Journal articles on the topic 'Cell membranes Effect of drugs on'
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1
Ramalho, Maria João, Stéphanie Andrade, Joana Angélica Loureiro, and Maria Carmo Pereira. "Interaction of Bortezomib with Cell Membranes Regulates Its Toxicity and Resistance to Therapy." Membranes 12, no. 9 (August 23, 2022): 823. http://dx.doi.org/10.3390/membranes12090823.
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Bortezomib (BTZ) is a potent proteasome inhibitor currently being used to treat multiple myeloma. However, its high toxicity and resistance to therapy severely limit the treatment outcomes. Drug–membrane interactions have a crucial role in drugs’ behavior in vivo, affecting their bioavailability and pharmacological activity. Additionally, drugs’ toxicity often occurs due to their effects on the cell membranes. Therefore, studying BTZ’s interactions with cell membranes may explain the limitations of its therapy. Due to the cell membranes’ complexity, lipid vesicles were proposed here as biomembrane models, focusing on the membrane’s main constituents. Two models with distinct composition and complexity were used, one composed of 1,2-dimyristoyl-sn-glycero-3-phosphocholine (DMPC) and the other containing DMPC, cholesterol (Chol), and sphingomyelin (SM). BTZ’s interactions with the models were evaluated regarding the drugs’ lipophilicity, preferential location, and effects on the membrane’s physical state. The studies were conducted at different pH values (7.4 and 6.5) to mimic the normal blood circulation and the intestinal environment, respectively. BTZ revealed a high affinity for the membranes, which proved to be dependent on the drug-ionization state and the membrane complexity. Furthermore, BTZ’s interactions with the cell membranes was proven to induce changes in the membrane fluidity. This may be associated with its resistance to therapy, since the activity of efflux transmembrane proteins is dependent on the membrane’s fluidity.
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Kotyńska, Joanna, and Monika Naumowicz. "Effect of Selected Anionic and Cationic Drugs Affecting the Central Nervous System on Electrical Properties of Phosphatidylcholine Liposomes: Experiment and Theory." International Journal of Molecular Sciences 22, no. 5 (February 25, 2021): 2270. http://dx.doi.org/10.3390/ijms22052270.
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Interactions between phospholipid membranes and selected drugs affecting the central nervous system (CNS) were investigated. Small, unilamellar liposomes were used as biomimetic cell membrane models. Microelectrophoretic experiments on two-component liposomes were performed using the electrophoretic light scattering technique (ELS). The effect of both positively (perphenazine, PF) and negatively (barbituric acid, BA) charged drugs on zwitterionic L-α-phosphatidylcholine (PC) membranes were analyzed. Experimental membrane surface charge density (δ) data were determined as a function of pH. Quantitative descriptions of the adsorption equilibria formed due to the binding of solution ions to analyzed two-component membranes are presented. Binding constants of the solution ions with perphenazine and barbituric acid-modified membranes were determined. The results of our research show that both charged drugs change surface charge density values of phosphatidylcholine membranes. It can be concluded that perphenazine and barbituric acid are located near the membrane surface, interacting electrostatically with phosphatidylcholine polar heads.
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Aszalos, A., G. C. Yang, and M. M. Gottesman. "Depolymerization of microtubules increases the motional freedom of molecular probes in cellular plasma membranes." Journal of Cell Biology 100, no. 5 (May 1, 1985): 1357–62. http://dx.doi.org/10.1083/jcb.100.5.1357.
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Depolymerization of microtubules resulted in an increase in the motional freedom of molecular probes in the plasma membranes of Chinese hamster ovary cells expressed by the order parameter, S, measured with two different lipid-soluble spin label probes, 5-doxyl stearic acid and 16-doxyl methylstearate. Treatment with a variety of microtubule-depolymerizing agents, including Colcemid, colchicine, vinblastine, podophyllotoxin, and griseofulvin, all had similar effects on motional freedom of the probes whereas beta-lumicolchicine was inactive. Several independent lines of evidence suggest that these changes in motional freedom of the probes were not the direct result of the interaction of these relatively hydrophobic drugs with the plasma membrane: the effects of the drugs were not immediate; the dose response of the Colcemid effect was the same as the dose response for depolymerization of microtubules; taxol, which stabilizes microtubules but does not affect motional freedom in the membranes, blocked the effect of Colcemid on motional freedom; a mutant cell line which is resistant to colchicine because of reduced uptake of the drug showed no effects of colchicine on probe motional freedom; and a Colcemid-resistant mutant cell line with an altered beta-tubulin showed no effect of Colcemid on motional freedom in the membrane. These results support the hypothesis that microtubules might affect, directly or indirectly, plasma membrane functions.
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Torrisi, Cristina, Giuseppe Antonio Malfa, Rosaria Acquaviva, Francesco Castelli, and Maria Grazia Sarpietro. "Effect of Protocatechuic Acid Ethyl Ester on Biomembrane Models: Multilamellar Vesicles and Monolayers." Membranes 12, no. 3 (February 28, 2022): 283. http://dx.doi.org/10.3390/membranes12030283.
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The interactions of drugs with cell membranes are of primary importance for several processes involved in drugs activity. However, these interactions are very difficult to study due to the complexity of biological membranes. Lipid model membranes have been developed and used to gain insight into drug–membrane interactions. In this study, the interaction of protocatechuic acid ethyl ester, showing radical-scavenging activity, antimicrobial, antitumor and anti-inflammatory effects, with model membranes constituted by multilamellar vesicles and monolayers made of DMPC and DSPC, has been studied. Differential scanning calorimetry and Langmuir–Blodgett techniques have been used. Protocatechuic acid ethyl ester interacted both with MLV and monolayers. However, a stronger interaction of the drug with DMPC-based model membranes has been obtained. The finding of this study could help to understand the protocatechuic acid ethyl ester action mechanism.
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Tzoneva, Rumiana, Tihomira Stoyanova, Annett Petrich, Desislava Popova, Veselina Uzunova, Albena Momchilova, and Salvatore Chiantia. "Effect of Erufosine on Membrane Lipid Order in Breast Cancer Cell Models." Biomolecules 10, no. 5 (May 22, 2020): 802. http://dx.doi.org/10.3390/biom10050802.
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Alkylphospholipids are a novel class of antineoplastic drugs showing remarkable therapeutic potential. Among them, erufosine (EPC3) is a promising drug for the treatment of several types of tumors. While EPC3 is supposed to exert its function by interacting with lipid membranes, the exact molecular mechanisms involved are not known yet. In this work, we applied a combination of several fluorescence microscopy and analytical chemistry approaches (i.e., scanning fluorescence correlation spectroscopy, line-scan fluorescence correlation spectroscopy, generalized polarization imaging, as well as thin layer and gas chromatography) to quantify the effect of EPC3 in biophysical models of the plasma membrane, as well as in cancer cell lines. Our results indicate that EPC3 affects lipid–lipid interactions in cellular membranes by decreasing lipid packing and increasing membrane disorder and fluidity. As a consequence of these alterations in the lateral organization of lipid bilayers, the diffusive dynamics of membrane proteins are also significantly increased. Taken together, these findings suggest that the mechanism of action of EPC3 could be linked to its effects on fundamental biophysical properties of lipid membranes, as well as on lipid metabolism in cancer cells.
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Pérez-Isidoro, R., and M. Costas. "The effect of neuroleptic drugs on DPPC/sphingomyelin/cholesterol membranes." Chemistry and Physics of Lipids 229 (July 2020): 104913. http://dx.doi.org/10.1016/j.chemphyslip.2020.104913.
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Britt, Hannah M., Clara A. García-Herrero, Paul W. Denny, Jackie A. Mosely, and John M. Sanderson. "Lytic reactions of drugs with lipid membranes." Chemical Science 10, no. 3 (2019): 674–80. http://dx.doi.org/10.1039/c8sc04831b.
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Suwalsky, Mario, Pedro L. Hernández, Fernando Villena, and Carlos P. Sotomayor. "The Anticancer Drug Cytarabine Does not Interact with the Human Erythrocyte Membrane." Zeitschrift für Naturforschung C 58, no. 11-12 (December 1, 2003): 885–90. http://dx.doi.org/10.1515/znc-2003-11-1225.
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Abstract Cytarabine, an analog of deoxycytidine, is an important agent in the treatment of ovarian carcinoma, acute myeloid and lymphoblastic leukemia. Its mechanism of action has been attributed to an interference with DNA replication. The plasma membrane has received increasing attention as a possible target of antitumor drugs, where the drugs may act as growth factor antagonists and receptor blockers, interfere with mitogenic signal transduction or exert direct cytotoxic effects. Furthermore, it has been reported that drugs that exert their antiproliferative effect by interacting with DNA generally cause structural and functional membrane alterations which may be essential for growth inhibition by these agents. This paper describes the studies undertaken to determine the structural effects induced by cytarabine to cell membranes. The results showed that cytarabine, at a concentration about one thousand times higher than that found in plasma when it is therapeutically administered, did not induce significant structural perturbation in any of these systems. Therefore, it can be unambiguously concluded that this widely used anticancer drug does not interact at all with erythrocyte membranes.
