen, or thrombin. However, when platelet responses to high concentrations of collagen or thrombin had been partially inhibited by prostacyclin (PGI2), ethanol had additional inhibitory effects on aggregation and secretion. These effects were also observed with aspirin- treated platelets stimulated with thrombin. Ethanol had no further inhibitory effect on aggregation of platelets stimulated with ADP, or the combination of ADP and epinephrine. Thus, the inhibitory effects of ethanol on platelet responses in the presence of PGI2 were very similar to its inhibitory effects in the absence of PGI2, when platelets were stimulated with lower concentrations of collagen or thrombin. Ethanol did not appear to exert its inhibitory effects by increasing cyclic AMP above basal levels and the additional inhibitory effects of ethanol in the presence of PGI2 did not appear to be brought about by further increases in platelet cyclic AMP levels.

scholarly journals Identification of 3-chymotrypsin like protease (3CLPro) inhibitors as potential anti-SARS-CoV-2 agents

2021 ◽  
Vol 4 (1) ◽  
Author(s):  
Vicky Mody ◽  
Joanna Ho ◽  
Savannah Wills ◽  
Ahmed Mawri ◽  
Latasha Lawson ◽  
...  
Keyword(s):  
Inhibitory Effect ◽  
Dynamics Simulation ◽  
Simulation Studies ◽  
Inhibitory Effects ◽  
Major Threat ◽  
Main Protease ◽  
Approved Drugs ◽  
Fda Approved Drugs ◽  
Computational Molecular Modeling

AbstractEmerging outbreak of severe acute respiratory syndrome coronavirus-2 (SARS-CoV-2) infection is a major threat to public health. The morbidity is increasing due to lack of SARS-CoV-2 specific drugs. Herein, we have identified potential drugs that target the 3-chymotrypsin like protease (3CLpro), the main protease that is pivotal for the replication of SARS-CoV-2. Computational molecular modeling was used to screen 3987 FDA approved drugs, and 47 drugs were selected to study their inhibitory effects on SARS-CoV-2 specific 3CLpro enzyme in vitro. Our results indicate that boceprevir, ombitasvir, paritaprevir, tipranavir, ivermectin, and micafungin exhibited inhibitory effect towards 3CLpro enzymatic activity. The 100 ns molecular dynamics simulation studies showed that ivermectin may require homodimeric form of 3CLpro enzyme for its inhibitory activity. In summary, these molecules could be useful to develop highly specific therapeutically viable drugs to inhibit the SARS-CoV-2 replication either alone or in combination with drugs specific for other SARS-CoV-2 viral targets.

scholarly journals Amphetamine-Decreased Progesterone and Estradiol Release in Rat Granulosa Cells: The Regulatory Role of cAMP- and Ca2+-Mediated Signaling Pathways

Biomedicines ◽  
2021 ◽  
Vol 9 (5) ◽  
pp. 493
Author(s):  
 Chung-Yu Chen ◽  
Chien-Rung Chen ◽  
Chiao-Nan Chen ◽  
Paulus S. Wang ◽  
Toby Mündel ◽  
...  
Keyword(s):  
Granulosa Cells ◽  
Prostaglandin F2α ◽  
Inhibitory Effect ◽  
Inhibitory Effects ◽  
Steroidogenic Enzyme ◽  
Estradiol Secretion ◽  
Basal Release ◽  
Ca2 Channels

The purpose of this study is to evaluate the amphetamine effects on progesterone and estradiol production in rat granulosa cells and the underlying cellular regulatory mechanisms. Freshly dispersed rat granulosa cells were cultured with various test drugs in the presence of amphetamine, and the estradiol/progesterone production and the cytosolic cAMP level were measured. Additionally, the cytosolic-free Ca2+ concentrations ([Ca2+]i) were measured to examine the role of Ca2+ influx in the presence of amphetamine. Amphetamine in vitro inhibited both basal and porcine follicle-stimulating hormone-stimulated estradiol/progesterone release, and amphetamine significantly decreased steroidogenic enzyme activities. Adding 8-Bromo-cAMP did not recover the inhibitory effects of amphetamine on progesterone and estradiol release. H89 significantly decreased progesterone and estradiol basal release but failed to enhance a further amphetamine inhibitory effect. Amphetamine was capable of further suppressing the release of estradiol release under the presence of nifedipine. Pretreatment with the amphetamine for 2 h decreased the basal [Ca2+]i and prostaglandin F2α-stimulated increase of [Ca2+]i. Amphetamine inhibits progesterone and estradiol secretion in rat granulosa cells through a mechanism involving decreased PKA-downstream steroidogenic enzyme activity and L-type Ca2+ channels. Our current findings show that it is necessary to study the possibility of amphetamine perturbing reproduction in females.

