scholarly journals Newly Synthesized Oxygenated Xanthones as Potential P-Glycoprotein Activators: In Vitro, Ex Vivo, and In Silico Studies

Molecules ◽  
2019 ◽  
Vol 24 (4) ◽  
pp. 707 ◽  
Author(s):  
Eva Martins ◽  
Vera Silva ◽  
Agostinho Lemos ◽  
Andreia Palmeira ◽  
Ploenthip Puthongking ◽  
...  
Keyword(s):  
In Silico ◽  
Crucial Role ◽  
Ex Vivo ◽  
Glycoprotein P ◽  
Docking Simulations ◽  
Knowing That ◽  
P Glycoprotein ◽  
In Silico Studies ◽  
Gp Model

P-glycoprotein (P-gp) plays a crucial role in the protection of susceptible organs, by significantly decreasing the absorption/distribution of harmful xenobiotics and, consequently, their toxicity. Therefore, P-gp has been proposed as a potential antidotal pathway, when activated and/or induced. Knowing that xanthones are known to interact with P-gp, the main goal was to study P-gp induction or/and activation by six new oxygenated xanthones (OX 1-6). Furthermore, the potential protection of Caco-2 cells against paraquat cytotoxicity was also assessed. The most promising compound was further tested for its ability to increase P-gp activity ex vivo, using everted intestinal sacs from adult Wistar-Han rats. The oxygenated xanthones interacted with P-gp in vitro, increasing P-gp expression and/or activity 24 h after exposure. Additionally, after a short-incubation period, several xanthones were identified as P-gp activators, as they immediately increased P-gp activity. Moreover, some xanthones decreased PQ cytotoxicity towards Caco-2 cells, an effect prevented under P-gp inhibition. Ex vivo, a significant increase in P-gp activity was observed in the presence of OX6, which was selectively blocked by a model P-gp inhibitor, zosuquidar, confirming the in vitro results. Docking simulations between a validated P-gp model and the tested xanthones predicted these interactions, and these compounds also fitted onto previously described P-gp induction and activation pharmacophores. In conclusion, the in vitro, ex vivo, and in silico results suggest the potential of some of the oxygenated xanthones in the modulation of P-gp, disclosing new perspectives in the therapeutics of intoxications by P-gp substrates.

In Vitro, In Silico and Ex Vivo Studies of Dihydroartemisinin Derivatives as Antitubercular Agents

2019 ◽  
Vol 19 (8) ◽  
pp. 633-644 ◽  
Author(s):  
Komal Kalani ◽  
Sarfaraz Alam ◽  
Vinita Chaturvedi ◽  
Shyam Singh ◽  
Feroz Khan ◽  
...  
Keyword(s):  
Bone Marrow ◽  
In Silico ◽  
Ex Vivo ◽  
Virulent Strain ◽  
Infection Model ◽  
Mouse Bone Marrow ◽  
Significant Activity ◽  
Macrophage Infection ◽  
In Silico Studies

Introduction: As a part of our drug discovery program for anti-tubercular agents, dihydroartemisinin (DHA-1) was screened against Mtb H37Rv, which showed moderate anti-tubercular activity (>25.0 µg/mL). These results prompted us to carry out the chemical transformation of DHA-1 into various derivatives and study their antitubercular potential. Materials and Methods: DHA-1 was semi-synthetically converted into four new acyl derivatives (DHA-1A – DHA-1D) and in-vitro evaluated for their anti-tubercular potential against Mycobacterium tuberculosis H37Rv virulent strain. The derivatives, DHA-1C (12-O-(4-nitro) benzoyl; MIC 12.5 µg/mL) and DHA-1D (12-O-chloro acetyl; MIC 3.12µg/mL) showed significant activity against the pathogen. Results: In silico studies of the most active derivative (DHA-1D) showed interaction with ARG448 inhibiting the mycobacterium enzymes. Additionally, it showed no cytotoxicity towards the Vero C1008 cells and Mouse bone marrow derived macrophages. Conclusion: DHA-1D killed 62% intracellular M. tuberculosis in Mouse bone marrow macrophage infection model. To the best of our knowledge, this is the first-ever report on the antitubercular potential of dihydroartemisinin and its derivatives. Since dihydroartemisinin is widely used as an antimalarial drug; these results may be of great help in anti-tubercular drug development from a very common, inexpensive, and non-toxic natural product.