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Rols, M. P., M. Golzio, B. Gabriel, and J. Teissié. "Factors Controlling Electropermeabilisation of Cell Membranes." Technology in Cancer Research & Treatment 1, no. 5 (October 2002): 319–27. http://dx.doi.org/10.1177/153303460200100502.
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Electric field pulses are a new approach for drug and gene delivery for cancer therapy. They induce a localized structural alteration of cell membranes. The associated physical mechanisms are well explained and can be safely controlled. A position dependent modulation of the membrane potential difference is induced when an electric field is applied to a cell. Electric field pulses with an overcritical intensity evoke a local membrane alteration. A free exchange of hydrophilic low molecular weight molecules takes place across the membrane. A leakage of cytosolic metabolites and a loading of polar drugs into the cytoplasm are obtained. The fraction of the cell surface which is competent for exchange is a function of the field intensity. The level of local exchange is strongly controlled by the pulse duration and the number of successive pulses. The permeabilised state is long lived. Its lifetime is under the control of the cumulated pulse duration. Cell viability can be preserved. Gene transfer is obtained but its mechanism is not a free diffusion. Plasmids are electrophoretically accumulated against the permeabilised cell surface and form aggregates due to the field effect. After the pulses, several steps follow: translocation to the cytoplasm, traffic to the nucleus and expression. Molecular structural and metabolic changes in cells remain mostly poorly understood. Nevertheless, while most studies were established on cells in culture ( in vitro), recent experiments show that similar effects are obtained on tissue ( in vivo). Transfer remains controlled by the physical parameters of the electrical treatment.
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Zhou, Yong, Elizabeth J. Dial, Rand Doyen, and Lenard M. Lichtenberger. "Effect of indomethacin on bile acid-phospholipid interactions: implication for small intestinal injury induced by nonsteroidal anti-inflammatory drugs." American Journal of Physiology-Gastrointestinal and Liver Physiology 298, no. 5 (May 2010): G722—G731. http://dx.doi.org/10.1152/ajpgi.00387.2009.
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The injurious effect of nonsteroidal anti-inflammatory drugs (NSAIDs) in the small intestine was not appreciated until the widespread use of capsule endoscopy. Animal studies found that NSAID-induced small intestinal injury depends on the ability of these drugs to be secreted into the bile. Because the individual toxicity of amphiphilic bile acids and NSAIDs directly correlates with their interactions with phospholipid membranes, we propose that the presence of both NSAIDs and bile acids alters their individual physicochemical properties and enhances the disruptive effect on cell membranes and overall cytotoxicity. We utilized in vitro gastric AGS and intestinal IEC-6 cells and found that combinations of bile acid, deoxycholic acid (DC), taurodeoxycholic acid, glycodeoxycholic acid, and the NSAID indomethacin (Indo) significantly increased cell plasma membrane permeability and became more cytotoxic than these agents alone. We confirmed this finding by measuring liposome permeability and intramembrane packing in synthetic model membranes exposed to DC, Indo, or combinations of both agents. By measuring physicochemical parameters, such as fluorescence resonance energy transfer and membrane surface charge, we found that Indo associated with phosphatidylcholine and promoted the molecular aggregation of DC and potential formation of larger and isolated bile acid complexes within either biomembranes or bile acid-lipid mixed micelles, which leads to membrane disruption. In this study, we demonstrated increased cytotoxicity of combinations of bile acid and NSAID and provided a molecular mechanism for the observed toxicity. This mechanism potentially contributes to the NSAID-induced injury in the small bowel.
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Bengü, Ergüden. "S. cerevisiae Outer and Inner Membranes are Compromised upon Benzyl Alcohol Treatment." International Journal of Membrane Science and Technology 8, no. 2 (December 7, 2021): 35–39. http://dx.doi.org/10.15379/2410-1869.2021.08.02.03.
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Although there are innovations in the treatment of diseases caused by fungi and medicines with multiple targets have been developed, the search for a drug with a broad spectrum and without any side effects continues to date. It is generally accepted that determining the cellular target responsible for the toxic effect opens up new possibilities for the development of new drugs. Especially the effects of antifungal agents on the surface components of the fungal cell, on cell wall synthesis and the identification of the target site are crucial in antifungal drug development. Thus studies on the fungal cell membranes in connection with the antifungal agents, aim to develop new strategies for the therapy of fungal infections. Antifungal agents targeting fungal cell wall and cell membrane components have increased in importance in clinical studies. In this study, understanding the mechanism of action of benzyl alcohol, a known membrane fluidizer, and the determination of its cellular targets are aimed. We have shown that in the presence of sorbitol, the osmotic stabilizer, benzyl alcohol becomes less effective against yeast cell. Moreover, benzyl alcohol disrupts cell membrane, causing leakage of ions to the extracellular medium. Nuclear membrane is distorted upon treatment of yeast cells with benzyl alcohol. Thus, we conclude that both outer and inner yeast cell membranes are compromised by the action of benzyl alcohol.
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Lu, Shirui, Pengxuan Zhao, Youbin Deng, and Yani Liu. "Mechanistic Insights and Therapeutic Delivery through Micro/Nanobubble-Assisted Ultrasound." Pharmaceutics 14, no. 3 (February 22, 2022): 480. http://dx.doi.org/10.3390/pharmaceutics14030480.
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Ultrasound with low frequency (20–100 kHz) assisted drug delivery has been widely investigated as a non-invasive method to enhance the permeability and retention effect of drugs. The functional micro/nanobubble loaded with drugs could provide an unprecedented opportunity for targeted delivery. Then, ultrasound with higher intensity would locally burst bubbles and release agents, thus avoiding side effects associated with systemic administration. Furthermore, ultrasound-mediated destruction of micro/nanobubbles can effectively increase the permeability of vascular membranes and cell membranes, thereby not only increasing the distribution concentration of drugs in the interstitial space of target tissues but also promoting the penetration of drugs through cell membranes into the cytoplasm. These advancements have transformed ultrasound from a purely diagnostic utility into a promising theragnostic tool. In this review, we first discuss the structure and generation of micro/nanobubbles. Second, ultrasound parameters and mechanisms of therapeutic delivery are discussed. Third, potential biomedical applications of micro/nanobubble-assisted ultrasound are summarized. Finally, we discuss the challenges and future directions of ultrasound combined with micro/nanobubbles.
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Ren, Lili, Lirong Qiu, Binbin Huang, Jun Yin, Yaning Li, Xiaolong Yang, and Guoguang Chen. "Preparation and Characterization of Anti-Cancer Crystal Drugs Based on Erythrocyte Membrane Nanoplatform." Nanomaterials 11, no. 10 (September 27, 2021): 2513. http://dx.doi.org/10.3390/nano11102513.
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The simple and functional modification of the nanoparticle’s surface is used to efficiently deliver chemotherapeutic drugs for anti-cancer treatment. Here, we construct a nanocrystalline drug delivery system with doxorubicin wrapped in red blood cell membranes for the treatment of mouse breast cancer models. Compared with traditional free drug treatments, the biodegradable natural red blood cell membrane is combined with pure crystalline drugs. The nanoparticles obtained by the preparation method have superior properties, such as good stability, significantly delaying the release of drugs and enhancing the inhibitory effect on tumor cells. This study shows that the design of RBC as an outsourced drug delivery system provides a promising foundation for the continued development, clinical trials, and nanomedicine research of anti-cancer drug nanocarriers in the future.
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Radhakrishnan, Navaneethan, Sunil C. Kaul, Renu Wadhwa, and Durai Sundar. "Phosphatidylserine Exposed Lipid Bilayer Models for Understanding Cancer Cell Selectivity of Natural Compounds: A Molecular Dynamics Simulation Study." Membranes 12, no. 1 (January 1, 2022): 64. http://dx.doi.org/10.3390/membranes12010064.
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Development of drugs that are selectively toxic to cancer cells and safe to normal cells is crucial in cancer treatment. Evaluation of membrane permeability is a key metric for successful drug development. In this study, we have used in silico molecular models of lipid bilayers to explore the effect of phosphatidylserine (PS) exposure in cancer cells on membrane permeation of natural compounds Withaferin A (Wi-A), Withanone (Wi-N), Caffeic Acid Phenethyl Ester (CAPE) and Artepillin C (ARC). Molecular dynamics simulations were performed to compute permeability coefficients. The results indicated that the exposure of PS in cancer cell membranes facilitated the permeation of Wi-A, Wi-N and CAPE through a cancer cell membrane when compared to a normal cell membrane. In the case of ARC, PS exposure did not have a notable influence on its permeability coefficient. The presented data demonstrated the potential of PS exposure-based models for studying cancer cell selectivity of drugs.
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Trombetta, Domenico, Francesco Castelli, Maria Grazia Sarpietro, Vincenza Venuti, Mariateresa Cristani, Claudia Daniele, Antonella Saija, Gabriela Mazzanti, and Giuseppe Bisignano. "Mechanisms of Antibacterial Action of Three Monoterpenes." Antimicrobial Agents and Chemotherapy 49, no. 6 (June 2005): 2474–78. http://dx.doi.org/10.1128/aac.49.6.2474-2478.2005.
