Drug-Membrane Interactions: Molecular Mechanisms Underlying Therapeutic and Toxic Effects of Drugs

2010 ◽  
pp. 191-214
Author(s):  
Marlene Lúcio ◽  
José L. F. C. Lima ◽  
Salette Reis
Keyword(s):  
Molecular Mechanisms ◽  
Toxic Effects ◽  
Membrane Interactions

Imidazolium-Based Ionic Liquids Affect Morphology and Rigidity of Living Cells: an Atomic Force Microscopy Study

2018 ◽  
Author(s):  
Massimiliano Galluzzi ◽  
Carsten Schulte ◽  
Paolo Milani ◽  
Alessandro Podestà
Keyword(s):  
Atomic Force Microscopy ◽  
Ionic Liquids ◽  
Cell Membrane ◽  
Molecular Mechanisms ◽  
Single Cells ◽  
Metastatic Cancer ◽  
Toxic Effects ◽  
Force Microscopy ◽  
Atomic Force ◽  
The Impact

The study of the toxicity, biocompatibility, and environmental sustainability of room-temperature Ionic Liquids (ILs) is still in its infancy. Understanding the impact of ILs on living organisms, especially from the aquatic ecosystem, is urgent, since on one side large amounts of these substances are widely employed as solvents in industrial chemical processes, and on the other side evidences of toxic effects of ILs on microorganisms and single cells have been observed. To date, the toxicity of ILs have been investigated by means of macroscopic assays aimed at characterizing the effective concentrations (like the EC50) that cause the dead of a significant fraction of the population of microorganisms and cells. These studies allowed to identify the cell membrane as the first target of the IL interaction, whose effectiveness was correlated to the lipophilicity of the cation, i.e. to the length of the lateral alkyl chain. Our study aimed at characterizing the molecular mechanisms of the toxicity of ILs. To this purpose, we carried out a combined topographic and mechanical analysis by Atomic Force Microscopy of living breast metastatic cancer cells (MDA-MB-231) upon interaction with imidazolium-based ILs. We showed that ILs are able to induce modifications of the overall rigidity (effective Young modulus) and morphology of the cells. Our results demonstrate that ILs act on the physical properties of the cell membrane, and possibly induce cytoskeletal reorganization, already at concentrations below the EC50. These potentially toxic effects are stronger at higher IL concentrations, as well as with longer lateral chains in the cation.<br>

scholarly journals Mechanistic principles underlying regulation of the actin cytoskeleton by phosphoinositides

2017 ◽  
Vol 114 (43) ◽  
pp. E8977-E8986 ◽  
Author(s):  
Yosuke Senju ◽  
Maria Kalimeri ◽  
Essi V. Koskela ◽  
Pentti Somerharju ◽  
Hongxia Zhao ◽  
...  
Keyword(s):  
Actin Cytoskeleton ◽  
Lipid Bilayer ◽  
Electrostatic Interactions ◽  
Molecular Mechanisms ◽  
Specific Binding ◽  
Lateral Diffusion ◽  
Lipid Binding ◽  
Actin Binding ◽  
Membrane Interactions ◽  
Dynamics Simulations

The actin cytoskeleton powers membrane deformation during many cellular processes, such as migration, morphogenesis, and endocytosis. Membrane phosphoinositides, especially phosphatidylinositol 4,5-bisphosphate [PI(4,5)P2], regulate the activities of many actin-binding proteins (ABPs), including profilin, cofilin, Dia2, N-WASP, ezrin, and moesin, but the underlying molecular mechanisms have remained elusive. Moreover, because of a lack of available methodology, the dynamics of membrane interactions have not been experimentally determined for any ABP. Here, we applied a combination of biochemical assays, photobleaching/activation approaches, and atomistic molecular dynamics simulations to uncover the molecular principles by which ABPs interact with phosphoinositide-rich membranes. We show that, despite using different domains for lipid binding, these proteins associate with membranes through similar multivalent electrostatic interactions, without specific binding pockets or penetration into the lipid bilayer. Strikingly, our experiments reveal that these proteins display enormous differences in the dynamics of membrane interactions and in the ranges of phosphoinositide densities that they sense. Profilin and cofilin display transient, low-affinity interactions with phosphoinositide-rich membranes, whereas F-actin assembly factors Dia2 and N-WASP reside on phosphoinositide-rich membranes for longer periods to perform their functions. Ezrin and moesin, which link the actin cytoskeleton to the plasma membrane, bind membranes with very high affinity and slow dissociation dynamics. Unlike profilin, cofilin, Dia2, and N-WASP, they do not require high “stimulus-responsive” phosphoinositide density for membrane binding. Moreover, ezrin can limit the lateral diffusion of PI(4,5)P2 along the lipid bilayer. Together, these findings demonstrate that membrane-interaction mechanisms of ABPs evolved to precisely fulfill their specific functions in cytoskeletal dynamics.

