Mechanistic In Vitro Dissection of the Inhibition of Amyloid Fibrillation by n-Acetylneuraminic Acid: Plausible Implication in Therapeutics for Neurodegenerative Disorders

2021 ◽  
Author(s):  
Nida Zaidi ◽  
Mohammad Rehan Ajmal ◽  
Syed Adeel Zaidi ◽  
Rizwan Hasan Khan
Keyword(s):  
Neurodegenerative Disorders ◽  
Acetylneuraminic Acid ◽  
Amyloid Fibrillation

scholarly journals A novel dephosphorylation targeting chimera selectively promoting tau removal in tauopathies

2021 ◽  
Vol 6 (1) ◽  
Author(s):  
Jie Zheng ◽  
Na Tian ◽  
Fei Liu ◽  
Yidian Zhang ◽  
Jingfen Su ◽  
...  
Keyword(s):  
Neurodegenerative Disorders ◽  
Protein Phosphatase ◽  
High Efficiency ◽  
Microtubule Assembly ◽  
Hyperphosphorylated Tau ◽  
Phosphatase 2A ◽  
Dependent Learning ◽  
The Brain

AbstractIntraneuronal accumulation of hyperphosphorylated tau is a hallmark pathology shown in over twenty neurodegenerative disorders, collectively termed as tauopathies, including the most common Alzheimer’s disease (AD). Therefore, selectively removing or reducing hyperphosphorylated tau is promising for therapies of AD and other tauopathies. Here, we designed and synthesized a novel DEPhosphorylation TArgeting Chimera (DEPTAC) to specifically facilitate the binding of tau to Bα-subunit-containing protein phosphatase 2A (PP2A-Bα), the most active tau phosphatase in the brain. The DEPTAC exhibited high efficiency in dephosphorylating tau at multiple AD-associated sites and preventing tau accumulation both in vitro and in vivo. Further studies revealed that DEPTAC significantly improved microtubule assembly, neurite plasticity, and hippocampus-dependent learning and memory in transgenic mice with inducible overexpression of truncated and neurotoxic human tau N368. Our data provide a strategy for selective removal of the hyperphosphorylated tau, which sheds new light for the targeted therapy of AD and related-tauopathies.

scholarly journals Prion Diseases: A Unique Transmissible Agent or a Model for Neurodegenerative Diseases?

Biomolecules ◽  
2021 ◽  
Vol 11 (2) ◽  
pp. 207
Author(s):  
Diane L. Ritchie ◽  
Marcelo A. Barria
Keyword(s):  
Public Health ◽  
Neurodegenerative Diseases ◽  
Prion Protein ◽  
Neurodegenerative Disorders ◽  
Prion Diseases ◽  
Experimental Models ◽  
Misfolded Proteins ◽  
Current Evidence

The accumulation and propagation in the brain of misfolded proteins is a pathological hallmark shared by many neurodegenerative diseases such as Alzheimer’s disease (Aβ and tau), Parkinson’s disease (α-synuclein), and prion disease (prion protein). Currently, there is no epidemiological evidence to suggest that neurodegenerative disorders are infectious, apart from prion diseases. However, there is an increasing body of evidence from experimental models to suggest that other pathogenic proteins such as Aβ and tau can propagate in vivo and in vitro in a prion-like mechanism, inducing the formation of misfolded protein aggregates such as amyloid plaques and neurofibrillary tangles. Such similarities have raised concerns that misfolded proteins, other than the prion protein, could potentially transmit from person-to-person as rare events after lengthy incubation periods. Such concerns have been heightened following a number of recent reports of the possible inadvertent transmission of Aβ pathology via medical and surgical procedures. This review will provide a historical perspective on the unique transmissible nature of prion diseases, examining their impact on public health and the ongoing concerns raised by this rare group of disorders. Additionally, this review will provide an insight into current evidence supporting the potential transmissibility of other pathogenic proteins associated with more common neurodegenerative disorders and the potential implications for public health.

