scholarly journals Mechanistic origin of drug interactions between translation-inhibiting antibiotics

2019 ◽  
Author(s):  
Bor Kavčič ◽  
Gašper Tkačik ◽  
Tobias Bollenbach
Keyword(s):  
Drug Interactions ◽  
Large Fraction ◽  
Drug Uptake ◽  
Bacterial Physiology ◽  
Antibiotic Action ◽  
Translation Factors ◽  
Growth Laws ◽  
Underlying Mechanisms ◽  
Kinetics Of

SummaryAntibiotics that interfere with translation, when combined, interact in diverse and difficult-to-predict ways. Here, we demonstrate that these interactions can be accounted for by “translation bottlenecks”: points in the translation cycle where antibiotics block ribosomal progression. To elucidate the underlying mechanisms of drug interactions between translation inhibitors, we generated translation bottlenecks genetically using inducible control of translation factors that regulate well-defined translation cycle steps. These perturbations accurately mimicked antibiotic action and their interactions, supporting that the interplay of different translation bottlenecks causes these interactions. We further showed that the kinetics of drug uptake and binding together with growth laws allows direct prediction of a large fraction of observed interactions, yet fails for suppression. Simultaneously varying two translation bottlenecks in the same cell revealed how the dense traffic of ribosomes and competition for translation factors results in previously unexplained suppression. This result highlights the importance of “continuous epistasis” in bacterial physiology.

scholarly journals Mitochondrial Protein Translation: Emerging Roles and Clinical Significance in Disease

2021 ◽  
Vol 9 ◽  
Author(s):  
Fei Wang ◽  
Deyu Zhang ◽  
Dejiu Zhang ◽  
Peifeng Li ◽  
Yanyan Gao
Keyword(s):  
Ribosomal Proteins ◽  
Large Fraction ◽  
Mitochondrial Protein ◽  
Mitochondrial Diseases ◽  
Protein Translation ◽  
Genetic System ◽  
Mitochondrial Rna ◽  
Trna Synthetases ◽  
Translation Factors ◽  
Genes Encoding

Mitochondria are one of the most important organelles in cells. Mitochondria are semi-autonomous organelles with their own genetic system, and can independently replicate, transcribe, and translate mitochondrial DNA. Translation initiation, elongation, termination, and recycling of the ribosome are four stages in the process of mitochondrial protein translation. In this process, mitochondrial protein translation factors and translation activators, mitochondrial RNA, and other regulatory factors regulate mitochondrial protein translation. Mitochondrial protein translation abnormalities are associated with a variety of diseases, including cancer, cardiovascular diseases, and nervous system diseases. Mutation or deletion of various mitochondrial protein translation factors and translation activators leads to abnormal mitochondrial protein translation. Mitochondrial tRNAs and mitochondrial ribosomal proteins are essential players during translation and mutations in genes encoding them represent a large fraction of mitochondrial diseases. Moreover, there is crosstalk between mitochondrial protein translation and cytoplasmic translation, and the imbalance between mitochondrial protein translation and cytoplasmic translation can affect some physiological and pathological processes. This review summarizes the regulation of mitochondrial protein translation factors, mitochondrial ribosomal proteins, mitochondrial tRNAs, and mitochondrial aminoacyl-tRNA synthetases (mt-aaRSs) in the mitochondrial protein translation process and its relationship with diseases. The regulation of mitochondrial protein translation and cytoplasmic translation in multiple diseases is also summarized.

Modelling of microbial processes that govern degradation of organic substrates in soil, with special reference to pesticides

1990 ◽  
Vol 329 (1255) ◽  
pp. 369-373 ◽  
Keyword(s):  
Microbial Population ◽  
Large Fraction ◽  
Organic Substrates ◽  
High Concentration ◽  
Deterministic Models ◽  
Soil Microbial ◽  
Low Concentrations ◽  
Biokinetic Parameters ◽  
Soil Microbial Population ◽  
Kinetics Of

We tried to develop deterministic models for kinetics of 2,4-D breakdown in the soil based on the following considerations: (i) at low concentrations degradation results from maintenance consumption by a large fraction of the soil microbial population; (ii) at high concentration in addition to the maintenance consumption there is a growth-associated carbon incorporation by a small specific microbial population. Values for the biokinetic parameters are consistent with those commonly found in the literature. Comparison between observed and simulated curves suggests that a non-negligible part of the pesticidal carbon exists as microbial by-products.

