scholarly journals The Fumarprotocetraric Acid Inhibits Tau Covalently, Avoiding Cytotoxicity of Aggregates in Cells

Molecules ◽  
2021 ◽  
Vol 26 (12) ◽  
pp. 3760
Author(s):  
Camila González ◽  
Constanza Cartagena ◽  
Leonardo Caballero ◽  
Francisco Melo ◽  
Carlos Areche ◽  
...  
Keyword(s):  
Cell Culture ◽  
Tau Protein ◽  
Deleterious Effect ◽  
Membrane Damage ◽  
Mechanisms Of Action ◽  
Pathological Mechanism ◽  
Cysteine Labeling ◽  
Β Sheet ◽  
Covalent Interactions ◽  
Pathological Confirmation

Neurodegenerative disorders, including Tauopathies that involve tau protein, base their pathological mechanism on forming proteinaceous aggregates, which has a deleterious effect on cells triggering an inflammatory response. Moreover, tau inhibitors can exert their mechanism of action through noncovalent and covalent interactions. Thus, Michael’s addition appears as a feasible type of interaction involving an α, β unsaturated carbonyl moiety to avoid pathological confirmation and further cytotoxicity. Moreover, we isolated three compounds from Antarctic lichens Cladonia cariosa and Himantormia lugubris: protolichesterinic acid (1), fumarprotocetraric acid (2), and lichesterinic acid (3). The maleimide cysteine labeling assay showed that compounds 1, 2, and 3 inhibit at 50 µM, but compounds 2 and 3 are statistically significant. Based on its inhibition capacity, we decided to test compound 2 further. Thus, our results suggest that compound 2 remodel soluble oligomers and diminish β sheet content, as demonstrated through ThT experiments. Hence, we added externally treated oligomers with compound 2 to demonstrate that they are harmless in cell culture. First, the morphology of cells in the presence of aggregates does not suffer evident changes compared to the control. Additionally, the externally added aggregates do not provoke a substantial LDH release compared to the control, indicating that treated oligomers do not provoke membrane damage in cell culture compared with aggregates alone. Thus, in the present work, we demonstrated that Michael’s acceptors found in lichens could serve as a scaffold to explore different mechanisms of action to turn tau aggregates into harmless species.

scholarly journals Pharmacological Modulators of Tau Aggregation and Spreading

2020 ◽  
Vol 10 (11) ◽  
pp. 858
Author(s):  
Antonio Dominguez-Meijide ◽  
Eftychia Vasili ◽  
Tiago Fleming Outeiro
Keyword(s):  
Tau Protein ◽  
Neurodegenerative Disorders ◽  
Molecular Mechanisms ◽  
Mechanisms Of Action ◽  
Tau Aggregation ◽  
The Brain ◽  
Pharmacological Modulators

Tauopathies are neurodegenerative disorders characterized by the deposition of aggregates composed of abnormal tau protein in the brain. Additionally, misfolded forms of tau can propagate from cell to cell and throughout the brain. This process is thought to lead to the templated misfolding of the native forms of tau, and thereby, to the formation of newer toxic aggregates, thereby propagating the disease. Therefore, modulation of the processes that lead to tau aggregation and spreading is of utmost importance in the fight against tauopathies. In recent years, several molecules have been developed for the modulation of tau aggregation and spreading. In this review, we discuss the processes of tau aggregation and spreading and highlight selected chemicals developed for the modulation of these processes, their usefulness, and putative mechanisms of action. Ultimately, a stronger understanding of the molecular mechanisms involved, and the properties of the substances developed to modulate them, will lead to the development of safer and better strategies for the treatment of tauopathies.

Self-assembled PEG–poly(l-valine) hydrogels as promising 3D cell culture scaffolds

2017 ◽  
Vol 5 (9) ◽  
pp. 1724-1733 ◽  
Author(s):  
Huijuan Song ◽  
Guang Yang ◽  
Pingsheng Huang ◽  
Deling Kong ◽  
Weiwei Wang
Keyword(s):  
Cell Culture ◽  
3D Cell Culture ◽  
Secondary Structures ◽  
Biomaterial Scaffolds ◽  
Self Assembled ◽  
Α Helix ◽  
Β Sheet ◽  
Biomedical Fields

Self-assembled PEGylated poly(l-valine) hydrogels with combinational α-helix and β-sheet secondary structures represented new biomaterial scaffolds in biomedical fields including but not limited to 3D cell culture.