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ABSTRACT In the present paper, we report the antimicrobial efficacy of three monoterpenes [linalyl acetate, (+)menthol, and thymol] against the gram-positive bacterium Staphylococcus aureus and the gram-negative bacterium Escherichia coli. For a better understanding of their mechanisms of action, the capability of these three monoterpenes to damage biomembranes was evaluated by monitoring the release, following exposure to the compounds under study, of the water-soluble fluorescent marker carboxyfluorescein from unilamellar vesicles with different lipidic compositions (phosphatidylcholine, phosphatidylcholine/phosphatidylserine [9:1], phosphatidylcholine/stearylamine [9:1], and phosphatidylglycerol/cardiolipin [9:1]). Furthermore, the interaction of the terpenes tested with dimyristoylphosphatidylcholine multilamellar vesicles as model membranes was monitored by means of differential scanning calorimetry. Finally, the results were related to the relative lipophilicity and water solubility of the compounds examined. Taken together, our findings lead us to speculate that the antimicrobial effect of (+)menthol, thymol, and linalyl acetate may result, at least partially, from a perturbation of the lipid fraction of microorganism plasma membrane, resulting in alterations of membrane permeability and in leakage of intracellular materials. Besides being related to physicochemical characteristics of the drugs (such as lipophilicity and water solubility), this effect seems to be dependent on lipid composition and net surface charge of microbial membranes. Furthermore, the drugs might cross the cell membranes, penetrating into the interior of the cell and interacting with intracellular sites critical for antibacterial activity.
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Sundukova, M. V., A. R. Mutina, O. S. Druginina, and A. I. Skorinkin. "Effects of drugs on water permeability of erythrocyte membranes." Biochemistry (Moscow) Supplement Series A: Membrane and Cell Biology 4, no. 2 (June 2010): 226–31. http://dx.doi.org/10.1134/s1990747810020157.
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Mastova, Anna V., Olga Yu Selyutina, Veronika I. Evseenko, and Nikolay E. Polyakov. "Photoinduced Oxidation of Lipid Membranes in the Presence of the Nonsteroidal Anti-Inflammatory Drug Ketoprofen." Membranes 12, no. 3 (February 22, 2022): 251. http://dx.doi.org/10.3390/membranes12030251.
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The damage of cell membranes induced by photosensitive drugs has attracted the significant attention of researchers in various fields of medicine. Ketoprofen (KP) is known to be the most photosensitive among the nonsteroidal anti-inflammatory drugs. The phototoxic side effects of KP and other non-steroidal anti-inflammatory drugs are associated with the action of free radicals, but there is insufficient information about the nature of these radicals. In the present study, free radicals formed upon KP irradiation within lipid membranes were studied using nuclear magnetic resonance (NMR) and chemically induced dynamic nuclear polarization (CIDNP) methods, as well as a molecular dynamics simulation. Our study confirmed the effective penetration of KP into the lipid bilayer and showed a significant effect of the nature of the medium on the photolysis mechanism. While, in a homogeneous solution, the main channel of KP photolysis is free radical-mediated monomolecular decomposition with formation of radical pairs of benzyl and CO2H● radicals, then, in the lipid membrane, the reaction route shifts towards the bimolecular reaction of KP photoreduction. In addition, the effect of the presence an electron donor (the amino acid tryptophan) on lipid oxidation has been studied. It was found that photoreaction of KP with tryptophan proceeds more efficiently than with lipid molecules.
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Frank, G. B. "Stereospecific opioid drug receptors on excitable cell membranes." Canadian Journal of Physiology and Pharmacology 63, no. 9 (September 1, 1985): 1023–32. http://dx.doi.org/10.1139/y85-168.
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In the past decade evidence has accumulated showing that there are stereospecific opioid drug receptors located on the surface membranes of neurones and skeletal muscle fibres which can block action potentials when opioid drugs are applied to the cells. The nature of this evidence and the difficulties involved in this area of investigation are discussed in detail. Two different mechanisms have been described for this depression of excitability; one, a direct blocking action on sodium channels (or the calcium channels in the case of cells with calcium action potentials) and the other, a stimulation of membrane potassium conductance which results in hyperpolarization and increased membrane conductance both of which decrease excitability. For the most part these different mechanisms seem to prevail in different cell types as will be discussed. Some other points discussed are as follows: first, in higher doses (or concentrations) opioids produce a local anestheticlike effect which cannot be antagonized by opioid antagonists; next, the opioid antagonists which are easily available and commonly employed change from antagonists to agonists as their concentration is increased; and finally, the evidence required for the demonstration of stereospecific opioid receptors is considered in some detail.
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Wang, L. H., K. G. Rothberg, and R. G. Anderson. "Mis-assembly of clathrin lattices on endosomes reveals a regulatory switch for coated pit formation." Journal of Cell Biology 123, no. 5 (December 1, 1993): 1107–17. http://dx.doi.org/10.1083/jcb.123.5.1107.
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The clathrin-coated pit lattice is held onto the plasma membrane by an integral membrane protein that binds the clathrin AP-2 subunit with high affinity. In vitro studies have suggested that this protein controls the assembly of the pit because membrane bound AP-2 is required for lattice assembly. If so, the AP-2 binding site must be a resident protein of the coated pit and recycle with other receptors that enter cells through this pathway. Proper recycling, however, would require the switching off of AP-2 binding to allow the binding site to travel through the endocytic pathway unencumbered. Evidence for this hypothesis has been revealed by the cationic amphiphilic class of drugs (CAD), which have previously been found to inhibit receptor recycling. Incubation of human fibroblasts in the presence of these drugs caused clathrin lattices to assemble on endosomal membranes and at the same time prevented coated pit assembly at the cell surface. These effects suggest that CADs reverse an on/off switch that controls AP-2 binding to membranes. We conclude that cells have a mechanism for switching on and off AP-2 binding during the endocytic cycle.
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Elexpe, Ane, Nerea Nieto, Claudia Fernández-Cuétara, Celtia Domínguez-Fernández, Teresa Morera-Herreras, María Torrecilla, Cristina Miguélez, et al. "Study of Tissue-Specific Reactive Oxygen Species Formation by Cell Membrane Microarrays for the Characterization of Bioactive Compounds." Membranes 11, no. 12 (November 29, 2021): 943. http://dx.doi.org/10.3390/membranes11120943.
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The production of reactive oxygen species (ROS) increases considerably in situations of cellular stress, inducing lipid peroxidation and multiple alterations in proteins and nucleic acids. However, sensitivity to oxidative damage varies between organs and tissues depending on the triggering process. Certain drugs used in the treatment of diverse diseases such as malaria have side effects similar to those produced by oxidative damage, although no specific study has been conducted. For this purpose, cell membrane microarrays were developed and the superoxide production evoked by the mitochondrial activity was assayed in the presence of specific inhibitors: rotenone, antimycin A and azide. Once the protocol was set up on cell membrane isolated from rat brain areas, the effect of six antimalarial drugs (atovaquone, quinidine, doxycycline, mefloquine, artemisinin, and tafenoquine) and two essential oils (Rosmarinus officinalis and Origanum majoricum) were evaluated in multiple human samples. The basal activity was different depending on the type of tissue, the liver, jejunum and adrenal gland being the ones with the highest amount of superoxide. The antimalarial drugs studied showed specific behavior according to the type of human tissue analyzed, with atovaquone and quinidine producing the highest percentage of superoxide formation, and doxycycline the lowest. In conclusion, the analysis of superoxide production evaluated in cell membranes of a collection of human tissues allowed for the characterization of the safety profile of these antimalarial drugs against toxicity mediated by oxidative stress.
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Шершунова, Е. А., И. Е. Ребров, В. В. Мищенко, А. И. Крюков, Е. А. Воротеляк, and О. С. Роговая. "Оценка жизнеспособности живых тканевых эквивалентов под действием импульсного тока со смещением." Письма в журнал технической физики 47, no. 13 (2021): 24. http://dx.doi.org/10.21883/pjtf.2021.13.51117.18606.
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The paper deals with an electrophysical device for combined electroporative-iontophoretic effect on biological membranes. The experimental results on the influence of a pulsed current source with displacement on the viability of living tissue equivalents (LTE) cells are presented. There were obtained values of pulse electrophysical parameters providing preservation of LTE cell vitality. According to the obtained data we suggest that such electrophysical parameters can be used for drugs delivery through the equivalent of the round window membrane and for creation in the future a technology for the administration of drugs through biological barriers with the possibility of their penetration into the inner ear using pulsed electrical installations.
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de Souza, Wanderley, and Juliany Cola Fernandes Rodrigues. "Sterol Biosynthesis Pathway as Target for Anti-trypanosomatid Drugs." Interdisciplinary Perspectives on Infectious Diseases 2009 (2009): 1–19. http://dx.doi.org/10.1155/2009/642502.