TOXIC EFFECTS OF ANTICANCER THERAPY

2021 ◽  
pp. 28-34
Author(s):  
Gelfer S.A. ◽  
Semenova V.V.
Keyword(s):  
Molecular Mechanisms ◽  
Anticancer Therapy ◽  
The United States ◽  
Toxic Effects ◽  
Malignant Neoplasms ◽  
Temporal Region ◽  
Repair System ◽  
Observation Data ◽  
Second Tumors ◽  
Accepted Practice

The generally accepted practice of medical technology is to record the first time sick, the results of dynamic observations of patients (follow-up). The first research groups for the study of malignant neoplasms (MNO) in children appeared in the United States in 1955. The article describes the importance of early rehabilitation of patients who have undergone cancer on the example of a clinical case. Advances in the treatment of cancer patients have resulted in a higher percentage of people cured. But very early after the start of the use of anticancer therapy (POT), doctors began to observe manifestations of an iatrogenic nature due to the use of toxic drugs and radiation. At the moment, the influence of genetic factors on the development of complications of chemotherapy and radiation therapy is being actively studied. The molecular mechanisms of the development of abnormally pronounced toxic effects in most cases are associated with disorders in the DNA repair system. To minimize the risk of severe toxic effects, these factors should be taken into account when choosing a treatment strategy. On the example of patient N., 18 years old, the condition after the end of treatment for rhabdomyosarcoma of the temporal region, the duration of remission is 12 years, one can see how the treatment can iatrogenically affect the patient's life in adulthood, having undergone treatment in childhood. With an early start of rehabilitation and timely identification of the long-term consequences of anticancer therapy, it is possible to improve the patient's quality of life. With the accumulation of observation data on the domestic cohort of children and adolescents who completed therapy 15-20 years ago, it will become possible to assess the burden of national health care in the structure of morbidity, disability, and the development of second tumors.

The molecular mechanisms of lithium-induced cardiotoxicity in male rats and its amelioration by N-acetyl cysteine

2020 ◽  
Vol 39 (5) ◽  
pp. 696-711
Author(s):  
Omaima I Abdel Hamid ◽  
Ebtesam M Ibrahim ◽  
Marwa HS Hussien ◽  
Shereen A ElKhateeb
Keyword(s):  
Sodium Chloride ◽  
Molecular Mechanisms ◽  
Troponin I ◽  
Cardiac Biomarkers ◽  
Toxic Effects ◽  
Male Rats ◽  
Albino Rats ◽  
Arterial Blood ◽  
Creatine Kinase Mb ◽  
Acetyl Cysteine

Lithium is one of the most powerful and commonly used medications for the treatment of various psychiatric diseases, especially bipolar disorder. However, it has a narrow therapeutic index with toxic effects on various organs. There are several case reports of lithium-induced arrhythmia and ischemia. The current work aimed to study the toxic effects of lithium on the heart of adult albino rats and its molecular mechanisms and the ameliorating effect of N-acetyl cysteine (NAC). Sixty adult male Wistar albino rats were classified into four groups; control, NAC-treated received NAC 500 mg/kg/week dissolved in 1 ml 0.9% sodium chloride intraperitoneal, lithium-treated received 52.5 mg/kg/day of lithium carbonate dissolved in 1 ml 0.9% sodium chloride orally by gavage, and lithium-and-NAC-treated (group IV) received lithium and NAC in the previous doses. After 12 weeks, the rats of group III showed a significant accumulation of ascites and a decrease in the mean arterial blood pressure and electrocardiographic (ECG) findings of ischemia and arrhythmia. In addition, there was an elevation in cardiac biomarkers creatine kinase MB (CK-MB), cardiac troponin I (cTnI), and several histological lesions with a significant increase in the area % of Van Gieson, endothelial nitric oxide synthase (eNOS), and 8-hydroxy-2′-deoxyguanosine (8-OHdG) immunoreaction. There was significant upregulation of microRNA-1, microRNA-21 (miRNA-21), and microRNA-29 (miRNA-29). MiRNA-21 was strongly positively correlated to the area % of 8-OHdG, while miRNA-29 was strongly positively correlated to the area % of Van Gieson staining. NAC significantly improved the cardiotoxic effects of lithium. Being a nontoxic and safe antioxidant, NAC can be used to ameliorate lithium-induced cardiac injury.

scholarly journals Molecular mechanisms of toxic effects of fotemustine in rat hepatocytes and subcellular rat liver fractions