P-Glycoprotein-Mediated Efflux Using a Rapidly Maturing Caco2 Clone (CLEFF4) in Only 5 Days without Requiring Modified Growth Medium

2020 ◽  
Vol 26 (1) ◽  
pp. 151-160
Author(s):  
Andrew Crowe
Keyword(s):  
Oral Absorption ◽  
Mdck Cells ◽  
Target Cells ◽  
Glycoprotein P ◽  
Caco2 Cells ◽  
P Glycoprotein ◽  
New Chemical Entities ◽  
Bidirectional Transport ◽  
Gp Model

In drug discovery it is essential that one of the parameters tested for any new chemical entity is its affinity for human efflux systems, most notably P-glycoprotein (P-gp). These efflux systems affect not only rates of oral absorption but also rates of excretion through the liver, blood–brain barrier, and accumulation in potential target cells that upregulate efflux systems. Current methods to determine drugs’ P-gp transport potential include in vitro bidirectional transport studies, and the two most common cell lines used are Caco2 and MDR1-transfected MDCK models. Caco2 cells are human but slow growing and require more than 3 weeks to mature, while MDCK cells are canine, but when transfected with human P-gp become a rapid model of P-gp affinity. Our laboratory has generated a Caco2 subclone called CLEFF4 that is fully human, yet now approaches the rapid nature of the MDCK model. No special medium is required. We have shown, in as little as 5 days postseeding, high transepithelial electrical resistance values of more than 1000 Ω·cm2 plus P-gp expression more than threefold higher than that of 21-day-old cells. Currently tested drugs included rhodamine 123 (Rh123), vinblastine, and doxorubicin, and all drugs exhibited P-gp-mediated efflux that was inhibited by PSC833. By day 6, bidirectional transport of Rh123 was as potent as that of mature Caco2 cells, for use in comparative P-gp affinity studies. We now have a human P-gp model that is rapid and works without any need for special accelerating medium. We believe this could be a welcome addition to the testing regime of new chemical entities.

P-glycoprotein expression and activity are differently modulated by Colchicine in Caco-2 cells: In vitro and in silico studies

2013 ◽  
Vol 221 ◽  
pp. S179-S180
Author(s):  
Fernando Remião ◽  
Renata Silva ◽  
Vânia Vilas-Boas ◽  
Daniel José Barbosa ◽  
Andreia Palmeira ◽  
...  
Keyword(s):  
In Silico ◽  
P Glycoprotein ◽  
In Silico Studies ◽  
Expression And Activity

Hypericin-mediated P-glycoprotein induction protects caco-2 cells against paraquat toxicity: In vitro and in silico studies

2015 ◽  
Vol 238 (2) ◽  
pp. S317 ◽  
Author(s):  
R. Silva ◽  
H. Carmo ◽  
V. Vilas-Boas ◽  
D.J. Barbosa ◽  
A. Palmeira ◽  
...  
Keyword(s):  
In Silico ◽  
P Glycoprotein ◽  
Paraquat Toxicity ◽  
In Silico Studies ◽  
Toxicity In Vitro

scholarly journals Water Extract from Inflorescences of Industrial Hemp Futura 75 Variety as a Source of Anti-Inflammatory, Anti-Proliferative and Antimycotic Agents: Results from In Silico, In Vitro and Ex Vivo Studies

Antioxidants ◽  
2020 ◽  
Vol 9 (5) ◽  
pp. 437 ◽  
Author(s):  
Giustino Orlando ◽  
Lucia Recinella ◽  
Annalisa Chiavaroli ◽  
Luigi Brunetti ◽  
Sheila Leone ◽  
...  
Keyword(s):  
In Silico ◽  
Ex Vivo ◽  
Hct116 Cell ◽  
Water Extract ◽  
Network Pharmacology ◽  
Rat Colon ◽  
Microsporum Gypseum ◽  
In Silico Studies ◽  
Industrial Hemp

Industrial hemp (Cannabis sativa) is traditionally cultivated as a valuable source of fibers and nutrients. Multiple studies also demonstrated antimicrobial, anti-proliferative, phytotoxic and insecticide effects of the essential oil from hemp female inflorescences. On the other side, only a few studies explored the potential pharmacological application of polar extracts from inflorescences. In the present study, we investigated the water extract from inflorescences of industrial hemp Futura 75 variety, from phytochemical and pharmacological point of view. The water extract was assayed for phenolic compound content, radical scavenger/reducing, chelating and anti-tyrosinase effects. Through an ex vivo model of toxicity induced by lipopolysaccharide (LPS) on isolated rat colon and liver, we explored the extract effects on serotonin, dopamine and kynurenine pathways and the production of prostaglandin (PG)E2. Anti-proliferative effects were also evaluated against human colon cancer HCT116 cell line. Additionally, antimycotic effects were investigated against Trichophyton rubrum, Trichophyton interdigitale, Microsporum gypseum. Finally, in silico studies, including bioinformatics, network pharmacology and docking approaches were conducted in order to predict the putative targets underlying the observed pharmacological and microbiological effects. Futura 75 water extract was able to blunt LPS-induced reduction of serotonin and increase of dopamine and kynurenine turnover, in rat colon. Additionally, the reduction of PGE2 levels was observed in both colon and liver specimens, as well. The extract inhibited the HCT116 cell viability, the growth of T. rubrum and T. interdigitale and the activity of tyrosinase, in vitro, whereas in silico studies highlighting the inhibitions of cyclooxygenase-1 (induced by carvacrol), carbonic anhydrase IX (induced by chlorogenic acid and gallic acid) and lanosterol 14-α-demethylase (induced by rutin) further support the observed pharmacological and antimycotic effects. The present findings suggest female inflorescences from industrial hemp as high quality by-products, thus representing promising sources of nutraceuticals and cosmeceuticals against inflammatory and infectious diseases.

