scholarly journals Lattice defects induced by microtubule-stabilizing agents exert a long-range effect on microtubule growth by promoting catastrophes

2021 ◽  
Vol 118 (51) ◽  
pp. e2112261118
Author(s):  
Ankit Rai ◽  
Tianyang Liu ◽  
Eugene A. Katrukha ◽  
Juan Estévez-Gallego ◽  
Szymon W. Manka ◽  
...  
Keyword(s):  
Lattice Defects ◽  
Structural Defects ◽  
Dynamic State ◽  
Range Effect ◽  
Drug Induced ◽  
Stabilizing Agents ◽  
Microtubule Severing ◽  
Microtubule Growth ◽  
Underlying Mechanisms ◽  
Induced Defects

Microtubules are dynamic cytoskeletal polymers that spontaneously switch between phases of growth and shrinkage. The probability of transitioning from growth to shrinkage, termed catastrophe, increases with microtubule age, but the underlying mechanisms are poorly understood. Here, we set out to test whether microtubule lattice defects formed during polymerization can affect growth at the plus end. To generate microtubules with lattice defects, we used microtubule-stabilizing agents that promote formation of polymers with different protofilament numbers. By employing different agents during nucleation of stable microtubule seeds and the subsequent polymerization phase, we could reproducibly induce switches in protofilament number and induce stable lattice defects. Such drug-induced defects led to frequent catastrophes, which were not observed when microtubules were grown in the same conditions but without a protofilament number mismatch. Microtubule severing at the site of the defect was sufficient to suppress catastrophes. We conclude that structural defects within the microtubule lattice can exert effects that can propagate over long distances and affect the dynamic state of the microtubule end.

scholarly journals Microtubule lattice defects promote catastrophes

2021 ◽  
Author(s):  
Ankit Rai ◽  
Tianyang Liu ◽  
Eugene A. Katrukha ◽  
Juan Estévez-Gallego ◽  
Ian Paterson ◽  
...  
Keyword(s):  
Lattice Defects ◽  
Structural Defects ◽  
Dynamic State ◽  
Stabilizing Agents ◽  
Microtubule Severing ◽  
Underlying Mechanisms

AbstractMicrotubules are dynamic cytoskeletal polymers that spontaneously switch between phases of growth and shrinkage. The probability of transitioning from growth to shrinkage, termed catastrophe, increases with microtubule age, but the underlying mechanisms are poorly understood. Here, we set out to test whether microtubule lattice defects formed during polymerization can affect growth at the plus end. To generate microtubules with lattice defects, we used microtubule-stabilizing agents that promote formation of polymers with different protofilament numbers. By employing different agents during nucleation of stable microtubule seeds and subsequent polymerization phase, we could reproducibly induce switches in protofilament number. Such switches led to frequent catastrophes, which were not observed when microtubules were grown in the same conditions but without a protofilament number mismatch. Microtubule severing at the site of the defect was sufficient to suppress catastrophes. We conclude that structural defects within microtubule lattice can affect the dynamic state of the plus end.

Liver and Statins: A Critical Appraisal of the Evidence

2019 ◽  
Vol 25 (42) ◽  
pp. 5835-5846 ◽  
Author(s):  
Anna Licata ◽  
Antonina Giammanco ◽  
Maria Giovanna Minissale ◽  
Salvatore Pagano ◽  
Salvatore Petta ◽  
...  
Keyword(s):  
Adverse Events ◽  
Association Studies ◽  
Organic Anion ◽  
Genome Wide Association Studies ◽  
Drug Induced ◽  
Drug Induced Liver Injury ◽  
Organic Anion Transporting Polypeptide ◽  
Treatment And Prevention ◽  
Genome Wide ◽  
Underlying Mechanisms