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Sterols are constituents of the cellular membranes that are essential for their normal structure and function. In mammalian cells, cholesterol is the main sterol found in the various membranes. However, other sterols predominate in eukaryotic microorganisms such as fungi and protozoa. It is now well established that an important metabolic pathway in fungi and in members of the Trypanosomatidae family is one that produces a special class of sterols, including ergosterol, and other 24-methyl sterols, which are required for parasitic growth and viability, but are absent from mammalian host cells. Currently, there are several drugs that interfere with sterol biosynthesis (SB) that are in use to treat diseases such as high cholesterol in humans and fungal infections. In this review, we analyze the effects of drugs such as (a) statins, which act on the mevalonate pathway by inhibiting HMG-CoA reductase, (b) bisphosphonates, which interfere with the isoprenoid pathway in the step catalyzed by farnesyl diphosphate synthase, (c) zaragozic acids and quinuclidines, inhibitors of squalene synthase (SQS), which catalyzes the first committed step in sterol biosynthesis, (d) allylamines, inhibitors of squalene epoxidase, (e) azoles, which inhibit C14α-demethylase, and (f) azasterols, which inhibitΔ24(25)-sterol methyltransferase (SMT). Inhibition of this last step appears to have high selectivity for fungi and trypanosomatids, since this enzyme is not found in mammalian cells. We review here the IC50 values of these various inhibitors, their effects on the growth of trypanosomatids (both in axenic cultures and in cell cultures), and their effects on protozoan structural organization (as evaluted by light and electron microscopy) and lipid composition. The results show that the mitochondrial membrane as well as the membrane lining the protozoan cell body and flagellum are the main targets. Probably as a consequence of these primary effects, other important changes take place in the organization of the kinetoplast DNA network and on the protozoan cell cycle. In addition, apoptosis-like and autophagic processes induced by several of the inhibitors tested led to parasite death.
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Martinelli, Carolina, Fabio Gabriele, Elena Dini, Francesca Carriero, Giorgia Bresciani, Bianca Slivinschi, Marco Dei Giudici, et al. "Development of Artificial Plasma Membranes Derived Nanovesicles Suitable for Drugs Encapsulation." Cells 9, no. 7 (July 6, 2020): 1626. http://dx.doi.org/10.3390/cells9071626.
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Extracellular vesicles (EVs) are considered as promising nanoparticle theranostic tools in many pathological contexts. The increasing clinical employment of therapeutic nanoparticles is contributing to the development of a new research area related to the design of artificial EVs. To this aim, different approaches have been described to develop mimetic biologically functional nanovescicles. In this paper, we suggest a simplified procedure to generate plasma membrane-derived nanovesicles with the possibility to efficiently encapsulate different drugs during their spontaneously assembly. After physical and molecular characterization by Tunable Resistive Pulse Sensing (TRPS) technology, transmission electron microscopy, and flow cytometry, as a proof of principle, we have loaded into mimetic EVs the isoquinoline alkaloid Berberine chloride and the chemotherapy compounds Temozolomide or Givinostat. We demonstrated the fully functionality of these nanoparticles in drug encapsulation and cell delivery, showing, in particular, a similar cytotoxic effect of direct cell culture administration of the anticancer drugs. In conclusion, we have documented the possibility to easily generate scalable nanovesicles with specific therapeutic cargo modifications useful in different drug delivery contexts.
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Stinson, Lisa F., Demelza J. Ireland, Matthew W. Kemp, Matthew S. Payne, Sarah J. Stock, John P. Newnham, and Jeffrey A. Keelan. "Effects of cytokine-suppressive anti-inflammatory drugs on inflammatory activation in ex vivo human and ovine fetal membranes." REPRODUCTION 147, no. 3 (March 2014): 313–20. http://dx.doi.org/10.1530/rep-13-0576.
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Intrauterine infection and inflammation are responsible for the majority of early (<32 weeks) spontaneous preterm births (PTBs). Anti-inflammatory agents, delivered intra-amniotically together with antibiotics, may be an effective strategy for preventing PTB. In this study, the effects of four cytokine-suppressive anti-inflammatory drugs (CSAIDs:N-acetyl cysteine (NAC), SB239063, TPCA-1 and NEMO binding domain inhibitor (NBDI)) were assessed on human and ovine gestational membrane inflammation. Full-thickness membranes were collected from healthy, term, human placentas delivered by Caesarean section (n=5). Using a Transwell model, they were stimulatedex vivowith γ-irradiation-killedEscherichia coliapplied to the amniotic face. Membranes from near-term, ovine placentas were stimulatedin uterowith lipopolysaccharide,Ureaplasma parvumor saline control and subjected to explant culture. The effects of treatment with CSAIDs or vehicle (1% DMSO) on accumulation of PGE2and cytokines (human interleukin 6 (IL6), IL10 and TNFα; ovine IL8 (oIL8)) were assessed in conditioned media at various time points (3–20 h). In human membranes, the IKKβ inhibitor TPCA-1 (7 μM) and p38 MAPK inhibitor SB239063 (20 μM) administered to the amniotic compartment were the most effective in inhibiting accumulation of cytokines and PGE2in the fetal compartment. NAC (10 mM) inhibited accumulation of PGE2and IL10 only; NBDI (10 μM) had no significant effect. In addition to the fetal compartment, SB239063 also exerted consistent and significant inhibitory effects in the maternal compartment. TPCA-1 and SB239063 suppressed oIL8 production, while all CSAIDs tested suppressed ovine PGE2production. These results support the further investigation of intra-amniotically delivered CSAIDs for the prevention of inflammation-mediated PTB.
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Gieszinger, Péter, Tamás Kiss, Piroska Szabó-Révész, and Rita Ambrus. "The Development of an In Vitro Horizontal Diffusion Cell to Monitor Nasal Powder Penetration Inline." Pharmaceutics 13, no. 6 (May 28, 2021): 809. http://dx.doi.org/10.3390/pharmaceutics13060809.
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The development of in vitro investigation models could be important using sensitive and fast methods during formulation. Intranasal applied drugs (meloxicam, lamotrigine, and levodopa) avoid the gastrointestinal tract and can achieve higher bioavailability, therefore a penetration extent is a key property. In this study, the in vitro adaptability of a modified horizontal diffusion cell was tested by using these model active pharmaceutical ingredients (APIs). The special factors consisted of the volume of the chambers, the arrangement of the stirrers, the design of probe input for real-time analysis and decreased membrane area. Membranes were impregnated by isopropyl myristate and by using phosphate buffer to evaluate the effect of API hydrophilicity on the diffusion properties. The lipophilicity of the API was proportional to the penetration extent through isopropyl myristate-impregnated membranes compared with buffer-soaked membranes. After evaluating the arithmetic mean of standard relative deviations and the penetrated extent of APIs at 15 min, Metricel® could be suggested for levodopa and meloxicam, and Whatman™ for lamotrigine. The modified model is suitable for inline, real-time detection, at nasal conditions, using small volumes of phases, impregnated membrane, to monitor the diffusion of the drug and to determine its concentration in the acceptor and donor phases.
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Saito, Kazutomo, Nozomu Abe, Hiroaki Toyama, Yutaka Ejima, Masanori Yamauchi, Hajime Mushiake, and Itsuro Kazama. "Second-Generation Histamine H1 Receptor Antagonists Suppress Delayed Rectifier K+-Channel Currents in Murine Thymocytes." BioMed Research International 2019 (April 30, 2019): 1–12. http://dx.doi.org/10.1155/2019/6261951.
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Background/Aims. Voltage-dependent potassium channels (Kv1.3) are predominantly expressed in lymphocyte plasma membranes. These channels are critical for the activation and proliferation of lymphocytes. Since second-generation antihistamines are lipophilic and exert immunomodulatory effects, they are thought to affect the lymphocyte Kv1.3-channel currents. Methods. Using the patch-clamp whole-cell recording technique in murine thymocytes, we tested the effects of second-generation antihistamines, such as cetirizine, fexofenadine, azelastine, and terfenadine, on the channel currents and the membrane capacitance. Results. These drugs suppressed the peak and the pulse-end currents of the channels, although the effects of azelastine and terfenadine on the peak currents were more marked than those of cetirizine and fexofenadine. Both azelastine and terfenadine significantly lowered the membrane capacitance. Since these drugs did not affect the process of endocytosis in lymphocytes, they were thought to have interacted directly with the plasma membranes. Conclusions. Our study revealed for the first time that second-generation antihistamines, including cetirizine, fexofenadine, azelastine, and terfenadine, exert suppressive effects on lymphocyte Kv1.3-channels. The efficacy of these drugs may be related to their immunomodulatory mechanisms that reduce the synthesis of inflammatory cytokine.
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Nissani, Edna, and Hagai Ginsburg. "Protonophoric effects of antimalarial drugs and alkylamines in Escherichia coli membranes." Biochimica et Biophysica Acta (BBA) - Biomembranes 978, no. 2 (January 1989): 293–98. http://dx.doi.org/10.1016/0005-2736(89)90127-2.
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Suwalsky, Mario, Pedro Hernández, Fernando Villena, and Carlos P. Sotomayor. "The Anticancer Drug Chlorambucil Interacts with the Human Erythrocyte Membrane and Model Phospholipid Bilayers." Zeitschrift für Naturforschung C 54, no. 12 (December 1, 1999): 1089–95. http://dx.doi.org/10.1515/znc-1999-1214.
