NMR spectroscopy analysis reveals an altered metabolic homeostasis in Arabidopsis seedlings treated with a cytokinesis inhibitor

AbstractIn plant cytokinesis, de novo formation of a cell plate evolving into the new cell wall partitions the cytoplasm of the dividing cell. Cell plate formation involves highly orchestrated vesicle accumulation, fusion, and membrane network maturation supported by the temporary integration of elastic and pliable callose. The small molecule, Endosidin 7 (ES7) arrests late cytokinesis in Arabidopsis by inhibiting callose deposition at the cell plate. Its effect is specific, as it does not broadly affect endomembrane trafficking or cytoskeletal organization. It has emerged as a very valuable tool for dissecting this essential plant process. In order to gain deeper insights regarding its mode of action and the effects of cytokinesis inhibition on overall plant growth, we investigated the effect of ES7 through a nuclear magnetic resonance spectroscopy metabolomics approach. In this case study, profiles of Arabidopsis leaf and root tissues were analyzed at different growth stages and ES7 exposure levels. The results show tissue-specific changes in the plant metabolic profile across a developmental gradient, and the effect that ES7 treatment has on the corresponding metabolome. The ES7 induced profile suggests metabolic compensations in central metabolism pathways in response to cytokinesis inhibition. Further, this study shows that long-term treatment of ES7 disrupts the homeostasis of primary metabolism in Arabidopsis seedlings, likely via alteration of hormonal regulation.

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NMR spectroscopy analysis reveals differential metabolic responses in arabidopsis roots and leaves treated with a cytokinesis inhibitor

PLoS ONE ◽

10.1371/journal.pone.0241627 ◽

2020 ◽

Vol 15 (11) ◽

pp. e0241627

Author(s):

Thomas E. Wilkop ◽

Minmin Wang ◽

Angelo Heringer ◽

Jaideep Singh ◽

Florence Zakharov ◽

...

Keyword(s):

Hormonal Regulation ◽

De Novo ◽

Cell Plate ◽

Term Treatment ◽

Resonance Spectroscopy ◽

Growth Stages ◽

Primary Metabolism ◽

Callose Deposition ◽

Plant Cytokinesis ◽

Long Term Treatment

In plant cytokinesis, de novo formation of a cell plate evolving into the new cell wall partitions the cytoplasm of the dividing cell. In our earlier chemical genomics studies, we identified and characterized the small molecule endosidin-7, that specifically inhibits callose deposition at the cell plate, arresting late-stage cytokinesis in arabidopsis. Endosidin-7 has emerged as a very valuable tool for dissecting this essential plant process. To gain insights regarding its mode of action and the effects of cytokinesis inhibition on the overall plant response, we investigated the effect of endosidin-7 through a nuclear magnetic resonance spectroscopy (NMR) metabolomics approach. In this case study, metabolomics profiles of arabidopsis leaf and root tissues were analyzed at different growth stages and endosidin-7 exposure levels. The results show leaf and root-specific metabolic profile changes and the effects of endosidin-7 treatment on these metabolomes. Statistical analyses indicated that the effect of endosidin-7 treatment was more significant than the developmental impact. The endosidin-7 induced metabolic profiles suggest compensations for cytokinesis inhibition in central metabolism pathways. This study further shows that long-term treatment of endosidin-7 profoundly changes, likely via alteration of hormonal regulation, the primary metabolism of arabidopsis seedlings. Hormonal pathway-changes are likely reflecting the plant’s responses, compensating for the arrested cell division, which in turn are leading to global metabolite modulation. The presented NMR spectral data are made available through the Metabolomics Workbench, providing a reference resource for the scientific community.

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Sustained-release Madopar HBS® compared with standard Madopar® in the long-term treatment of de novo parkinsonian patients

Acta Neurologica Scandinavica ◽

10.1111/j.1600-0404.1996.tb00163.x ◽

2009 ◽

Vol 93 (1) ◽

pp. 14-20 ◽

Cited By ~ 66

Author(s):

E. Dupont ◽

A. Andersen ◽

J. Boas ◽

E. Boisen ◽

R. Borgmann ◽

...