scholarly journals Ambient-temperature Conditioning as a Probe of Double-C Transformation Mechanisms in Pu-2.0 at. % Ga

2008 ◽  
Vol 1104 ◽  
Author(s):  
Jason R Jeffries ◽  
Kerri J. M. Blobaum ◽  
Mark A. Wall ◽  
Adam J. Schwartz
Keyword(s):  
Ttt Diagram ◽  
Optimal Conditioning ◽  
High Temperature Anneal ◽  
Conditioning Treatment ◽  
Conditioning Temperature ◽  
Δ Phase ◽  
Transformation Mechanisms ◽  
Temperature Transformation ◽  
Underlying Mechanisms ◽  
Kinetics Of

AbstractThe gallium-stabilized Pu-2.0 at. % Ga alloy undergoes a partial or incomplete low-temperature martensitic transformation from the metastable δ phase to the gallium-containing, monoclinic α′ phase near -100 °C. This transformation has been shown to occur isothermally and it displays anomalous double-C kinetics in a time-temperature-transformation (TTT) diagram, where two nose temperatures anchoring an upper- and lower-C describe minima in the time for the initiation of transformation. The underlying mechanisms responsible for the double-C behavior are currently unresolved, although recent experiments suggest that a conditioning treatment—wherein, following an anneal at 375 °C, the sample is held at a sub-anneal temperature for a period of time—significantly influences the upper-C of the TTT diagram. As such, elucidating the effects of the conditioning treatment upon the δ⟶α′ transformation can provide valuable insights into the fundamental mechanisms governing the double-C kinetics of the transition. Following a high-temperature anneal, a differential scanning calorimeter (DSC) was used to establish an optimal conditioning curve that depicts the amount of α′ formed during the transformation as a function of conditioning temperature for a specified time. With the optimal conditioning curve as a baseline, the DSC was used to explore the circumstances under which the effects of the conditioning treatment were destroyed, resulting in little or no transformation.

scholarly journals Combination Treatment with Cold Physical Plasma and Pulsed Electric Fields Augments ROS Production and Cytotoxicity in Lymphoma

Cancers ◽  
2020 ◽  
Vol 12 (4) ◽  
pp. 845 ◽  
Author(s):  
Christina M. Wolff ◽  
Juergen F. Kolb ◽  
Klaus-Dieter Weltmann ◽  
Thomas von Woedtke ◽  
Sander Bekeschus
Keyword(s):  
Electric Fields ◽  
Combination Treatment ◽  
Argon Plasma ◽  
Pulsed Electric Fields ◽  
Drug Uptake ◽  
Minor Role ◽  
Ros Production ◽  
Treatment Regimens ◽  
Underlying Mechanisms ◽  
Physical Plasma

New approaches in oncotherapy rely on the combination of different treatments to enhance the efficacy of established monotherapies. Pulsed electric fields (PEFs) are an established method (electrochemotherapy) for enhancing cellular drug uptake while cold physical plasma is an emerging and promising anticancer technology. This study aimed to combine both technologies to elucidate their cytotoxic potential as well as the underlying mechanisms of the effects observed. An electric field generator (0.9–1.0 kV/cm and 100-μs pulse duration) and an atmospheric pressure argon plasma jet were employed for the treatment of lymphoma cell lines as a model system. PEF but not plasma treatment induced cell membrane permeabilization. Additive cytotoxicity was observed for the metabolic activity and viability of the cells while the sequence of treatment in the combination played only a minor role. Intriguingly, a parallel combination was more effective compared to a 15-min pause between both treatment regimens. A combination effect was also found for lipid peroxidation; however, none could be observed in the cytosolic and mitochondrial reactive oxygen species (ROS) production. The supplementation with either antioxidant, a pan-caspase-inhibitor or a ferroptosis inhibitor, all partially rescued lymphoma cells from terminal cell death, which contributes to the mechanistic understanding of this combination treatment.

scholarly journals Thymosin beta 4 sequesters the majority of G-actin in resting human polymorphonuclear leukocytes.

