Добірка наукової літератури з теми "Cardioglycosides"

Some of the secondary metabolites present in red algae are terpenoids, quinones, flavonoids, alkaloids, essential oils, diarylheptanoids, steroids, cardioglycosides, oils and fats, tannins, carbohydrates. Activity of rhizomes, leaves and flowers red leaf is as antimicrobial, anti-fungal, anti-oxidants, anti-tumor, anti-cancer and vasodilator. One way to improve the physical, chemical and bioactivity properties of natural compounds was to make them into nanoparticles. In this study, the isolation of bioactive compounds contained in red laos rhizome by maceration method using ethanol solvent was done, then partitioned with n-hexane and ethyl acetate. The extracts thus obtained are fabricated into nanoparticles. Extracts in bulk and nanoparticles were then tested for cytotoxic activity using BSLT method. Results of analysis with PSA showed that ethanol extract had size 410,8 nm, n-hexane extract 220,7 nm and ethyl acetate extract 208,3 nm. The results of cytotoxic tests showed that nanoparticle size increased cytotoxic activity. Ethyl acetate extract was most active compared to ethanol and n-hexane extracts with LC50values of 17.919; 84,956; 166,526 ppm. Whereas the nanoparticle size was respectively 10,491; 74,072 and 84,197 ppm. Cytotoxic activity increases with nanoparticle fabrication.

The present study was performed to investigate the phytochemical screening, total phenol, tannin content, antioxidant and antibacterial activity from seed extracts of Cucurbita pepo and Cucurbita maxima (Tindivanam). The phytochemical analysis revealed the presence of active ingredients such as steroids, cardioglycosides, phenols, terpenoids, alkaloids and tannins in the seed extract of Cucurbita pepo followed by Cucurbita maxima. Gallic acid (GA), Tannic acid (TA) and Butylated Hydroxy Toluene (BHT) were taken as standard in case of total phenol, tannin and antioxidant activity respectively. Total phenol and tannin content were quantitatively estimated which recorded maximum in Cucurbita pepo (8.37±0.2 mg Gallic Acid Equivalents (GAE)/g and 20.47 ± 0.37 mg Tannic Acid Equivalents (TAE)/g). The seed extracts were evaluated for antioxidant activities by DPPH (1, 1– Diphenyl -2- picryl - hydrazyl) radical scavenging assay. Among the two species with different solvents used, maximum antioxidant activity was found in the acetone seed extract (84.27±0.19%) of Cucurbita pepo followed by Cucurbita maxima (67.83 ± 0.37%). Different concentrations of acetone seed extracts were tested for the anti-bacterial activity against Bacillus subtilis, Bacillus cereus, Staphylococcus aureus, Pseudomonas aeruginosa and Escherichia coli using the agar disc diffusion technique. The acetone seed extracts of Cucurbita pepo had superior level of antimicrobial activity. The powerful antibacterial effect is attributed to the greater amount of tannins compound in the acetone seed extracts of Cucurbita pepo.

Digitoxin and digoxin 4'''-(3-carboxypropanoates)(4'''-hemisuccinates) III and X were prepared by an indirect method, using dicyclohexylcarbodiimide-induced condensation of the cardioglycoside with 4-(2,2,2-trichloroethoxy)-4-oxobutanoic acid in dichloromethane in the presence of 4-dimethylaminopyridine or pyridine followed by removal of the 2,2,2-trichloroethyl group with zinc in a mixture of tetrahydrofuran, acetic acid and water. The hemisuccinates III and X were condensed with L-tyrosine methyl ester in tetrahydrofuran, using N-ethoxycarbonyl-2-ethoxy-1,2-dihydroquinoline as the coupling reagent. Structure of the products was proved by 1H NMR and 13C NMR spectra. The conjugates IV and XI were labelled with [125I] in the L-tyrosine moiety. The obtained radioligands V and XII are designed as a part of the RIA system for cardioglycoside analyses.