Keyword(s):

Sustained Release ◽

De Novo ◽

Term Treatment ◽

Long Term Treatment

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1,25-Dihydroxyvitamin D Maintains Brush Border Membrane NaPi2a and Attenuates Phosphaturia in Hyp Mice

Endocrinology ◽

10.1210/en.2019-00186 ◽

2019 ◽

Vol 160 (10) ◽

pp. 2204-2214 ◽

Cited By ~ 1

Author(s):

Janaina S Martins ◽

Eva S Liu ◽

W Bruce Sneddon ◽

Peter A Friedman ◽

Marie B Demay

Keyword(s):

Brush Border ◽

Hormonal Regulation ◽

Fibroblast Growth Factor 23 ◽

Term Treatment ◽

Scaffolding Protein ◽

Phosphate Reabsorption ◽

Dihydroxyvitamin D ◽

Protein Levels ◽

1,25 Dihydroxyvitamin D ◽

Long Term Treatment

Abstract Phosphate homeostasis is critical for many cellular processes and is tightly regulated. The sodium-dependent phosphate cotransporter, NaPi2a, is the major regulator of urinary phosphate reabsorption in the renal proximal tubule. Its activity is dependent upon its brush border localization that is regulated by fibroblast growth factor 23 (FGF23) and PTH. High levels of FGF23, as are seen in the Hyp mouse model of human X-linked hypophosphatemia, lead to renal phosphate wasting. Long-term treatment of Hyp mice with 1,25-dihydroxyvitamin D (1,25D) or 1,25D analogues has been shown to improve renal phosphate wasting in the setting of increased FGF23 mRNA expression. Studies were undertaken to define the cellular and molecular basis for this apparent FGF23 resistance. 1,25D increased FGF23 protein levels in the cortical bone and circulation of Hyp mice but did not impair FGF23 cleavage. 1,25D attenuated urinary phosphate wasting as early as one hour postadministration, without suppressing FGF23 receptor/coreceptor expression. Although 1,25D treatment induced expression of early growth response 1, an early FGF23 responsive gene required for its phosphaturic effects, it paradoxically enhanced renal phosphate reabsorption and NaPi2a protein expression in renal brush border membranes (BBMs) within one hour. The Na-H+ exchange regulatory factor 1 (NHERF1) is a scaffolding protein thought to anchor NaPi2a to the BBM. Although 1,25D did not alter NHERF1 protein levels acutely, it enhanced NHERF1-NaPi2a interactions in Hyp mice. 1,25D also prevented the decrease in NHERF1/NaPi2a interactions in PTH-treated wild-type mice. Thus, these investigations identify a novel role for 1,25D in the hormonal regulation of renal phosphate handling.

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Effect of Lacosamide and Ethosuximide Chronic Treatment on Neural Precursor Cells and Cognitive Functions after Pilocarpine Induced Status Epilepticus in Mice

Brain Sciences ◽

10.3390/brainsci11081014 ◽

2021 ◽

Vol 11 (8) ◽

pp. 1014

Author(s):

Aleksandra Szewczyk ◽

Mirosław Zagaja ◽

Joanna Szala-Rycaj ◽

Maciej Maj ◽

Marta Andres-Mach

Keyword(s):

Status Epilepticus ◽

Cognitive Functions ◽

Term Treatment ◽

Cell Counting ◽

Resonance Spectroscopy ◽

Long Term Treatment ◽

Newborn Neurons ◽

Imagej Software ◽

The Impact

Seizures in about 40% of patients with epilepsy fail to respond to anti-seizure medication (ASM) and may lead to uncontrolled and prolonged seizures often inducing status epilepticus (SE). The aim of the study was to evaluate the impact of a long-term treatment with two different generation ASMs: ethosuximide (ETS, a classic ASM) and lacosamide (LCM, a 3rd generation ASM) on neural stem cells’ (NSCs’) proliferation and learning and memory functions after pilocarpine (PILO)-induced SE in mice. The following drugs were used: LCM (10 mg/kg), ETS (20 mg/kg), and PILO (300 mg/kg). Cell counting was done using confocal microscope and ImageJ software. Cognitive functions were evaluated with the Morris water maze (MWM) test. The level of several selected neurometabolites was measured with magnetic resonance spectroscopy (MRS). Obtained results indicated no significant impact of ETS treatment on the neurogenesis process in PILO mice. Interestingly, LCM significantly decreased the total amount of newborn neurons. The MWM test indicated no significant changes in the time and distance traveled by the ETS and LCM groups compared to PILO control mice, although all measured parameters were more favorable for the PILO mice treated with ASM. Conclusions: The presented results show that long term treatment with LCM and ETS seems to be safe for the cognitive functions and the proper course of neurogenesis in the mouse PILO-induced SE model, although one should remember that LCM administered chronically may act to reduce new neurons’ formation.