1992 ◽  
Vol 119 (5) ◽  
pp. 1261-1270 ◽  
Author(s):  
L Cassimeris ◽  
D Safer ◽  
V T Nachmias ◽  
S H Zigmond
Keyword(s):  
Polymorphonuclear Leukocytes ◽  
Actin Polymerization ◽  
Large Fraction ◽  
Reverse Phase Hplc ◽  
Thymosin Beta 4 ◽  
Rapid Changes ◽  
Human Pmns ◽  
Human Polymorphonuclear Leukocytes ◽  
Kinetics Of

Thymosin beta 4 (T beta 4), a 5-kD peptide which binds G-actin and inhibits its polymerization (Safer, D., M. Elzinga, and V. T. Nachmias. 1991. J. Biol. Chem. 266:4029-4032), appears to be the major G-actin sequestering protein in human PMNs. In support of a previous study by Hannappel, E., and M. Van Kampen (1987. J. Chromatography. 397:279-285), we find that T beta 4 is an abundant peptide in these cells. By reverse phase HPLC of perchloric acid supernatants, human PMNs contain approximately 169 fg/cell +/- 90 fg/cell (SD), corresponding to a cytoplasmic concentration of approximately 149 +/- 80.5 microM. On non-denaturing polyacrylamide gels, a large fraction of G-actin in supernatants prepared from resting PMNs has a mobility similar to the G-actin/T beta 4 complex. Chemoattractant stimulation of PMNs results in a decrease in this G-actin/T beta 4 complex. To determine whether chemoattractant induced actin polymerization results from an inactivation of T beta 4, the G-actin sequestering activity of supernatants prepared from resting and chemoattractant stimulated cells was measured by comparing the rates of pyrenyl-actin polymerization from filament pointed ends. Pyrenyl actin polymerization was inhibited to a greater extent in supernatants from stimulated cells and these results are qualitatively consistent with T beta 4 being released as G-actin polymerizes, with no chemoattractant-induced change in its affinity for G-actin. The kinetics of bovine spleen T beta 4 binding to muscle pyrenyl G-actin are sufficiently rapid to accommodate the rapid changes in actin polymerization and depolymerization observed in vivo in response to chemoattractant addition and removal.

Kinetics of drug-drug interactions

1973 ◽  
Vol 1 (6) ◽  
pp. 553-567 ◽  
Author(s):  
Malcolm Rowland ◽  
Shaikh B. Matin
Keyword(s):  
Drug Interactions ◽  
Kinetics Of

Nucleation rates and the kinetics of particle growth I. The pure birth process

1964 ◽  
Vol 277 (1369) ◽  
pp. 155-166 ◽  
Keyword(s):  
Differential Equations ◽  
Chemical Reaction ◽  
Growth Kinetics ◽  
Particle Growth ◽  
Growth Data ◽  
Birth Process ◽  
Irreversible Chemical Reaction ◽  
Growth Laws ◽  
Infinite Set ◽  
Kinetics Of

A model of particle growth kinetics in a condensing system is investigated in which the mechanism is presumed to be an irreversible chemical reaction which proceeds at the particle-atm osphere interface. General growth laws for the assembly of particles are derived from the resulting infinite set of differential equations and tested against growth data on sulphur hydrosols. The relation between the model and the well-known pure birth process of mathematical statistics is emphasized.

scholarly journals Effects of ornithine α-ketoglutarate on insulin secretion in rat pancreatic islets: implication of nitric oxide synthase and glutamine synthetase pathways

2003 ◽  
Vol 89 (2) ◽  
pp. 249-257 ◽  
Author(s):  
Christina Schneid ◽  
Sylviane Darquy ◽  
Luc Cynober ◽  
Gérard Reach ◽  
Jean-Pascal De Bandt
Keyword(s):  
Insulin Secretion ◽  
Islets Of Langerhans ◽  
Human Subjects ◽  
Mechanisms Of Action ◽  
Methionine Sulfoximine ◽  
Underlying Mechanisms ◽  
Rat Islets Of Langerhans ◽  
Oxide Synthase ◽  
Kinetics Of