An indirect method for preparation of hemisuccinates (hydrogen butanedioates) is described, consisting in reaction of hydroxy derivatives with 2-(trimethylsilyl)ethyl hemisuccinate (I) followed by removal of the 2-(trimethylsilyl)ethyl group from the mixed succinate with tetrabutylammonium fluoride. It has been applied to the synthesis of hemisuccinates derived from cholesterol (II), (20E)-21-methoxycarbonylpregna-5,20-dien-3β-ol (V), digitoxigenin (XII), digitoxin (XV) and digoxin (XVIII). The method, however, is not suitable for the preparation of estrone hemisuccinate X which is cleaved with tetrabutylammonium fluoride to give estrone(VIII).

Recent investigations demonstrate increased Na/H exchanger-1 (NHE-1) activity and plasma levels of ouabain-like factor in spontaneously hypertensive rats. At nanomolar concentrations, ouabain increases Na-K-ATPase activity, induces cell proliferation, and activates complex signaling cascades. We hypothesize that the activity of NHE-1 and Na-K-ATPase are interdependent. To test whether treatment with picomolar ouabain regulates Na-K-ATPase through an NHE-1-dependent mechanism, we examined the role of NHE-1 in ouabain-mediated stimulation of Na-K-ATPase in kidney proximal tubule cell lines [opossum kidney (OK), HK-2, HKC-5, and HKC-11] and rat kidney basolateral membranes. Ouabain stimulated Na-K-ATPase activity and tyrosine phosphorylation in cells that express NHE-1 (OK, HKC-5, and HKC-11) but not in HK-2 cells that express very low levels of NHE-1. Inhibition of NHE-1 with 5 μM EIPA, a NHE-1-specific inhibitor, prevented ouabain-mediated stimulation of86Rb uptake and Na-K-ATPase phosphorylation in OK, HKC-5, and HKC-11 cells. Expression of wild-type NHE-1 in HK2 cells restored regulation of Na-K-ATPase by picomolar ouabain. Treatment with picomolar ouabain increased membrane expression of Na-K-ATPase and enhanced NHE-1-Na-K-ATPase α1-subunit association. Treatment with ouabain (1 μg·kg body wt−1·day−1) increased Na-K-ATPase activity, expression, phosphorylation, and association with NHE-1 increased in rat kidney cortical basolateral membranes. Eight days' treatment with ouabain (1 μg·kg body wt−1·day−1) resulted in increased blood pressure in these rats. These results suggest that the association of NHE-1 with Na-K-ATPase is critical for ouabain-mediated regulation of Na-K-ATPase and that these effects may play a role in cardioglycoside-stimulated hypertension.