scholarly journals In Vitro α-Glucosidase and α-Amylase Inhibitory Activities of Free and Bound Phenolic Extracts from the Bran and Kernel Fractions of Five Sorghum Grain Genotypes

Foods ◽  
2020 ◽  
Vol 9 (9) ◽  
pp. 1301
Author(s):  
Yun Xiong ◽  
Ken Ng ◽  
Pangzhen Zhang ◽  
Robyn Dorothy Warner ◽  
Shuibao Shen ◽  
...  
Keyword(s):  
Digestive System ◽  
Inhibitory Concentration ◽  
Inhibitory Effect ◽  
Inhibitory Effects ◽  
Phenolic Contents ◽  
Inhibitory Activities ◽  
Sorghum Grain ◽  
Global Health Challenge ◽  
Phenolic Extracts

Diabetes is a global health challenge. Currently, an effective treatment for diabetes is to reduce the postprandial hyperglycaemia by inhibiting the carbohydrate hydrolysing enzymes in the digestive system. In this study, we investigated the in vitro α-glucosidase and α-amylase inhibitory effects of free and bound phenolic extracts, from the bran and kernel fractions of five sorghum grain genotypes. The results showed that the inhibitory effect of sorghum phenolic extracts depended on the phenolic concentration and composition. Sorghum with higher phenolic contents generally had higher inhibitory activity. Among the tested extracts, the brown sorghum (IS131C)-bran-free extract (BR-bran-free, half-maximal inhibitory concentration (IC50) = 18 ± 11 mg sorghum/mL) showed the strongest inhibition against α-glucosidase which was comparable to that of acarbose (IC50 = 1.39 ± 0.23 mg acarbose/mL). The red sorghum (Mr-Buster)-kernel-bound extract (RM-kernel-bound, IC50 = 160 ± 12 mg sorghum/mL) was the most potent in inhibiting α-amylase but was much weaker compared to acarbose (IC50 = 0.50 ± 0.03 mg acarbose/mL).

A STUDY OF THE INHIBITORY EFFECTS OF CHICK WHOLE EYE EXTRACT ON THE DEVELOPMENT OF THE LENS OF THE CHICK EMBRYO IN VITRO

1966 ◽  
Vol 44 (4) ◽  
pp. 661-676 ◽  
Author(s):  
Robert P. Thompson
Keyword(s):  
Chick Embryo ◽  
Nutrient Medium ◽  
Inhibitory Effect ◽  
Reactive System ◽  
Vesicle Formation ◽  
Inhibitory Effects ◽  
Muscle Extract ◽  
Lens Vesicle ◽  
And Control

To demonstrate the phenomenon of homologous inhibition by clearly interpretable results in a readily reactive system, experiments were carried out to study the effect of chick whole eye extract on the development of the vesicular lens of the chick embryo in vitro. The heads of embryos of 11 through 13 somites were explanted onto nutrient medium diluted with varying amounts of the extract, and cultured for 30 hours. A total of 35 embryos exposed to concentrations of 1:1, 1:2, and 1:4 (extract to medium) showed complete inhibition of lens vesicle formation. Of a total of 53 embryos on concentrations of 1:8, 1:16, 1:32, and 1:64, more than 50% showed inhibition of vesicle formation. The inhibitory effect disappeared at a concentration of 1:128. Control material exposed to some equivalent concentrations of nutrient medium – saline mixtures showed inhibition of vesicle formation in only 15% of 33 embryos. Of a total of 27 control embryos exposed to ventricular muscle extract, approximately one-third showed inhibition of vesicle formation at concentrations of 1:8 and 1:16, with the inhibitory effect disappearing at 1:32. The implications of this result are discussed. Other factors and control experiments are described and their value is assessed.

scholarly journals Study of Baicalin toward COVID-19 Treatment: In silico Target Analysis and in vitro Inhibitory Effects on SARS-CoV-2 Proteases