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The plasma membrane has gained increasing attention as a possible target of antitumor drugs. It has been reported that they act as growth factor antagonists, growth factor receptor blockers, interfere with mitogenic signal transduction or exert direct cytotoxic effects. Chlorambucil (4-[p-(bis[2-chloroethyl]amino)phenyl]butyric acid) is an alkylating agent widely used in the treatment of chronic lymphocytic leukaemia. Contradictory reports have been published concerning its interaction with cell membranes. Whereas a decrease in the fluidity of Ehrlich ascite tumor cells has been adduced, no evidences were found that chlorambucil changes membrane lipid fluidity and alkylating agents had effects in these systems even at highly toxic concentrations. Our results showed that chlorambucil at a dose equivalent to its therapeutical concentration in the plasma (3.6 μm) caused the human erythrocyte membrane to develop cup-shaped forms (stomatocytes). Accordingly to the bilayer couple hypothesis, this means that the drug is inserted into the inner monolayer of the erythrocyte membrane, a conclusion supported by X-ray diffraction performed on multilayers of dimyristoylphosphatidylcholine (DMPC) and dimyristoylphosphatidylethanolamine (DMPE), representative of phospholipid classes located in the outer and inner monolayers of the erythrocyte membrane, respectively. It is concluded that the cytotoxic effect of chlorambucil might be due to alteration of the structure and therefore of the physiological properties of cell membranes such as fluidity, permeability, receptor and channel functions.
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Bjerregaard, Henning F. "Side-specific Toxic Effects on the Membranes of Cultured Renal Epithelial Cells (A6)." Alternatives to Laboratory Animals 23, no. 4 (July 1995): 485–90. http://dx.doi.org/10.1177/026119299502300411.
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- A cultured epithelial cell line from toad kidney (A6) was used to investigate side-specific toxicity related to the apical (outer) and basolateral (inner) membranes of epithdia. Well-known inhibitors and stimulators of ion transport were used to show that the ion transport proteins are asymmetrically distributed: the apical membrane contains sodium and chloride channels and the basolateral membrane contains Na+/K+ pumps, Na+/Cl- co-transporters, potassium channels and receptors for antidiuretic hormone The data demonstrate that the cellular toxicity of chemicals decreases when they are added to the apical side, illustrating that the epithelium acts as a functional barrier. However, the side-specific toxicity was more pronounced for ions and water-soluble molecules than for organic solvents, indicating that A6 epitheha can be used to distinguish between drugs that target specific membrane proteins and those that target membrane lipids. Furthermore, the cell line could be used to pick up chemicals that, at low concentrations inhibit sodium absorption and chloride secretion, without having any effect on cellular toxicity.
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Loffredo, Maria Rosa, Filippo Savini, Sara Bobone, Bruno Casciaro, Henrik Franzyk, Maria Luisa Mangoni, and Lorenzo Stella. "Inoculum effect of antimicrobial peptides." Proceedings of the National Academy of Sciences 118, no. 21 (May 21, 2021): e2014364118. http://dx.doi.org/10.1073/pnas.2014364118.
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The activity of many antibiotics depends on the initial density of cells used in bacterial growth inhibition assays. This phenomenon, termed the inoculum effect, can have important consequences for the therapeutic efficacy of the drugs, because bacterial loads vary by several orders of magnitude in clinically relevant infections. Antimicrobial peptides are a promising class of molecules in the fight against drug-resistant bacteria because they act mainly by perturbing the cell membranes rather than by inhibiting intracellular targets. Here, we report a systematic characterization of the inoculum effect for this class of antibacterial compounds. Minimum inhibitory concentration values were measured for 13 peptides (including all-D enantiomers) and peptidomimetics, covering more than seven orders of magnitude in inoculated cell density. In most cases, the inoculum effect was significant for cell densities above the standard inoculum of 5 × 105 cells/mL, while for lower densities the active concentrations remained essentially constant, with values in the micromolar range. In the case of membrane-active peptides, these data can be rationalized by considering a simple model, taking into account peptide–cell association, and hypothesizing that a threshold number of cell-bound peptide molecules is required in order to cause bacterial killing. The observed effect questions the clinical utility of activity and selectivity determinations performed at a fixed, standardized cell density. A routine evaluation of the dependence of the activity of antimicrobial peptides and peptidomimetics on the inoculum should be considered.
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Gerber, Werner, Johan Steyn, Awie Kotzé, and Josias Hamman. "Beneficial Pharmacokinetic Drug Interactions: A Tool to Improve the Bioavailability of Poorly Permeable Drugs." Pharmaceutics 10, no. 3 (July 26, 2018): 106. http://dx.doi.org/10.3390/pharmaceutics10030106.
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Simultaneous oral intake of herbs, supplements, foods and drugs with other drug(s) may result in pharmacokinetic or pharmacodynamic interactions with the latter. Although these interactions are often associated with unwanted effects such as adverse events or inefficacy, they can also produce effects that are potentially beneficial to the patient. Beneficial pharmacokinetic interactions include the improvement of the bioavailability of a drug (i.e., by enhancing absorption and/or inhibiting metabolism) or prolongation of a drug’s plasma level within its therapeutic window (i.e., by decreasing excretion), whereas beneficial pharmacodynamic interactions include additive or synergistic effects. Mechanisms by which pharmacokinetic interactions can cause beneficial effects include enhancement of membrane permeation (e.g., structural changes in the epithelial cell membranes or opening of tight junctions), modulation of carrier proteins (e.g., inhibition of efflux transporters and stimulation of uptake transporters) and inhibition of metabolic enzymes. In the current review, selected pharmacokinetic interactions between drugs and various compounds from different sources including food, herb, dietary supplements and selected drugs are discussed. These interactions may be exploited in the future to the benefit of the patient, for example, by delivering drugs that are poorly bioavailable in therapeutic levels via alternative routes of administration than parenteral injection.
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Faúndez, Victor, Jim-Tong Horng, and Regis B. Kelly. "ADP Ribosylation Factor 1 Is Required for Synaptic Vesicle Budding in PC12 Cells." Journal of Cell Biology 138, no. 3 (August 11, 1997): 505–15. http://dx.doi.org/10.1083/jcb.138.3.505.
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Carrier vesicle generation from donor membranes typically progresses through a GTP-dependent recruitment of coats to membranes. Here we explore the role of ADP ribosylation factor (ARF) 1, one of the GTP-binding proteins that recruit coats, in the production of neuroendocrine synaptic vesicles (SVs) from PC12 cell membranes. Brefeldin A (BFA) strongly and reversibly inhibited SV formation in vivo in three different PC12 cell lines expressing vesicle-associated membrane protein–T Antigen derivatives. Other membrane traffic events remained unaffected by the drug, and the BFA effects were not mimicked by drugs known to interfere with formation of other classes of vesicles. The involvement of ARF proteins in the budding of SVs was addressed in a cell-free reconstitution system (Desnos, C., L. Clift-O'Grady, and R.B. Kelly. 1995. J. Cell Biol. 130:1041–1049). A peptide spanning the effector domain of human ARF1 (2–17) and recombinant ARF1 mutated in its GTPase activity, both inhibited the formation of SVs of the correct size. During in vitro incubation in the presence of the mutant ARFs, the labeled precursor membranes acquired different densities, suggesting that the two ARF mutations block at different biosynthetic steps. Cell-free SV formation in the presence of a high molecular weight, ARF-depleted fraction from brain cytosol was significantly enhanced by the addition of recombinant myristoylated native ARF1. Thus, the generation of SVs from PC12 cell membranes requires ARF and uses its GTPase activity, probably to regulate coating phenomena.
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Bogacz, Anna, Donata Deka-Pawlik, Joanna Bartkowiak-Wieczorek, Monika Karasiewicz, Radosław Kujawski, Aleksandra Kowalska, Aleksandra Chałas, Bogusław Czerny, Edmund Grześkowiak, and Przemysław M. Mrozikiewicz. "The effect of herbal materials on the p-glycoprotein activity and function." Herba Polonica 59, no. 4 (December 1, 2013): 129–41. http://dx.doi.org/10.2478/hepo-2013-0029.
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Abstract P-glycoprotein (P-gp) encoded by the MDR1 (multidrug resistance 1) gene is ATP-dependent transporting protein which is localizated in the cell membrane. P-gp is expressed mainly in organs with the secretory functions and its physiological role concerns tissue protection against xenobiotics. P-glycoprotein is involved in the permeability barriers of the blood-brain, blood-placenta directly protecting these organs. It participates in the transport of many drugs and other xenobiotics affecting their absorption, distribution, metabolism and excretion. The high P-gp activity in the cell membranes of cancer tissue is a major cause of lack of effectiveness of chemotherapy. Hence, the methods which could increase the sensibility of these pathological cells to cytostatics are still being searched. In the experimental studies it was shown that natural plant substances may have an effect on the expression level and activity of P-glycoprotein. Hypericum perforatum, Ginkgo biloba and Camellia sinensis increase P-gp activity while curcumin from Curcuma longa, piperine and silymarin inhibit this protein. Taking into account a wide substrate spectrum of P-gp, application of our knowledge on interactions of herbals and synthetic drugs should be considered in order to improve drug impact on different tissues.