Effects of Berberine on Diabetes and Cognitive Impairment in an Animal Model: The Mechanisms of Action

2021 ◽  
pp. 1-17
Author(s):  
Jing-Hua Zhang ◽  
Jin-Feng Zhang ◽  
Jun Song ◽  
Yu Bai ◽  
Lan Deng ◽  
...  
Keyword(s):  
Insulin Resistance ◽  
Cognitive Impairment ◽  
Cognitive Function ◽  
Glucose Metabolism ◽  
Tau Protein ◽  
Neuronal Apoptosis ◽  
Mechanisms Of Action ◽  
Diabetic Rats ◽  
Tunel Assay ◽  
Phosphorylated Tau

Diabetes is a group of metabolic disorders with an increased risk of developing cognitive impairment and dementia. The hippocampus in the forebrain contains an abundance of insulin receptors related to cognitive function and plays an important role in the pathophysiology of neurodegenerative disorders. Berberine from traditional Chinese medicine has been used to treat diabetes and diabetic cognitive impairment, although its related mechanisms are largely unknown. In this study, a STZ diabetes rat model feeding with a high-fat diet was used to test the effects of berberine compared with metformin. Oral glucose tolerance and hyperinsulinemic-euglycemic clamp were used for glucose metabolism and insulin resistance. The Morris water maze was used to observe the compound effects on cognitive impairment. Serum and hippocampal [Formula: see text]-amyloid peptide (A[Formula: see text], Tau and phosphorylated Tau protein deposition in the hippocampi were measured. The TUNEL assay was used to detect the neuronal apoptosis, supported by histomorphological changes and transmissional electron microscopy (TEM) image. Our data showed that the diabetic rats had a significantly cognitive impairment. In addition to improving glucose metabolism and reducing insulin resistance, berberine significantly improved the cognitive function in the rat. Berberine also effectively decreased the expression of hippocampal tau protein, phosphorylated Tau, and increased insulin receptor antibodies. Moreover, berberine downregulated the abnormal phosphorylation of A[Formula: see text] and Tau protein and improved hippocampal insulin signaling. The TUNEL assay confirmed that berberine reduced hippocampal neuronal apoptosis supported by TEM. Thus, berberine significantly improved the cognitive function in diabetic rats by changing the peripheral and central insulin resistance. The reduction of neuronal injury, A[Formula: see text] deposition, abnormal phosphorylation of Tau protein, and neuronal apoptosis in the hippocampus were observed as the related mechanisms of action.

scholarly journals Macrocyclic β-Sheet Peptides That Inhibit the Aggregation of a Tau-Protein-Derived Hexapeptide

2011 ◽  
Vol 133 (9) ◽  
pp. 3144-3157 ◽  
Author(s):  
Jing Zheng ◽  
Cong Liu ◽  
Michael R. Sawaya ◽  
Balraju Vadla ◽  
Shafiullah Khan ◽  
...  
Keyword(s):  
Tau Protein ◽  
Β Sheet

P4-014: LOW DOSES OF LITHIUM CHANGE PKA, AKT AND TAU PROTEIN IN CORTICAL AND HIPPOCAMPAL NEURONS CELL CULTURE

2014 ◽  
Vol 10 ◽  
pp. P788-P789
Author(s):  
Vanessa de Jesus Rodrigues de Paula ◽  
Marília Palma Carvalho ◽  
Wagner Gattaz ◽  
Orestes Vicente Forlenza
Keyword(s):  
Cell Culture ◽  
Tau Protein ◽  
Hippocampal Neurons ◽  
Low Doses

scholarly journals Metabolomics Applied to the Study of Extracellular Vesicles

Metabolites ◽  
2019 ◽  
Vol 9 (11) ◽  
pp. 276 ◽  
Author(s):  
Charles Williams ◽  
Mari Palviainen ◽  
Niels-Christian Reichardt ◽  
Pia R.-M. Siljander ◽  
Juan M. Falcón-Pérez
Keyword(s):  
Cell Culture ◽  
Extracellular Vesicles ◽  
Pulmonary Arteries ◽  
Mechanisms Of Action ◽  
Clinical Applications ◽  
Metabolomic Analysis ◽  
Isolation Method ◽  
Non Invasive ◽  
Cell Culture Systems ◽  
Protein Nucleic Acid

Cell-secreted extracellular vesicles (EVs) have rapidly gained prominence as sources of biomarkers for non-invasive biopsies, owing to their ubiquity across human biofluids and physiological stability. There are many characterisation studies directed towards their protein, nucleic acid, lipid and glycan content, but more recently the metabolomic analysis of EV content has also gained traction. Several EV metabolite biomarker candidates have been identified across a range of diseases, including liver disease and cancers of the prostate and pancreas. Beyond clinical applications, metabolomics has also elucidated possible mechanisms of action underlying EV function, such as the arginase-mediated relaxation of pulmonary arteries or the delivery of nutrients to tumours by vesicles. However, whilst the value of EV metabolomics is clear, there are challenges inherent to working with these entities—particularly in relation to sample production and preparation. The biomolecular composition of EVs is known to change drastically depending on the isolation method used, and recent evidence has demonstrated that changes in cell culture systems impact upon the metabolome of the resulting EVs. This review aims to collect recent advances in the EV metabolomics field whilst also introducing researchers interested in this area to practical pitfalls in applying metabolomics to EV studies.

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