En réponse à l'expression d'oncogène (tel que BRAF-V600E), à des traitements génotoxiques ou à d'autres stress, les cellules eucaryotes peuvent éviter l'apoptose et déclencher la sénescence. La sénescence est un destin cellulaire caractérisé par un arrêt prolifératif quasi-irréversible et une reprogrammation transcriptionnelle profonde, conduisant notamment à une sécrétion importante de facteurs inflammatoires collectivement appelés phénotype sécrétoire associé à la sénescence (SASP). En raison de l'augmentation de la demande sécrétoire et de stress chroniques, la protéostase peut être perturbée en sénescence. Comme elle limite la prolifération de cellules susceptibles de présenter un potentiel pré-néoplastique, la sénescence est un processus essentiel de suppression tumorale ; cependant, l'accumulation de cellules sénescentes au cours du vieillissement, dans des contextes pathologiques, ou après chimiothérapie ou radiothérapie, est préjudiciable et entraîne un dysfonctionnement tissulaire. Les sénolytiques sont des composés qui induisent sélectivement l'apoptose dans les cellules sénescentes tout en épargnant les cellules normales, et leur application thérapeutique s'est avérée une stratégie pharmacologique efficace dans différents contextes pathologiques où la sénescence joue un rôle moteur. Le but de ce projet était d'identifier de nouveaux composés sénolytiques, notamment dans la sénescence induite par BRAF-V600E, et de caractériser leurs mécanismes d'action, ajoutant ainsi à la compréhension de la régulation des voies de survie cellulaire en sénescence. Les cardioglycosides constituent une classe de composés qui ont été identifiés comme de puissants sénolytiques dans le criblage d'une chimiothèque de repositionnement. Nous avons montré que les cellules sénescentes BRAF-V600E étaient remarquablement sensibles à la sénolyse induite par les cardioglycosides. Nous avons démontré que les cellules sénescentes BRAF-V600E ont un flux autophagique accru, essentiel à leur survie, et que les cardioglycosides agissent comme sénolytiques en inhibant l'autophagie via la transduction du signal par la Na,K-ATPase. En conséquence, le blocage de l'autophagie par d'autres voies, comme avec la chloroquine, était également sénolytique. Pour mieux comprendre la régulation de l'autophagie et de la protéostase en sénescence et identifier de nouvelles cibles sénolytiques, nous avons ensuite évalué le stress du réticulum endoplasmique et la réponse aux protéines mal repliées (UPR) dans différents modèles de sénescence. En parallèle, nous avons criblé diverses chimiothèques, dans lesquelles nous avons identifié des sénolytiques potentiels ciblant différentes facettes de la protéostase. Notamment, nous avons découvert que le senseur de l'UPR Ire1 était régulé à la hausse en sénescence induite par l'expression d'oncogènes. Ire1 régule le destin cellulaire par plusieurs voies, et de nombreux composés qui modulent de manière différentielle son activité sont disponibles. Nous avons donc utilisé un panel de modulateurs d'Ire1 pour commencer à caractériser son rôle en sénescence, et établir de nouvelles stratégies sénolytiques. En résumé, nos résultats soulignent le potentiel sénolytique du ciblage de l'autophagie et de la protéostase dans la sénescence induite par l'expression d'oncogènes, et l'importance de caractériser en détails les mécanismes d'action des sénolytiques pour identifier de nouvelles cibles et voies de régulation
In response to oncogene expression (such as BRAF-V600E), genotoxic insults, or other stresses, eukaryotic cells can suppress apoptosis and enter senescence. Senescence is a cell fate characterized by a quasi-irreversible proliferative arrest and deep transcriptional reprogramming, notably leading to an important secretion of inflammatory factors collectively termed the senescence-associated secretory phenotype (SASP). Due to increased secretory demands and chronic stress, proteostasis may be challenged in senescence. As it limits the proliferation of cells possibly bearing pre-neoplastic potential, senescence is an essential tumor suppressing process; however, the accumulation of senescent cells during aging, in pathological contexts, or following chemotherapy or radiotherapy, is detrimental and leads to tissue dysfunction. Senolytics are drugs that selectively induce apoptosis in senescent cells while sparing normal cells, and their therapeutical application has proved a valuable pharmacological strategy in pathological contexts in which senescence plays a driving role. The aim of this project was to identify novel senolytic compounds, notably in BRAF-V600E-induced senescence, and to characterize their mechanisms of action, thereby adding to the understanding of cell survival pathways regulation in senescence. Cardioglycosides constitute a class of drugs that were identified as potent senolytics in the screen of a repurposing library. We showed that BRAF-V600E senescent cells were remarkably sensitive to senolysis induced by cardioglycosides. We demonstrated that BRAF-V600E senescent cells have a heightened autophagy flux that is essential to their survival, and that cardioglycosides acted as senolytics by inhibiting autophagy through Na,K-ATPase signal transduction. Accordingly, blocking autophagy through other routes such as with chloroquine was also senolytic. To gain insight into the regulation of autophagy and proteostasis in senescence and identify new senolytic targets, we then assessed endoplasmic reticulum stress and the unfolded protein response (UPR) in different senescence models. In parallel, we screened various chemical libraries, in which we identified potential senolytics targeting different facets of proteostasis. Interestingly, we found that UPR sensor Ire1 was upregulated in oncogene-induced senescence. Ire1 regulates cell fate through several pathways, and many small compounds that differentially modulate its activity are available. We thus employed a panel of Ire1 modulators to begin characterizing its role in senescence, and establish novel senolytic strategies. Collectively, our results highlight the senolytic potential of targeting autophagy and proteostasis in oncogene-induced senescence, and the importance of deciphering the mechanisms of action of senolytics to identify new targets and regulatory pathways