2021 ◽  
pp. 122-137
Author(s):  
Chingju Lin ◽  
Fuu-Jen Tsai ◽  
Yuan-Man Hsu ◽  
Tsung-Jung Ho ◽  
Guo-Kai Wang ◽  
...  
Keyword(s):  
Molecular Docking ◽  
Binding Affinity ◽  
Pathway Analysis ◽  
Acute Inflammation ◽  
Inhibitory Effect ◽  
Pharmacological Effects ◽  
Inhibitory Effects ◽  
Rna Dependent Rna Polymerase ◽  
Negative Impacts

Negative impacts of COVID-19 on human health and economic and social activities urge scientists to develop effective treatments. Baicalin is a natural flavonoid, extracted from a traditional medicinal plant, previously reported with anti-inflammatory activity. In this study, we used pharmacophore fitting and molecular docking to screen and determine docking patterns and the binding affinity of baicalin on 3 major targets of SARS-CoV-2 (3-chymotrypsin-like cysteine protease [3CLpro], papain-like protease [PLpro], and RNA-dependent RNA polymerase). The obtained data revealed that baicalin has high pharmacophore fitting on 3CLpro and predicted good binding affinity on PLpro. Moreover, using the enzymatic assay, we examined the inhibitory effect of baicalin in vitro on the screened enzymes. Baicalin also exhibits inhibitory effect on these proteases in vitro. Additionally, we performed pharmacophore-based screening of baicalin on human targets and conducted pathway analysis to explore the potential cytoprotective effects of baicalin in the host cell that may be beneficial for COVID-19 treatment. The result suggested that baicalin has multiple targets in human cell that may induce multiple pharmacological effects. The result of pathway analysis implied that these targets may be associated with baicalin-induced bioactivities that are involved with signals of pro-inflammation factors, such as cytokine and chemokine. Taken together with supportive data from the literature, the bioactivities of bailalin may be beneficial for COVID-19 treatment by reducing cytokine-induced acute inflammation. In conclusion, baicalin is potentially a good candidate for developing new therapeutic to treat COVID-19.

scholarly journals Μελέτη μορίων του πρωτόζωου Leishmania που εμπλέκονται στην πρόοδο του κυτταρικού κύκλου

2014 ◽  
Author(s):  
Αλέξανδρος Αλεξανδράτος
Keyword(s):  
Heat Shock ◽  
Elongation Factor ◽  
Alpha Subunit ◽  
Elongation Factor 2 ◽  
Mitochondrial Processing Peptidase ◽  
Eukaryotic Elongation Factor 2 ◽  
Eukaryotic Elongation Factor ◽  
Processing Peptidase