scholarly journals Pharmacological Properties and Chemical Profiles of Passiflora foetida L. Extracts: Novel Insights for Pharmaceuticals and Nutraceuticals

Processes ◽  
2020 ◽  
Vol 8 (9) ◽  
pp. 1034
Author(s):  
Annalisa Chiavaroli ◽  
Simonetta Cristina Di Simone ◽  
Kouadio Ibrahime Sinan ◽  
Maria Chiara Ciferri ◽  
Giancarlo Angeles Flores ◽  
...  
Keyword(s):  
Hydrogen Peroxide ◽  
In Silico ◽  
Ex Vivo ◽  
Mouse Skin ◽  
Skin Inflammation ◽  
Water Extracts ◽  
Methanolic Extracts ◽  
In Silico Studies ◽  
Passiflora Foetida

In the present study, Passiflora foetida extracts characterized by different polarities were studied for their phytochemical profile, enzyme inhibitory, and antioxidant potentials. In silico, in vitro and ex vivo studies were also carried out on methanol and water extracts for predicting pharmacokinetics and pharmacodynamics. In this regard, neuronal HypoE22 cells, isolated mouse skin tissues, and pathogen dermatophytes strains were exposed to extracts. Emphasis was given to the preventing effects induced by the extracts on hydrogen peroxide-induced alterations of prostaglandin E2 (PGE2), l-dopa, and serotonin. Chemical analysis revealed the presence of similar compounds in infusion and methanolic extracts. The ex vivo studies also showed protective skin properties by P. foetida water and methanol extracts, as evidenced by the decrease of hydrogen peroxide-induced PGE2 level. Additionally, the blunting effects on hydrogen peroxide-induced l-dopa levels are consistent with the anti-tyrosinase effect exerted by both extracts. In silico studies demonstrated the affinity of extracts’ phytochemicals, namely apigenin, chrysoeriol, loliolide, luteolin, quercetin, and vitexin, towards cyclo-oxygenase-2 and tyrosinase. Finally, microbiological tests demonstrated the efficacy of P. foetida methanol and water extracts as anti-mycotic agents against Trichophyton and Arthroderma species, involved in skin inflammation. Hence, P. foetida L. extracts could represent potential sources of pharmaceuticals and nutraceuticals.

scholarly journals Quercetin and Coumarin Inhibit Dipeptidyl Peptidase-IV and Exhibits Antioxidant Properties: In Silico, In Vitro, Ex Vivo

Biomolecules ◽  
2020 ◽  
Vol 10 (2) ◽  
pp. 207 ◽  
Author(s):  
Anand-Krishna Singh ◽  
Pankaj Kumar Patel ◽  
Komal Choudhary ◽  
Jaya Joshi ◽  
Dhananjay Yadav ◽  
...  
Keyword(s):  
Oxidative Stress ◽  
In Silico ◽  
Ex Vivo ◽  
Antioxidant Properties ◽  
Dipeptidyl Peptidase ◽  
Dipeptidyl Peptidase Iv ◽  
Food Ingredients ◽  
Dpp Iv ◽  
In Silico Studies

Quercetin and coumarin, two naturally occurring phytochemicals of plant origin, are known to regulate hyperglycemia and oxidative stress. The present study was designed to evaluate the inhibitory activity of quercetin and coumarin on dipeptidyl peptidase-IV (DPP-IV) and their antioxidant potential. DPP-IV inhibition assays were performed, and evaluated IC50 values of diprotin A, quercetin, coumarin, and sitagliptin were found to be 0.653, 4.02, 54.83, and 5.49 nmol/mL, respectively. Furthermore, in silico studies such as the drug-likeliness and docking efficiency of quercetin and coumarin to the DPP-IV protein were performed; the ex vivo antiperoxidative potential of quercetin and coumarin were also evaluated. The results of the present study showed that the DPP-IV inhibitory potential of quercetin was slightly higher than that of sitagliptin. Virtual docking revealed the tight binding of quercetin with DPP-IV protein. Quercetin and coumarin reduced oxidative stress in vitro and ex vivo systems. We report for the first time that both compounds inhibited the DPP-IV along with antioxidant activity and thus may be use as function food ingredients in the prevention of diabetes.

Antioxidative and anti-proliferative potential of Curculigo orchioides Gaertn in oxidative stress induced cytotoxicity: In vitro, ex vivo and in silico studies

2018 ◽  
Vol 115 ◽  
pp. 244-259 ◽  
Author(s):  
Iram Iqbal Hejazi ◽  
Rashmin Khanam ◽  
Syed Hassan Mehdi ◽  
Abdul Roouf Bhat ◽  
M.Moshahid Alam Rizvi ◽  
...  
Keyword(s):  
Oxidative Stress ◽  
In Silico ◽  
Ex Vivo ◽  
Proliferative Potential ◽  
Curculigo Orchioides ◽  
In Silico Studies
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