Protective effect of nigella sativa extract and thymoquinone on serum/glucose deprivation-induced PC12 cells death

2011 ◽  
Vol 26 (S2) ◽  
pp. 908-908
Author(s):  
H.R. Sadeghnia ◽  
S.H. Mousavi ◽  
Z. Tayarani-Najaran ◽  
M. Asghari
Keyword(s):  
Cell Viability ◽  
Pc12 Cells ◽  
Neurodegenerative Disorders ◽  
Nigella Sativa ◽  
Glucose Deprivation ◽  
Serum Glucose ◽  
Ros Production ◽  
Protective Effects ◽  
Intracellular Ros

The serum/glucose deprivation (SGD)-induced cell death in cultured PC12 cells represents a useful in vitro model for the study of brain ischemia and neurodegenerative disorders.Nigella sativa L. and its active component, thymoquinone (TQ) have been known as a source of antioxidants. In the present study, the protective effects of N. sativa and TQ on cell viability and reactive oxygen species (ROS) production in cultured PC12 cells were investigated under SGD conditions. PC12 Cells were pretreated with different concentrations of N. sativa extract (15.62–250 μg/ml) and TQ (1.17–150 μM) for 2 h and then subjected to SGD for 6 or 18 h. Cell viability was quantitated by MTT assay. Intracellular ROS production was measured by flow cytometry using 2’,7’-dichlorofluorescin diacetate (DCF-DA) as a probe. SGD induced significant cells toxicity after 6, 18, or 24 h (p < 0.001). Pretreatment with N. sativa (15.62–250 μg/ml) and TQ (1.17–37.5 μM) reduced SGD-induced cytotoxicity in PC12 cells after 6 and 18 h. A significant increase in intracellular ROS production was seen following SGD (p < 0.001). N. sativa (250 μg/ml, p < 0.01) and TQ (2.34, 4.68, 9.37 μM, p < 0.01) pretreatment reversed the increased ROS production following ischemic insult. The experimental results suggest that N. sativa extract and TQ protects the PC12 cells against SGD-induced cytotoxicity via antioxidant mechanisms. Our findings might raise the possibility of potential therapeutic application of N. sativa extract and TQ for managing cerebral ischemic and neurodegenerative disorders.

scholarly journals Pharmaceutical Applications of Molecular Tweezers, Clefts and Clips

Molecules ◽  
2019 ◽  
Vol 24 (9) ◽  
pp. 1803 ◽  
Author(s):  
Amira Mbarek ◽  
Ghina Moussa ◽  
Jeanne Leblond Chain
Keyword(s):  
Cardiovascular Disease ◽  
Neurodegenerative Disorders ◽  
Therapeutic Agents ◽  
Mechanistic Studies ◽  
Molecular Tweezers ◽  
The Past ◽  
Pharmaceutical Applications ◽  
Controlled Motion

Synthetic acyclic receptors, composed of two arms connected with a spacer enabling molecular recognition, have been intensively explored in host-guest chemistry in the past decades. They fall into the categories of molecular tweezers, clefts and clips, depending on the geometry allowing the recognition of various guests. The advances in synthesis and mechanistic studies have pushed them forward to pharmaceutical applications, such as neurodegenerative disorders, infectious diseases, cancer, cardiovascular disease, diabetes, etc. In this review, we provide a summary of the synthetic molecular tweezers, clefts and clips that have been reported for pharmaceutical applications. Their structures, mechanism of action as well as in vitro and in vivo results are described. Such receptors were found to selectively bind biological guests, namely, nucleic acids, sugars, amino acids and proteins enabling their use as biosensors or therapeutics. Particularly interesting are dynamic molecular tweezers which are capable of controlled motion in response to an external stimulus. They proved their utility as imaging agents or in the design of controlled release systems. Despite some issues, such as stability, cytotoxicity or biocompatibility that still need to be addressed, it is obvious that molecular tweezers, clefts and clips are promising candidates for several incurable diseases as therapeutic agents, diagnostic or delivery tools.

scholarly journals Antioxidant and Anti-Inflammatory Effects of Citrus Flavonoid Hesperetin: Special Focus on Neurological Disorders