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Salerno, Simona, Maria Penelope De Santo, Enrico Drioli, and Loredana De Bartolo. "Nano- and Micro-Porous Chitosan Membranes for Human Epidermal Stratification and Differentiation." Membranes 11, no. 6 (May 27, 2021): 394. http://dx.doi.org/10.3390/membranes11060394.
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The creation of partial or complete human epidermis represents a critical aspect and the major challenge of skin tissue engineering. This work was aimed at investigating the effect of nano- and micro-structured CHT membranes on human keratinocyte stratification and differentiation. To this end, nanoporous and microporous membranes of chitosan (CHT) were prepared by phase inversion technique tailoring the operational parameters in order to obtain nano- and micro-structured flat membranes with specific surface properties. Microporous structures with different mean pore diameters were created by adding and dissolving, in the polymeric solution, polyethylene glycol (PEG Mw 10,000 Da) as porogen, with a different CHT/PEG ratio. The developed membranes were characterized and assessed for epidermal construction by culturing human keratinocytes on them for up to 21 days. The overall results demonstrated that the membrane surface properties strongly affect the stratification and terminal differentiation of human keratinocytes. In particular, human keratinocytes adhered on nanoporous CHT membranes, developing the structure of the corneum epidermal top layer, characterized by low thickness and low cell proliferation. On the microporous CHT membrane, keratinocytes formed an epidermal basal lamina, with high proliferating cells that stratified and differentiated over time, migrating along the z axis and forming a multilayered epidermis. This strategy represents an attractive tissue engineering approach for the creation of specific human epidermal strata for testing the effects and toxicity of drugs, cosmetics and pollutants.
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Ireland, Demelza J., Elizabeth A. Nathan, Shaofu Li, Adrian K. Charles, Lisa F. Stinson, Matthew W. Kemp, John P. Newnham, and Jeffrey A. Keelan. "Preclinical evaluation of drugs to block inflammation-driven preterm birth." Innate Immunity 23, no. 1 (November 30, 2016): 20–33. http://dx.doi.org/10.1177/1753425916672313.
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Intrauterine inflammation, the major cause of early preterm birth, can have microbial and sterile aetiologies. We assessed in a Transwell model the anti-inflammatory efficacies of five drugs on human extraplacental membranes delivered after preterm spontaneous labour (30–34 wk). Drugs [TPCA1 (IKKβ inhibitor), 5 z-7-oxozeaenol (OxZ, TAK1 inhibitor), inhibitor of NF-κB essential modulator binding domain (iNBD), SB239063 (p38 MAPK inhibitor) and N-acetyl cysteine (free radical scavenger free radicals)] were added after 12 h equilibration to the amniotic compartment. Concentrations of IL-6, TNF-α, MCP-1, IL-1β and PGE2 in the media, and IL6, TNFA and PTGS2 mRNA expression levels in membranes, were determined after 12 h. Data were analysed using mixed models analyses. Thirteen of the 28 membranes had histological chorioamnionitis (HCA+); five were positive for bacterial culture and six for fetal inflammatory reaction. Baseline PGE2 and cytokine production was similar between HCA– and HCA+ membranes. Anti-inflammatory effects were also similar between HCA– and HCA+ membranes. TPCA1 and OxZ were the most effective drugs; each inhibited amniotic secretion of 4/5 pro-inflammatory mediators and mRNA levels of 2/3, regardless of stimulus. We conclude that treatment with TPCA1 or OxZ, in combination with antibiotics, may minimise the adverse effects of intrauterine inflammation in pregnancy.
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Sánchez-San Martín, Claudia, Tomás López, Carlos F. Arias, and Susana López. "Characterization of Rotavirus Cell Entry." Journal of Virology 78, no. 5 (March 1, 2004): 2310–18. http://dx.doi.org/10.1128/jvi.78.5.2310-2318.2004.
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ABSTRACT While recently we have learned much about the viral and cellular proteins involved in the initial attachment of rotaviruses to MA104 cells, the mechanism by which these viruses reach the interior of the cell is poorly understood. For this study, we observed the effects of drugs and of dominant-negative mutants, known to impair clathrin-mediated endocytosis and endocytosis mediated by caveolae, on rotavirus cell infection. Rotaviruses were able to enter cells in the presence of compounds that inhibit clathrin-mediated endocytosis as well as cells overexpressing a dominant-negative form of Eps15, a protein crucial for the assembly of clathrin coats. We also found that rotaviruses infected cells in which caveolar uptake was blocked; treatment with the cholesterol binding agents nystatin and filipin, as well as transfection of cells with dominant-negative caveolin-1 and caveolin-3 mutants, had no effect on rotavirus infection. Interestingly, cells treated with methyl-β-cyclodextrin, a drug that sequesters cholesterol from membranes, and cells expressing a dominant-negative mutant of the large GTPase dynamin, which is known to function in several membrane scission events, were not infected by rotaviruses, indicating that cholesterol and dynamin play a role in the entry of rotaviruses.
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Tanimura, Susumu, A.-i. Hirano, Junya Hashizume, Masahiro Yasunaga, Takumi Kawabata, Kei-ichi Ozaki, and Michiaki Kohno. "Anticancer Drugs Up-regulate HspBP1 and Thereby Antagonize the Prosurvival Function of Hsp70 in Tumor Cells." Journal of Biological Chemistry 282, no. 49 (September 12, 2007): 35430–39. http://dx.doi.org/10.1074/jbc.m707547200.
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The 70-kDa heat shock protein (Hsp70) is up-regulated in a wide variety of tumor cell types and contributes to the resistance of these cells to the induction of cell death by anticancer drugs. Hsp70 binding protein 1 (HspBP1) modulates the activity of Hsp70 but its biological significance has remained unclear. We have now examined whether HspBP1 might interfere with the prosurvival function of Hsp70, which is mediated, at least in part, by inhibition of the death-associated permeabilization of lysosomal membranes. HspBP1 was found to be expressed at a higher level than Hsp70 in all normal and tumor cell types examined. Tumor cells with a high HspBP1/Hsp70 molar ratio were more susceptible to anticancer drugs than were those with a low ratio. Ectopic expression of HspBP1 enhanced this effect of anticancer drugs in a manner that was both dependent on the ability of HspBP1 to bind to Hsp70 and sensitive to the induction of Hsp70 by mild heat shock. Furthermore, anticancer drugs up-regulated HspBP1 expression, whereas prevention of such up-regulation by RNA interference reduced the susceptibility of tumor cells to anticancer drugs. Overexpression of HspBP1 promoted the permeabilization of lysosomal membranes, the release of cathepsins from lysosomes into the cytosol, and the activation of caspase-3 induced by anticancer drugs. These results suggest that HspBP1, by antagonizing the prosurvival activity of Hsp70, sensitizes tumor cells to cathepsin-mediated cell death.
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Rudnytska, M., and T. Palladina. "Influence of methyure and ivin preparations on vacuolar Ca2+/H+ antiporter of Zea mays L. root cells under salt stress." Bulletin of Taras Shevchenko National University of Kyiv. Series: Biology 79, no. 3 (2019): 68–71. http://dx.doi.org/10.17721/1728_2748.2019.79.68-71.
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Because calcium plays an important role in the regulation of growth and development processes in plant organism as well as the formation of a specific physiological response to the action of various stressors, acting as a secondary messenger, the purpose of the study was to study the effect of heterocyclic drugs Methyure and Ivin of root cells Zea mays L. under salt stress. The roots of maize hybrids of Ostrich CB were exposed in the presence of 0.1 M sodium chloride for 1 and 10 days. Vacuolar membranes were obtained from corn root homogenate by centrifugation in a sucrose step gradient. The activity of the Са2+/Н+-antiporter was evaluated by the proton release from vesicles by adding calcium ions to the incubation medium, expressing ∆F% per mg of protein per minute. Under control conditions, heterocyclic drugs Methyure and Ivin do not affect the activity of Са2+/Н+-antiporter in the vacuolar membranes of corn roots and do not significantly contribute to the development of stress response in plants. At the same time, under the conditions of salt exposure of maize seedlings the opposite directed effect of Methyure and Ivin on the activity of Са2+/Н+-antiporter in the membranes of root vacuoles was revealed. Thus, under prolonged salt exposure, Methyure increases the activity of Са2+/Н+-antiporter in the vacuolar membrane of the root and, on the contrary, Ivin reduces it, which may be due to the differences in chemical composition of these heterocyclic drugs. The results, that were obtained, indicate that the salt-protective effect of the heterocyclic drug Methyure may also be due to its effect on the functional activity of the Са2+/Н+-antiporter in the vacuolar membrane of corn root.
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Trombino, Sonia, Federica Curcio, Teresa Poerio, Michele Pellegrino, Rossella Russo, and Roberta Cassano. "Chitosan Membranes Filled with Cyclosporine A as Possible Devices for Local Administration of Drugs in the Treatment of Breast Cancer." Molecules 26, no. 7 (March 26, 2021): 1889. http://dx.doi.org/10.3390/molecules26071889.