1996 ◽  
Vol 17 (4) ◽  
pp. 715-724 ◽  
Author(s):  
Jan P.G. Brakenhoff ◽  
Jan N.M. Commandeur ◽  
Lars W. Wormhoudt ◽  
Ed J. Groot ◽  
Nico P.E. Vermeulen
Keyword(s):  
Rat Liver ◽  
Molecular Mechanisms ◽  
Rat Hepatocytes ◽  
Toxic Effects

Toxic Effects of Metal Oxide Nanoparticles Based on the Enzymatic Activity and Biosynthesis of β-Galactosidase Using a Mutant Strain of E. coli

2020 ◽  
Vol 20 (3) ◽  
pp. 1440-1446
Author(s):  
In Chul Kong ◽  
Xin Yang ◽  
Wonil Wi ◽  
Minji Kim ◽  
Kyung-Seok Ko
Keyword(s):  
Enzyme Activity ◽  
Metal Oxide ◽  
Mutant Strain ◽  
Molecular Mechanisms ◽  
Metal Oxide Nanoparticles ◽  
Metabolic Process ◽  
Toxic Effects ◽  
Systematic Research ◽  
Oxide Nanoparticles ◽  
E Coli

The effects of six metal oxide nanoparticles (MO-NPs) on the activity and biosynthesis of an enzyme (β-galactosidase) were examined using a mutant strain of E. coli. Different sensitivities were observed according to the type of NP and metabolic process. The toxic effects on enzyme activity were significantly greater than on biosynthesis (p < 0.011), except in the presence of NiO. In both cases, ZnO NP caused the greatest inhibition among the tested NPs, followed by CuO. The EC50s for ZnO were 0.19 and 3.68 mg/L for enzyme activity and biosynthesis, respectively. Similar orders of toxicity were observed as follows: ZnO > CuO > NiO > Co3O4 > TiO2, Al2O3 for enzyme activity; and ZnO > CuO > NiO ≫ Al2O3, TiO2, Co3O4 for the biosynthetic process. More systematic research, including in-depth studies like investigation of the molecular mechanisms, is necessary to elucidate the detailed mechanisms of inhibition involved in both metabolic processes.

scholarly journals Influence of cadmium contamination on brain glial cells: consequences and bioindication possibilities

2020 ◽  
Vol 49 ◽  
pp. 67-83
Author(s):  
V. S. Nedzvetsky ◽  
V. Ya. Gasso ◽  
A. M. Hahut ◽  
I. A. Hasso
Keyword(s):  
Oxidative Stress ◽  
Glial Cells ◽  
Functional Activity ◽  
Molecular Mechanisms ◽  
Glucose Utilization ◽  
Animal Health ◽  
Toxic Effects ◽  
Low Doses ◽  
Cellular Models ◽  
The Brain

Cadmium (Cd) is a heavy metal that currently presents in almost all components of the environment. Cd is a ubiquitous pollutant that is constantly entering the environment from industry and agriculture, mining, forest fires and many more sources. Some occupational diseases have aftereffects associated with Cd cytotoxicity. Despite long-term studies of the toxic effects of Cd, its cytotoxicity of low doses and the chronic effects on the nerve tissue cells remain undiscovered. The results of determining the Cd neurotoxicity indicate a disturbance of the permeability of the blood-brain barrier, the accumulation of Cd in the brain and the deterioration of the functional activity of the central nervous system. One of the main cellular targets for Cd in the brain are astrocytes. Astrocytes provide nutrition and functional activity of neurons, as well as recovery of physical and metabolic damage. The cytoskeleton of astrocytes is built of glial fibrillary acidic protein (GFAP). GFAP participates in important functions of astrocytes and its condition reflects the astrocytes reactivity. The molecular mechanisms of the neurotoxic effects of Cd on the glial cytoskeleton remain unknown. Glioblastomas are widely used to study the cytotoxic mechanisms of various compounds, including heavy metals, as cellular models of astrocytes. Taking into account the role of oxidative stress in a cell damage, as well as the reactive response of glial cells, we study the influence of low doses of Cd on oxidative stress and expression of GFAP and glucose-6-phosphate dehydrogenase (G6PD) in U373GM cells. Doses of 2-10 μM Cd induced a dose-dependent increase in reactive oxygen species and lipid peroxidation products. The same doses inhibited the expression of the cytoskeletal marker of astrocytes (GFAP) and metabolic marker of glucose utilization (G6PD). The obtained results indicate a pronounced cytotoxic effect of low doses of Cd in the astrocytic cell model U373GM. In addition, the astroglial cytotoxicity of Cd may be mediated by oxidative damage, inhibition of glial intermediate filament expression, and glucose utilization disorders. These parameters can be promising biomarkers of toxic effects both for the assessment of human and animal health and for determining the state of the environment as a whole.

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