Adverse drug reactions (ADRs) represent an important cause of morbidity and mortality worldwide. Statins are a class of drugs whose main adverse effects are drug-induced liver injury (DILI) and myopathy. Some of these may be predictable, due to their pharmacokinetic and pharmacodynamic properties, while others, unfortunately, are idiosyncratic. Genetic factors may also influence patient susceptibility to DILI and myopathy in the case of statins. This review will first discuss the role of statins in cardiovascular disease treatment and prevention and the underlying mechanisms of action. Furthermore, to explore the susceptibility of statin-induced adverse events such as myopathy and hepatotoxicity, it will then focus on the recent Genome-Wide Association Studies (GWAS) concerning the transporter genes, Cytochrome P450 (CYP), organic anion-transporting polypeptide (OATP) and ABCB1 and ABCC1, which seem to play a role in the development of clinically relevant adverse events. Finally, we appraise the evidence for and against the use of statins in metabolic syndrome and in HCV-infected patients, in terms of their safety and efficacy in cardiovascular events.

scholarly journals Congenital hypothyroidism impairs spine growth of dentate granule cells by downregulation of CaMKIV

2021 ◽  
Vol 7 (1) ◽  
Author(s):  
Qingying Tang ◽  
Shuxia Chen ◽  
Hui Wu ◽  
Honghua Song ◽  
Yongjun Wang ◽  
...  
Keyword(s):  
Congenital Hypothyroidism ◽  
Granule Cells ◽  
Spine Density ◽  
Drug Induced ◽  
Distinct Cell Type ◽  
Cognitive Behaviors ◽  
Dentate Granule Cells ◽  
Rat Pups ◽  
Cognitive Deficiency ◽  
Underlying Mechanisms

AbstractCongenital hypothyroidism (CH), a common neonatal endocrine disorder, can result in cognitive deficits if delay in diagnose and treatment. Dentate gyrus (DG) is the severely affected subregion of the hippocampus by the CH, where the dentate granule cells (DGCs) reside in. However, how CH impairs the cognitive function via affecting DGCs and the underlying mechanisms are not fully elucidated. In the present study, the CH model of rat pups was successfully established, and the aberrant dendrite growth of the DGCs and the impaired cognitive behaviors were observed in the offspring. Transcriptome analysis of hippocampal tissues following rat CH successfully identified that calcium/calmodulin-dependent protein kinase IV (CaMKIV) was the prominent regulator involved in mediating deficient growth of DGC dendrites. CaMKIV was shown to be dynamically regulated in the DG subregion of the rats following drug-induced CH. Interference of CaMKIV expression in the primary DGCs significantly reduced the spine density of dendrites, while addition of T3 to the primary DGCs isolated from CH pups could facilitate the spine growth of dendrites. Insights into relevant mechanisms revealed that CH-mediated CaMKIV deficiency resulted in the significant decrease of phosphorylated CREB in DGCs, in association with the abnormality of dendrites. Our results have provided a distinct cell type in hippocampus that is affected by CH, which would be beneficial for the treatment of CH-induced cognitive deficiency.

scholarly journals Maternal Neutrophil Depletion Fails to Avert Systemic Lipopolysaccharide-Induced Early Pregnancy Defects in Mice

2021 ◽  
Vol 22 (15) ◽  
pp. 7932
Author(s):  
Sourav Panja ◽  
John T. Benjamin ◽  
Bibhash C. Paria
Keyword(s):  
Early Pregnancy ◽  
Normal Pregnancy ◽  
Mrna Levels ◽  
Interesting Approach ◽  
Blastocyst Implantation ◽  
Neutrophil Depletion ◽  
Underlying Mechanisms ◽  
Myd88 Signaling ◽  
Induced Defects ◽  
Dose Dependent

Maternal infection-induced early pregnancy complications arise from perturbation of the immune environment at the uterine early blastocyst implantation site (EBIS), yet the underlying mechanisms remain unclear. Here, we demonstrated in a mouse model that the progression of normal pregnancy from days 4 to 6 induced steady migration of leukocytes away from the uterine decidual stromal zone (DSZ) that surrounds the implanted blastocyst. Uterine macrophages were found to be CD206+ M2-polarized. While monocytes were nearly absent in the DSZ, DSZ cells were found to express monocyte marker protein Ly6C. Systemic endotoxic lipopolysaccharide (LPS) exposure on day 5 of pregnancy led to: (1) rapid (at 2 h) induction of neutrophil chemoattractants that promoted huge neutrophil infiltrations at the EBISs by 24 h; (2) rapid (at 2 h) elevation of mRNA levels of MyD88, but not Trif, modulated cytokines at the EBISs; and (3) dose-dependent EBIS defects by day 7 of pregnancy. Yet, elimination of maternal neutrophils using anti-Ly6G antibody prior to LPS exposure failed to avert LPS-induced EBIS defects allowing us to suggest that activation of Tlr4-MyD88 dependent inflammatory pathway is involved in LPS-induced defects at EBISs. Thus, blocking the activation of the Tlr4-MyD88 signaling pathway may be an interesting approach to prevent infection-induced pathology at EBISs.