Τα είδη του γένους Leishmania αποτελούν υποχρεωτικά ενδοκυττάρια πρωτοζωικά παράσιτα που προκαλούν ένα ευρύ φάσμα ασθενειών, τις λεισμανιάσεις. Η λεϊσμανίαση θεωρείται νόσος εξέχουσας σπουδαιότητας, με 2 εκατομμύρια νέα κρούσματα το χρόνο, χρήζουσας μεγάλης κοινωνικής και οικονομικής σημασίας. Για τον έλεγχο των συνεχώς αυξανόμενων κρουσμάτων, είναι επιτακτική ανάγκη η ανάπτυξη νέων μη-τοξικών φαρμάκων που θα στοχεύουν σε μόρια-στόχους σημαντικά για την ολοκλήρωση του παρασιτικού κύκλου ζωής. Κατ’ αυτόν τον τρόπο κρίνεται απαραίτητη η μελέτη μηχανισμών και παραγόντων μολυσματικότητας του παρασίτου, που ελέγχουν τον κυτταρικό κύκλο και τη διαφοροποίηση του παρασίτου. Στα πλαίσια αυτά, έχει δειχθεί ότι η επισωμική υπερέκφραση της συνδετικής ιστόνης Η1 του παρασίτου Leishmania (LeishH1) οδηγεί στην καθυστέρηση της ολοκλήρωσης του κυτταρικού κύκλου, αλλά παράλληλα και στη μείωση του ρυθμού διαφοροποίησης των παρασίτων από προμαστιγωτές σε αμαστιγωτές μορφές, έχοντας σαν αποτέλεσμα τη μείωση της μολυσματικότητας του παρασίτου τόσο in vitro όσο και in vivo. Στόχος αυτής της διατριβής ήταν η ανάδειξη μορίων που επηρεάζουν τη μολυσματικότητα του παρασίτου, μελετώντας το προτέωμα των μη μολυσματικών παρασίτων που υπερεκφράζουν την LeishH1. Η συγκριτική μελέτη των παρασίτων που υπερεκφράζουν τη LeishH1 σε σχέση με τα παράσιτα ελέγχου, είχε επίσης ως σκοπό την περαιτέρω μελέτη του βιολογικού ρόλου της LeishH1 στα παράσιτα και τη διερεύνηση του ρόλου της στη γονιδιακή ρύθμιση του παρασίτου. Η συγκριτική πρωτεομική ανάλυση με ηλεκτροφόρηση δυο-διαστάσεων, των παρασίτων που υπερεκφράζουν την LeishH1 σε σχέση με τα παράσιτα ελέγχου, κατέδειξε πως μόνο μια μικρή ομάδα πρωτεϊνών παρουσιάζει διαφορική έκφραση. Συγκεκριμένα, τρεις πρωτεΐνες [heat shock protein 83 (HSP83), eukaryotic elongation factor 2(eEF-2), alpha subunit of the mitochondrial processing peptidase (α-MPP)] παρουσιάζουν χαμηλότερα επίπεδα έκφρασης ενώ άλλες δυο (α/β τουμπουλίνη, ΜΑΡ) παρουσιάζουν μεγαλύτερη κατανομή έκφρασης. Πειράματα αλυσιδωτής αντίδρασης πολυμεράσης αντίστροφης μεταγραφάσης πραγματικού χρόνου, επιβεβαίωσαν το αποτέλεσμα αυτό, υποδηλώνοντας ότι η LeishH1 δεν είναι γενικός καταστολέας της μεταγραφής αλλά επηρεάζει ένα ειδικό υποσύνολο πρωτεϊνών, σε προ- ή μετα-μεταγραφικό επίπεδο. Ανάμεσα στις πρωτεΐνες με διαφορική έκφραση ήταν και η τουμπουλίνη. Η διαφορική έκφραση της πρωτεΐνης αντικατοπτρίζεται άμεσα στη μορφολογία των παρασίτων που υπερεκφράζουν την LeishH1, καθώς τα παράσιτα αυτά παρουσιάζουν μικρότερο και πιο στρογγυλό σχήμα και μεγαλύτερη μορφολογική ετερογένεια. Μια ακόμα πρωτεΐνη με διαφορική έκφραση, ήταν και η HSP83, η οποία παρουσίασε χαμηλότερα επίπεδα. Θέλοντας να εξακριβώσουμε σε ποιο επίπεδο παρεμβαίνει η LeishH1 στο μηχανισμό έκφρασης της HSP83, συγκρίναμε τα επίπεδα του mRNA και η ανάλυση κατέδειξε ότι δεν υπάρχουν διαφορές στα επίπεδα αυτά. Επίσης, μελετήθηκε ο ρυθμός έκφρασης της πρωτεΐνης μέσω της μεταβολικής σήμανσης των πρωτεϊνών και αποκαλύφθηκε πως σε αυτό το στάδιο εντοπίζεται η παρεμβολή της LeishH1, καθώς τα παράσιτα που την υπερεκφράζουν παρουσιάζουν χαμηλότερο ρυθμό έκφρασης της HSP83. Συμπερασματικά διαφαίνεται πως υπάρχει μια συσχέτιση μεταξύ μονοπατιών που εμπλέκονται στην αντίσταση έναντι φαρμακευτικών ουσιών, στην απόπτωση και τη μολυσματικότητα. Κατ’ αυτόν τον τρόπο, τα ειδικά σήματα και οι μηχανισμοί που ρυθμίζουν τη διαφοροποίηση/μολυσματικότητα του παρασίτου και την απόπτωση/απόκριση στο στρες, χρήζουν περαιτέρω διερεύνησης καθώς φαίνεται να αποτελούν τις δυο όψεις του ίδιου νομίσματος.