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The aim of this work is the design, preparation and characterization of membranes based on cyclosporine A (CsA) and chitosan carboxylate (CC) to be used as an implantable subcutaneous medical device for a prolonged therapeutic effect in the treatment of breast cancer. The choice to use CsA is due to literature data that have demonstrated its possible antitumor activity on different types of neoplastic cells. To this end, CsA was bound to CC through an amidation reaction to obtain a prodrug to be dispersed in a chitosan-based polymeric membrane. The reaction intermediates and the final product were characterized by Fourier transform infrared spectroscopy (FT-IR) and proton nuclear magnetic resonance (1H-NMR). Membranes were analyzed by differential scanning calorimetry (DSC) and scanning electron microscopy (SEM). The data obtained showed the effective formation of the amide bond between CsA and CC and the complete dispersion of CsA inside the polymeric membrane. Furthermore, preliminary tests, conducted on MDA-MB-231, a type of breast cancer cell line, have shown a high reduction in the proliferation of cancer cells. These results indicate the possibility of using the obtained membranes as an interesting strategy for the release of cyclosporin-A in breast cancer patients.
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Segovia, Roser, Judith Solé, Ana Maria Marqués, Yolanda Cajal, and Francesc Rabanal. "Unveiling the Membrane and Cell Wall Action of Antimicrobial Cyclic Lipopeptides: Modulation of the Spectrum of Activity." Pharmaceutics 13, no. 12 (December 17, 2021): 2180. http://dx.doi.org/10.3390/pharmaceutics13122180.
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Antibiotic resistance is a major public health challenge, and Gram-negative multidrug-resistant bacteria are particularly dangerous. The threat of running out of active molecules is accelerated by the extensive use of antibiotics in the context of the COVID-19 pandemic, and new antibiotics are urgently needed. Colistin and polymyxin B are natural antibiotics considered as last resort drugs for multi-resistant infections, but their use is limited because of neuro- and nephrotoxicity. We previously reported a series of synthetic analogues inspired in natural polymyxins with a flexible scaffold that allows multiple modifications to improve activity and reduce toxicity. In this work, we focus on modifications in the hydrophobic domains, describing analogues that broaden or narrow the spectrum of activity including both Gram-positive and Gram-negative bacteria, with MICs in the low µM range and low hemolytic activity. Using biophysical methods, we explore the interaction of the new molecules with model membranes that mimic the bacterial inner and outer membranes, finding a selective effect on anionic membranes and a mechanism of action based on the alteration of membrane function. Transmission electron microscopy observation confirms that polymyxin analogues kill microbial cells primarily by damaging membrane integrity. Redistribution of the hydrophobicity within the polymyxin molecule seems a plausible approach for the design and development of safer and more selective antibiotics.
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Babichev, V. N., N. S. Ignatyev, and M. I. Balabolkin. "ATP-dependent K+ channels of pancreatic ß-cells under the effects of some sulfonylurea drugs." Problems of Endocrinology 39, no. 5 (October 15, 1993): 43–46. http://dx.doi.org/10.14341/probl11989.
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The authors analyze the relationships between electrophysiologic processes taking place on (J-cell membranes under the effects of some second generation sulfonylurea drugs: glycaside, glybenclamide, and glypizine and their secretogenic effects on insulin secretion. All the tested drugs induced complete blocking of K+-ATP-dependent channels when administered in concentrations from 1 to 20 pM (physiologic doses). Glucose had a similar effect. The canal is closed very soon, within 30 sec, and is closed for approximately 10 min, rapidly opening after the drug is washed away. Reduced activity of the channels up to their closure is conducive to the onset of insulin secretion. Glybenclamide proved to be the most potent suppressor of individual channel activity, this being confirmed by its more potent hypoglycemic effect as compared to glyclaside or glypizine.
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Seba, M. V., M. O. Khomenko, D. K. Nosevych, M. I. Golubev, V. G. Kaplunenko, I. V. Byelinska, and V. K. Rybalchenko. "INFLUENCE OF NEUROTROPIC AND METABOLIC DRUGS ON STRUCTURAL AND FUNCTIONAL STATE OF LIPID MATRIX OF THE CELL MEMBRANE." Animal Science and Food Technology 11, no. 3 (December 2020): 50–61. http://dx.doi.org/10.31548/animal2020.03.056.
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Lately, more and more often to stimulate the reproductive function of animals people use biochemical products, which are based on neurotropic and metabolic compounds and trace elements of nanobiotechnological origin. In order to new biotechnical drugs search and development, and more effective and safe combinations of dietary supplements in them, one should know Biochemical mechanisms of membranotropic action of these substances on a cell. Since these substances can lead to physiological changes in the cell and trigger nonspecific toxic effects on the body of animals depending on dose and period of action. The article presents the results of studies on the effects of neurotropic and metabolic drugs on structural and functional state of lipid matrix of the cell membrane. In experiment were used four drugs: hlutam 1-M (Sodium Glutaminate), stymulin (Sodium Glutaminate, Sodium Succinate), nanovulin-VHR (Sodium Glutaminate, Sodium Succinate, Copper Citrate), nanovulin-R (Sodium Glutaminate, Sodium Succinate, L-arginine, Copper Citrate). The main task of the experiment was to investigate the concentration effects and primary mechanisms of membranotropic influence of the components of investigated drugs in the range of physiological concentrations of the active substance on the structural and functional state of the lipid matrix of cell membranes. According to research results, it was found that Sodium Glutaminate, which is part of all the investigational drugs, affects the polarity of the hydrophobic zone of the membrane and increases the polarity of the lipid surround. An application of Sodium glutaminate with Succinate in same drug (stimulin, nanovulin-VHR, nanovulin-R) reduces the destructive effects of Sodium Glutamate on the lipid membrane of cells. Also, it should be noted that Copper Citrate in combination with Glutaminate and Succinate (nanovulin-VHR, nanovolin-R) excludes the membrane-stabilizing and membrane-disruptive effects of their influence on the structure of lipid packing in the bilayer. From the results of the research we can suggest, that aquachelates penetrate the hydrophobic lipid bilayer zone, as evidenced by the total fluorescence quenching of pyrene.
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Lin, Zhenyu, Hao Chen, Jiawei Xu, Jie Wang, Huijing Wang, Shifen Huang, and Shanshan Xu. "A Review of the Release Profiles and Efficacies of Chemotherapy Drug-Loaded Electrospun Membranes." Polymers 15, no. 2 (January 4, 2023): 251. http://dx.doi.org/10.3390/polym15020251.
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Electrospun fibrous membranes loaded with chemotherapy drugs have been broadly studied, many of which have had promising data demonstrating therapeutic effects on cancer cell inhibition, tumor size reduction, the life extension of tumor-bearing animals, and more. Nevertheless, their drug release profiles are difficult to predict since their degradation pattern varies with crystalline polymers. In addition, there is room for improving their release performances, optimizing the release patterns, and achieving better therapeutic outcomes. In this review, the key factors affecting electrospun membrane drug release profiles have been systematically reviewed. Case studies of the release profiles of typical chemotherapy drugs are carried out to determine the preferred polymer choices and techniques to achieve the expected prolonged or enhanced release profiles. The therapeutic effects of these electrospun, chemo-drug-loaded membranes are also discussed. This review aims to assist in the design of future drug-loaded electrospun materials to achieve preferred release profiles with enhanced therapeutic efficacies.
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Cantín, Celia, Javier Holguera, Laura Ferreira, Enrique Villar, and Isabel Muñoz-Barroso. "Newcastle disease virus may enter cells by caveolae-mediated endocytosis." Journal of General Virology 88, no. 2 (February 1, 2007): 559–69. http://dx.doi.org/10.1099/vir.0.82150-0.
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The entry into cells of Newcastle disease virus (NDV), a prototype member of the paramyxoviruses, is believed to occur by direct fusion at the plasma membrane through a pH-independent mechanism. In addition, NDV may enter host cells by an endocytic pathway. Treatment of cells with drugs that block caveolae-dependent endocytosis reduced NDV fusion and infectivity, the degree of inhibition being dependent on virus concentration. The inhibitory effect was reduced greatly when drugs were added after virus adsorption. Cells treated with methyl β-cyclodextrin, a drug that sequesters cholesterol from membranes, reduced the extent of fusion, infectivity and virus–cell binding; this indicates that cholesterol plays a role in NDV entry. Double-labelling immunofluorescence assays performed with anti-NDV monoclonal antibodies and antibodies against the early endosome marker EEA1 revealed the localization of the virus in these intracellular structures. Using fluorescence microscopy, it was found that cell–cell fusion was enhanced at low pH. It is concluded that NDV may infect cells through a caveolae-dependent endocytic pathway, suggesting that this pathway could be an alternative route for virus entry into cells.
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Ivanov, L. V., E. V. Shcherbak, and N. T. Kartel. "Evaluation of the of a numder of natural and modified polysaccharides on the microviscosity of rat erythrocyte membranes using the spin probe method." Surface 12(27) (December 30, 2020): 327–36. http://dx.doi.org/10.15407/surface.2020.12.327.