scholarly journals Machine Learning for Predicting Risk of Drug-Induced Autoimmune Diseases by Structural Alerts and Daily Dose

2021 ◽  
Vol 18 (13) ◽  
pp. 7139
Author(s):  
Yue Wu ◽  
Jieqiang Zhu ◽  
Peter Fu ◽  
Weida Tong ◽  
Huixiao Hong ◽  
...  
Keyword(s):  
Machine Learning ◽  
Autoimmune Diseases ◽  
Odds Ratio ◽  
Area Under Curve ◽  
Predictive Performance ◽  
Drug Induced ◽  
Drug Candidates ◽  
Daily Dose ◽  
Structural Alerts ◽  
Underlying Mechanisms

An effective approach for assessing a drug’s potential to induce autoimmune diseases (ADs) is needed in drug development. Here, we aim to develop a workflow to examine the association between structural alerts and drugs-induced ADs to improve toxicological prescreening tools. Considering reactive metabolite (RM) formation as a well-documented mechanism for drug-induced ADs, we investigated whether the presence of certain RM-related structural alerts was predictive for the risk of drug-induced AD. We constructed a database containing 171 RM-related structural alerts, generated a dataset of 407 AD- and non-AD-associated drugs, and performed statistical analysis. The nitrogen-containing benzene substituent alerts were found to be significantly associated with the risk of drug-induced ADs (odds ratio = 2.95, p = 0.0036). Furthermore, we developed a machine-learning-based predictive model by using daily dose and nitrogen-containing benzene substituent alerts as the top inputs and achieved the predictive performance of area under curve (AUC) of 70%. Additionally, we confirmed the reactivity of the nitrogen-containing benzene substituent aniline and related metabolites using quantum chemistry analysis and explored the underlying mechanisms. These identified structural alerts could be helpful in identifying drug candidates that carry a potential risk of drug-induced ADs to improve their safety profiles.

scholarly journals Neurogenic Erectile Dysfunction. Where Do We Stand?

Medicines ◽  
2021 ◽  
Vol 8 (1) ◽  
pp. 3
Author(s):  
Charalampos Thomas ◽  
Charalampos Konstantinidis
Keyword(s):  
Erectile Dysfunction ◽  
Large Cohort ◽  
Sexual Performance ◽  
Drug Induced ◽  
Underlying Mechanisms

Erectile Dysfunction (ED) is the persistent inability to attain and maintain an erection sufficient to permit satisfactory sexual performance, causing tremendous effects on both patients and their partners. The pathophysiology of ED remains a labyrinth. The underlying mechanisms of ED may be vasculogenic, neurogenic, anatomical, hormonal, drug-induced and/or psychogenic. Neurogenic ED consists of a large cohort of ED, accounting for about 10% to 19% of all cases. Its diversity does not allow an in-depth clarification of all the underlying mechanisms nor a “one size fits all” therapeutical approach. In this review, we focus on neurogenic causes of ED, trying to elucidate the mechanisms that lie beneath it and how we manage these patients.