Ornithine α-ketoglutarate (OKG) administration in human subjects elicits insulin secretion. We investigated whether this action was related to an effect of OKG on islets of Langerhans, and addressed the underlying mechanisms of action. For this purpose the influence of OKG on insulin secretion was measured in isolated rat islets of Langerhans under two different conditions. In incubated islets, OKG (0·25 to 2·5 mmol/l) significantly and dose-relatedly increased insulin secretion (1·7- to 4·2-fold; P<0·05 v. basal). To study the kinetics of OKG-stimulated insulin secretion, perifusion experiments were performed, which showed that OKG affected insulin secretion in both initial and later phases. Experiments using α-ketoglutarate (α-KG) (1 mmol/l) or ornithine (Orn) (2 mmol/l) alone, in concentrations equal to that of OKG, showed that the OKG-induced insulin secretion could not be obtained by either component alone, suggesting that an α-KG–Orn interaction is mandatory for the insulin-secreting effect to occur. Since data obtained in vivo suggest that effects of OKG may depend on the synthesis of NO, glutamine and/or polyamines, three metabolic pathways potentially involved in insulin secretion, we then evaluated their contribution by means of their respective inhibitors: α-NG-nitroarginine methyl ester (l-NAME), methionine sulfoximine (MSO) and difluoromethylornithine (DFMO). Both l-NAME and MSO were able significantly to reduce OKG-induced insulin secretion (30 and 40 % respectively; P<0·05), while DFMO was ineffective. Thus OKG is an effective stimulator of insulin secretion, requiring the joint presence of both Orn and α-KG, and acting mainly via the synthesis of NO and glutamine. A better understanding of OKG insulino-secretory properties and its mechanisms of action are a prerequisite for its use in insulin-compromised situations.

scholarly journals Hematopoietic Stem Cells Transplantation Can Normalize Thyroid Function in a Cystinosis Mouse Model

Endocrinology ◽  
2016 ◽  
Vol 157 (4) ◽  
pp. 1363-1371 ◽  
Author(s):  
H. P. Gaide Chevronnay ◽  
V. Janssens ◽  
P. Van Der Smissen ◽  
C. J. Rocca ◽  
X. H. Liao ◽  
...  
Keyword(s):  
Stem Cell ◽  
Large Fraction ◽  
Cell Lineage ◽  
Lysosomal Storage ◽  
Tunneling Nanotubes ◽  
Hematopoietic Stem ◽  
Cystine Transporter ◽  
Hematopoietic Stem Cells Transplantation ◽  
Underlying Mechanisms ◽  
Hsc Transplantation

Abstract Hypothyroidism is the most frequent and earliest endocrine complication in cystinosis, a multisystemic lysosomal storage disease caused by defective transmembrane cystine transporter, cystinosin (CTNS gene). We recently demonstrated in Ctns−/− mice that altered thyroglobulin biosynthesis associated with endoplasmic reticulum stress, combined with defective lysosomal processing, caused hypothyroidism. In Ctns−/− kidney, hematopoietic stem cell (HSC) transplantation provides long-term functional and structural protection. Tissue repair involves transfer of cystinosin-bearing lysosomes from HSCs differentiated as F4/80 macrophages into deficient kidney tubular cells, via tunneling nanotubes that cross basement laminae. Here we evaluated the benefit of HSC transplantation for cystinotic thyroid and investigated the underlying mechanisms. HSC engraftment in Ctns−/− thyroid drastically decreased cystine accumulation, normalized the TSH level, and corrected the structure of a large fraction of thyrocytes. In the thyroid microenvironment, HSCs differentiated into a distinct, mixed macrophage/dendritic cell lineage expressing CD45 and major histocompatibility complex II but low CD11b and F4/80. Grafted HSCs closely apposed to follicles and produced tunneling nanotube-like extensions that crossed follicular basement laminae. HSCs themselves further squeezed into follicles, allowing extensive contact with thyrocytes, but did not transdifferentiate into Nkx2.1-expressing cells. Our observations revealed significant differences of basement lamina porosity between the thyroid and kidney and/or intrinsic macrophage invasive properties once in the thyroid microenvironment. The contrast between extensive thyrocyte protection and low HSC abundance at steady state suggests multiple sequential encounters and/or remanent impact. This is the first report demonstrating the potential of HSC transplantation to correct thyroid disease and supports a major multisystemic benefit of stem cell therapy for cystinosis.

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