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The risk of drug resistance during long-acting antimicrobial therapy

10.1101/2021.07.10.21260044 ◽

2021 ◽

Author(s):

Anjalika Nande ◽

Alison Lynn Hill

Keyword(s):

Drug Resistance ◽

Antimicrobial Therapy ◽

De Novo ◽

Drug Clearance ◽

Term Treatment ◽

Chronic Infections ◽

Drug Levels ◽

Long Term Treatment ◽

Long Acting

The emergence of drug resistance during antimicrobial therapy is a major global health problem, especially for chronic infections like HIV, hepatitis B and C, and TB. Sub-optimal adherence to long-term treatment is an important contributor to resistance risk. New long-acting drugs are being developed for weekly, monthly, or less frequent dosing to improve adherence, but may lead to long-term exposure to intermediate drug levels. In this study we analyze the effect of dosing frequency on the risk of resistance evolving in the presence of time-varying drug levels. We find that long-acting therapies can increase, decrease, or have little effect on resistance, depending on the source (pre-existing or de novo) and degree (full or partial) of resistance, and whether the drug is absorbed -- as well as cleared -- more slowly. For long-acting therapies with slow drug clearance but rapid absorption, and for partially-resistant strains, longer dosing intervals tend to reduce resistance risks even if they don't improve adherence, and adherence improvements amplify these effects. In other scenarios, long-acting therapies are more susceptible to resistance and must substantially improve adherence to overcome this deficit. If subpopulations of microbes persist and can reactivate during suboptimal treatment, longer-acting therapies may substantially increase the risk of resistance. Our results show that drug kinetics affect selection for resistance in a complicated manner, and that pathogen-specific models are needed to evaluate the benefit of new long-acting therapies.

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Faculty Opinions recommendation of Increased glutamine in patients undergoing long-term treatment for schizophrenia: a proton magnetic resonance spectroscopy study at 3 T.

Faculty Opinions – Post-Publication Peer Review of the Biomedical Literature ◽

10.3410/f.718240428.793489703 ◽

2014 ◽

Author(s):

Alfredo Carlo Altamura ◽

Massimiliano Buoli

Keyword(s):

Magnetic Resonance ◽

Magnetic Resonance Spectroscopy ◽

Proton Magnetic Resonance ◽

Proton Magnetic Resonance Spectroscopy ◽

Term Treatment ◽

Resonance Spectroscopy ◽

Spectroscopy Study ◽

Magnetic Resonance Spectroscopy Study ◽

Long Term Treatment

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Cytosolic And Membrane Proteins In Plant Cytokinesis

Microscopy and Microanalysis ◽

10.1017/s1431927600019565 ◽

1999 ◽

Vol 5 (S2) ◽

pp. 1248-1249

Author(s):

S. Y. Bednarek ◽

C. Dickey

Keyword(s):

Cell Wall ◽

De Novo ◽

Higher Plants ◽

Cell Plate ◽

Equatorial Region ◽

Yeast Cells ◽

Daughter Cells ◽

Cytoskeletal Structure ◽

Plant Cytokinesis ◽

Common Cell

The mechanism of cytokinesis in higher plants is distinct from that of animal and yeast cells. Dividing plant cells are separated by the de novo construction of the cell-plate across the inside of the cell. Assembly of this new organelle is directed by a specialized cytoskeletal structure called the phragmoplast, a unique macromolecular scaffold that appears late in mitosis and is composed of intermediate filaments, microfilaments, and microtubules. Secretory vesicles are guided along the phragmoplast cytoskeleton toward the equatorial region of the structure where they coalesce and fuse to form a membranous tubular-vesicular network within which cell wall biosynthesis is initiated. A smoother more plate-like structure develops and extends radially outward as additional vesicles are added to the growing margin of the cell-plate until it ultimately fuses with the parental plasma membrane yielding two daughter cells separated by a common cell wall and extracellular space.

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