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Based on the pharmacokinetics of nitazole, proprietary oral administration of the rabbit analyzes various aspects of its use as auxiliary substances in the preparation of dosage forms with controlled absorption of starch, carboxymethyl starch, dialdehyde starch, sodium alginate and chitosan. Our analysis of pharmacokinetic curves revealed a correlation between the presence and magnitude of the negative charge in the polymer of starch derivatives and an increase in the bioavailability of nitazole, the absorption rate estimated by tmax and from the equations describing the curves in the framework of the single-particle absorption model. It can be assumed that the change in the bioavailability of nitazole in the presence of starch derivatives is associated with the ion-ion or ion-dipole interaction of the positively charged imine group of nitazole and negatively charged groups of starch derivatives. Obviously, in the mechanism of absorption of nitazole, the limiting stage is the stage of dissolution of nitazole in the stomach.Since the absorption of nitazole may also depend on the microviscosity of the membranes of the cells of the walls of the stomach, the effect of the above polysaccharides on the microviscosity of the membranes of red blood cells as model cells has been studied. However, the work revealed a noticeable effect of only chitosan on the microviscosity of erythrocyte membranes, in which there was some immobilization of the conformational mobility of the lipid bilayer of the cell membranes upon binding of the oppositely charged chitosan to the surface of the erythrocyte membranes. The remaining negatively charged polysaccharides did not significantly affect the microviscosity of the membranes, apparently due to the processes of electrostatic repulsion from red blood cell cells. The totality of the data obtained has expanded our knowledge about the mechanisms of the possible effect of high molecular weight polysaccharides on the bioavailability of various drugs when creating drugs with controlled absorption.
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Liu, Ying, Hao Qi, Run-Guang Sun, and Wen-Fang Chen. "An investigation into the combined effect of static magnetic fields and different anticancer drugs on K562 cell membranes." Tumori Journal 97, no. 3 (May 2011): 386–92. http://dx.doi.org/10.1177/030089161109700322.
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Olszewski-Hamilton, U., M. Svoboda, T. Thalhammer, V. Buxhofer-Ausch, K. Geissler, and G. Hamilton. "Organic Anion Transporting Polypeptide 5A1 (OATP5A1) in Small Cell Lung Cancer (SCLC) Cells: Possible Involvement in Chemoresistance to Satraplatin." Biomarkers in Cancer 3 (January 2011): BIC.S7151. http://dx.doi.org/10.4137/bic.s7151.
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Background The role of organic anion transporting polypeptide 5A1 (OATP5A1) a member of a family of drug transporters that mediate cellular uptake of drugs has not been characterized so far. Methods Gene expression levels of OATP5A1 in small cell lung cancer (SCLC) cell lines were determined by real-time qPCR and chemosensitivity of HEK-293- SLCO5A1-transfected cells to satraplatin in MTT assays. Results Significant expression of this transporter was found at the mRNA level, primarily in drug-resistant SCLC cells, and SLCO5A1-transfected HEK-293 cells showed higher resistance to satraplatin. OATP5A1 is found preferentially in cytoplasmic membranes of tumor cells, including SCLC. Conclusions OATP5A1 seems to effect intracellular transport of drugs and may participate in chemoresistance of SCLC by sequestration, rather than mediating cellular uptake. Since satraplatin failed to improve survival in SCLC patients, the relation of OATP5A1 expression to clinical drug resistance and its use as marker of chemoresistance should be further investigated.
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Shah, Vatsal R., Yamini D. Shah, and Mansi N. Athalye. "Novel approaches in development of cell penetrating peptides." Journal of Applied Pharmaceutical Research 9, no. 1 (March 15, 2021): 1–7. http://dx.doi.org/10.18231/joapr.2021.9.1.08.24.
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Therapeutic cargos which are impermeable to the cell can be delivered by cell penetrating peptides (CPPs). CPP-cargo complexes accumulate by endocytosis inside the cells but they fail to reach the cytosolic space properly as they are often trapped in the endocytic organelles. Here the CPP mediated endosomal escape and some strategies used to increase endosomal escape of CPP-cargo conjugates are discussed with evidence. Potential benefits can be obtained by peptides such as reduction in side effects, biocompatibility, easier synthesis and can be obtained at lower administered doses. The particular peptide known as cell penetrating peptides are able to translocate themselves across membrane with the carrier drugs with different mechanisms. This is of prime importance in drug delivery systems as they have capability to cross physiological membranes. This review describes various mechanisms for effective drug delivery and associated challenges
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Schmid, Dirk, Gerd-Rüdiger Burmester, Robert Tripmacher, Greg Fici, Philip von Voigtlander, and Frank Buttgereit. "Short-Term Effects of the 21-Aminosteroid Lazaroid Tirilazad Mesylate (PNU-74006F) and the Pyrrolopyrimidine Lazaroid PNU-101033E on Energy Metabolism of Human Peripheral Blood Mononuclear Cells." Bioscience Reports 21, no. 1 (February 1, 2001): 101–10. http://dx.doi.org/10.1023/a:1010494320266.
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Two groups of antioxidant compounds, the 21-aminosteroids and the pyrrolopyrimidines, have been found to act as neuroprotective drugs against lipid peroxidation in the injured CNS. Like glucocorticoids at high doses they are assumed to produce their effects at least in part by direct membrane stabilizing effects. In order to prove this hypothesis, we have investigated in this study the effects of these drugs on the energy metabolism of activated human peripheral blood mononuclear cells (PBMC) since these cells have been shown to serve as a suitable test system for substances affecting processes of ATP turnover. We compared the in vitro effects of (i) the 21-aminosteroid lazaroid tirilazad, (ii) the pyrrolopyrimidine lazaroid PNU-101033E and (iii) the glucocorticoid methylprednisolone on mitogen-induced respiration rate and ATP-consumption. We show that tirilazad inhibits concanavalin A-stimulated respiration rate and sodium cycling across the plasma membrane. The effect of methylprednisolone is similar indicating corresponding cellular mechanisms. However, unlike methylprednisolone, tirilazad produced no significant effect on calcium cycling across the plasma membrane. PNU-101033E in our test system caused cytotoxic effects on PBMC that did not allow us to quantify cellular actions on energy metabolism. Our results underline the view that tirilazad, first, is mimicking the high-dose immunosuppressive pharmacology of glucocorticoids such as methylprednisolone and, second, is likely to produce its therapeutic effects by direct physicochemical interactions with cellular membranes.
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Wysoczynski, Marcin, Ryan Reca, Magda Kucia, Janina Ratajczak, and Mariusz Z. Ratajczak. "Novel Evidence That Statin-Mediated Perturbation of Lipid Raft Formation Ameliorates Bleeding- Related Thrombocytosis." Blood 106, no. 11 (November 16, 2005): 2164. http://dx.doi.org/10.1182/blood.v106.11.2164.2164.
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Abstract The a-chemokine stromal derived factor 1 (SDF-1) plays an important role in maturation/platelet formation of megakaryocytes (Megs), and we recently reported that the responsiveness of hematopoietic cells to SDF-1 is optimal when its corresponding CXCR4 receptor is included into membrane lipid rafts (Blood2005; 105:40). The formation of lipid rafts in vivo may be perturbed by cholesterol-lowering drugs, e.g., statins. Statins are effective in lowering LDL cholesterol and exert several pleiotropic effects on mature platelets, e.g., inhibit their activation. This latter effect is probably due to lowering of the cholesterol content in the membranes of mature platelets leading to the perturbation of membrane lipid raft formation which is required for proper platelet activation and signaling. However, under steady state conditions statins do not influence platelet production, no studies have been performed on their effects on platelet production in reactive thrombocytosis. In determining whether lipid raft formation plays a role in SDF-1- and stress-dependent thrombocytosis, we found that SDF-1 most efficiently stimulates in vitro platelet production when CXCR4 is included into membrane lipid rafts on Megs. At the molecular level, depletion of cholesterol from Megs membranes i) perturbed the responsiveness of megakaryocytic progenitors to an SDF-1 gradient, ii) inhibited SDF-1-mediated calcium flux and MAPKp42/44, AKT and STAT 1–6 phosphorylation in normal human Megs and (iii) inhibited F-actin polymerization, MMP-9 and VEGF secretion, and adhesion to endothelium and fibrinogen. More importantly we found that ex vivo-expanded human Megs, produced significantly fewer platelets during their transendothelial migration after preincubation with cholesterol-lowering MbCD. To evaluate whether cholesterol depletion from Megs affects platelet production we exposed C57Bl6 mice to statins (orally, 21 days, 750 mg/mouse) and observed that statins did not influence peripheral blood cell counts. However, when mice were acutely bled this treatment led to a significant amelioration of post-bleeding thrombocytosis as compared to untreated (control) mice. At the same time, recovery of erythrocyte and leukocyte counts was unaffected. Thus we demonstrated for the first time that statins affect CXCR4-mediated thrombopoiesis by perturbing lipid raft formation and should be considered as potential drugs to prevent post-trauma or post-operative thrombocytosis.