IMB-BZ as an Inhibitor Targeting ESX-1 Secretion System to Control Mycobacterial Infection

2021 ◽  
Author(s):  
Pingping Jia ◽  
Yi Zhang ◽  
Jian Xu ◽  
Mei Zhu ◽  
Shize Peng ◽  
...  
Keyword(s):  
Drug Resistance ◽  
Mycobacterial Infection ◽  
Underlying Mechanism ◽  
Inhibitory Effect ◽  
New Drugs ◽  
Dependent Manner ◽  
High Potency ◽  
Resistance Development

Abstract Background Resistance to anti-tuberculosis (TB) drug is a major issue in TB control, and demands the discovery of new drugs targeting virulence factor ESX-1. Methods We first established a high-throughput screen (HTS) assay for the discovery of ESX-1 secretion inhibitors. The positive hits were then evaluated for the potency of diminishing the survival of virulent mycobacterium and reducing bacterial virulence. We further investigated the probability of inducing drug-resistance and the underlying mechanism using M-PFC. Results A robust HTS assay was developed to identify small molecules that inhibit ESX-1 secretion without impairing bacterial growth in vitro. A hit named IMB-BZ specifically inhibits the secretion of CFP-10 and reduces virulence in an ESX-1-dependent manner, therefore resulting in significant reduction in intracellular and in vivo survival of mycobacteria. Blocking the CFP-10-EccCb1 interaction directly or indirectly underlies the inhibitory effect of IMB-BZ on the secretion of CFP-10. Importantly, our finding shows that the ESX-1 inhibitors pose low risk of drug resistance development by mycobacteria in vitro as compared with traditional anti-TB drug, and exhibit high potency against chronic mycobacterial infection. Conclusion Targeting ESX-1 may lead to the development of novel therapeutics for tuberculosis. IMB-BZ holds the potential for future development into a new anti-TB drug.

In vitro inhibitory effects of glucosamine, chondroitin and diacerein on human hepatic CYP2D6

2021 ◽  
Vol 36 (4) ◽  
pp. 259-270
Author(s):  
Boon Hooi Tan ◽  
Nafees Ahemad ◽  
Yan Pan ◽  
Uma Devi Palanisamy ◽  
Iekhsan Othman ◽  
...  
Keyword(s):  
Cytochrome P450 ◽  
High Performance ◽  
Inhibitory Effect ◽  
Inhibitory Effects ◽  
Time Curve ◽  
Clinical Drugs ◽  
Inhibition Potencies ◽  
P450 2D6

Abstract Objectives Glucosamine, chondroitin and diacerein are natural compounds commonly used in treating osteoarthritis. Their concomitant intake may trigger drug–natural product interactions. Cytochrome P450 (CYP) has been implicated in such interactions. Cytochrome P450 2D6 (CYP2D6) is a major hepatic CYP involved in metabolism of 25% of the clinical drugs. This study aimed to investigate the inhibitory effect of these antiarthritic compounds on CYP2D6. Methods CYP2D6 was heterologously expressed in Escherichia coli. CYP2D6–antiarthritic compound interactions were studied using in vitro enzyme kinetics assay and molecular docking. Results The high-performance liquid chromatography (HPLC)-based dextromethorphan O-demethylase assay was established as CYP2D6 marker. All glucosamines and chondroitins weakly inhibited CYP2D6 (IC50 values >300 µM). Diacerein exhibited moderate inhibition with IC50 and K i values of 34.99 and 38.27 µM, respectively. Its major metabolite, rhein displayed stronger inhibition potencies (IC50=26.22 μM and K i =32.27 μM). Both compounds exhibited mixed-mode of inhibition. In silico molecular dockings further supported data from the in vitro study. From in vitro–in vivo extrapolation, rhein presented an area under the plasma concentration-time curve (AUC) ratio of 1.5, indicating low potential to cause in vivo inhibition. Conclusions Glucosamine, chondroitin and diacerein unlikely cause clinical interaction with the drug substrates of CYP2D6. Rhein, exhibits only low potential to cause in vivo inhibition.

Ascorbic acid, sucrose and olive oil lipids mitigate the inhibitory effects of pectin on the bioaccessibility and Caco-2 cellular uptake of ferulic acid and naringenin

2020 ◽  
Vol 11 (5) ◽  
pp. 4138-4145
Author(s):  
Johanita Kruger ◽  
Nadine Sus ◽  
Jan Frank
Keyword(s):  
Ascorbic Acid ◽  
Ferulic Acid ◽  
Olive Oil ◽  
Cellular Uptake ◽  
Inhibitory Effect ◽  
Inhibitory Effects

Sucrose and olive oil successfully negate the inhibitory effect of pectin on the overall in vitro availability of ferulic acid and naringenin by substantially increasing the bioaccessibility and not cellular uptake of the phenolics.

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