Anticancer drug-induced cardiac rhythm disorders: Current knowledge and basic underlying mechanisms

2018 ◽  
Vol 189 ◽  
pp. 89-103 ◽  
Author(s):  
Joachim Alexandre ◽  
Javid J. Moslehi ◽  
Kevin R. Bersell ◽  
Christian Funck-Brentano ◽  
Dan M. Roden ◽  
...  
Keyword(s):  
Anticancer Drug ◽  
Cardiac Rhythm ◽  
Current Knowledge ◽  
Drug Induced ◽  
Underlying Mechanisms

Centrosome cohesion is regulated by a balance of kinase and phosphatase activities

2001 ◽  
Vol 114 (20) ◽  
pp. 3749-3757 ◽  
Author(s):  
Patrick Meraldi ◽  
Erich A. Nigg
Keyword(s):  
Protein Phosphatase ◽  
Kinase Activity ◽  
Dominant Negative ◽  
Dominant Negative Mutant ◽  
Microtubule Depolymerization ◽  
Drug Induced ◽  
Microtubule Network ◽  
Similar Phenotype ◽  
Underlying Mechanisms

Centrosome cohesion and separation are regulated throughout the cell cycle, but the underlying mechanisms are not well understood. Since overexpression of a protein kinase, Nek2, is able to trigger centrosome splitting (the separation of parental centrioles), we have surveyed a panel of centrosome-associated kinases for their ability to induce a similar phenotype. Cdk2, in association with either cyclin A or E, was as effective as Nek2, but several other kinases tested did not significantly interfere with centrosome cohesion. Centrosome splitting could also be triggered by inhibition of phosphatases, and protein phosphatase 1α (PP1α) was identified as a likely physiological antagonist of Nek2. Furthermore, we have revisited the role of the microtubule network in the control of centrosome cohesion. We could confirm that microtubule depolymerization by nocodazole causes centrosome splitting. Surprisingly, however, this drug-induced splitting also required kinase activity and could specifically be suppressed by a dominant-negative mutant of Nek2. These studies highlight the importance of protein phosphorylation in the control of centrosome cohesion, and they point to Nek2 and PP1α as critical regulators of centrosome structure.

scholarly journals Evaluation of the relevance of DILI predictive hypotheses in early drug development: review of in vitro methodologies vs. BDDCS classification

2018 ◽  
Vol 7 (3) ◽  
pp. 358-370 ◽  
Author(s):  
Rosa Chan ◽  
Leslie Z. Benet
Keyword(s):  
Liver Injury ◽  
Drug Development ◽  
Safety Concern ◽  
Drug Induced ◽  
Development Review ◽  
Drug Induced Liver Injury ◽  
Underlying Mechanisms ◽  
Early Drug

Drug-induced liver injury (DILI) is a major safety concern; it occurs frequently; it is idiosyncratic; it cannot be adequately predicted; and a multitude of underlying mechanisms has been postulated.

Toxicity of Atenolol and Propranolol on Rat Heart Mitochondria

Drug Research ◽  
2020 ◽  
Vol 70 (04) ◽  
pp. 151-157 ◽  
Author(s):  
Enayatollah Seydi ◽  
Yasaman Tabbati ◽  
Jalal Pourahmad
Keyword(s):  
Mitochondrial Membrane ◽  
Heart Diseases ◽  
Isolated Heart ◽  
Chain Complex ◽  
Heart Mitochondria ◽  
Cytochrome C Release ◽  
Drug Induced ◽  
Rat Heart Mitochondria ◽  
Β Receptor ◽  
Underlying Mechanisms

AbstractPropranolol and atenolol are known as β receptor blocker drugs. These drugs are used to treat some heart diseases. There are controversies in the relationship between the use of beta-blocker drugs and the level of reactive oxygen species (ROS). Mitochondria as one of the most important sources of ROS are considered as one of the targets of drug-induced cardiotoxicity. The aim of this study was to evaluate the effects of propranolol and atenolol on mitochondria isolated from the heart. To achieve this aim, several markers of mitochondrial and cellular toxicity were evaluated. The key results of this study are the increased ROS level, collapse in mitochondrial membrane potential (MMP), mitochondrial swelling and cytochrome c release as well as disruption of respiratory chain complex II in mitochondria in isolated heart mitochondria after exposure to propranolol and atenolol. The results indicate an increase in caspase-3 activity and a decrease in the ATP level in cardiomyocytes after exposure to propranolol and atenolol. The underlying mechanisms of propranolol and atenolol induced cardiotoxicity may be associated with alterations in mitochondrial function, oxidative stress, and changes in the mitochondrial membrane.

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