Antioxidants ◽  
2020 ◽  
Vol 9 (7) ◽  
pp. 609 ◽  
Author(s):  
Amjad Khan ◽  
Muhammad Ikram ◽  
Jong Ryeal Hahm ◽  
Myeong Ok Kim
Keyword(s):  
Neurodegenerative Disorders ◽  
In Vitro Models ◽  
Experimental Models ◽  
Special Focus ◽  
Neuroprotective Effects ◽  
Beneficial Effects ◽  
Wide Range ◽  
Underlying Mechanisms

Neurodegenerative disorders have emerged as a serious health issue in the current era. The most common neurodegenerative disorders are Alzheimer’s disease (AD), Parkinson’s disease, multiple sclerosis, and amyotrophic lateral sclerosis (ALS). These diseases involve progressive impairment of neurodegeneration and memory impairment. A wide range of compounds have been identified as potential neuroprotective agents against different models of neurodegeneration both in vivo and in vitro. Hesperetin, a flavanone class of citrus flavonoid, is a derivative of hesperidin found in citrus fruits such as oranges, grapes, and lemons. It has been extensively reported that hesperetin exerts neuroprotective effects in experimental models of neurodegenerative diseases. In this systematic review, we have compiled all the studies conducted on hesperetin in both in vivo and in vitro models of neurodegeneration. Here, we have used an approach to lessen the bias in each study, providing a least biased, broad understanding of findings and impartial conclusions of the strength of evidence and the reliability of findings. In this review, we collected different papers from a wide range of journals describing the beneficial effects of hesperetin on animal models of neurodegeneration. Our results demonstrated consistent neuroprotective effects of hesperetin against different models of neurodegeneration. In addition, we have summarized its underlying mechanisms. This study provides the foundations for future studies and recommendations of further mechanistic approaches to conduct preclinical studies on hesperetin in different models.

scholarly journals Curcumin-Loaded Nanoparticles Based on Amphiphilic Hyaluronan-Conjugate Explored as Targeting Delivery System for Neurodegenerative Disorders

2020 ◽  
Vol 21 (22) ◽  
pp. 8846
Author(s):  
Giuseppe Pepe ◽  
Enrica Calce ◽  
Valentina Verdoliva ◽  
Michele Saviano ◽  
Vittorio Maglione ◽  
...  
Keyword(s):  
Huntington's Disease ◽  
Huntington’S Disease ◽  
Delivery System ◽  
Neurodegenerative Disorders ◽  
Natural Polysaccharide ◽  
Promising Therapeutic Approach ◽  
Targeting Delivery ◽  
Effective Delivery ◽  
Vitro Model

Identification of molecules able to promote neuroprotective mechanisms can represent a promising therapeutic approach to neurodegenerative disorders including Huntington’s disease. Curcumin is an antioxidant and neuroprotective agent, even though its efficacy is limited by its poor absorption, rapid metabolism, systemic elimination, and limited blood–brain barrier (BBB) permeability. Herein, we report on novel biodegradable curcumin-containing nanoparticles to favor the compound delivery and potentially enhance its brain bioavailability. The prepared hyaluronan-based materials able to self-assemble in stable spherical nanoparticles, consist of natural fatty acids chemically conjugated to the natural polysaccharide. The aim of this study is to provide a possible effective delivery system for curcumin with the expectation that, after having released the drug at the specific site, the biopolymer can degrade to nontoxic fragments before renal excretion, since all the starting materials are provided by natural resource. Our findings demonstrate that curcumin-encapsulated nanoparticles enter the cells and reduce their susceptibility to apoptosis in an in vitro model of Huntington’s disease.

scholarly journals Complement alternative pathway activation by chronic lymphocytic leukemia cells: its role in their hepatosplenic localization

Blood ◽  
1984 ◽  
Vol 63 (2) ◽  
pp. 463-467 ◽  
Author(s):  
F Praz ◽  
G Karsenty ◽  
JL Binet ◽  
P Lesavre
Keyword(s):  
Chronic Lymphocytic Leukemia ◽  
Alternative Pathway ◽  
Lymphocytic Leukemia ◽  
Leukemic Cells ◽  
Complement Alternative Pathway ◽  
Acetylneuraminic Acid ◽  
Pathway Activation ◽  
Do So

Abstract Using affinity-purified 125I-F(ab')2 anti-human C3, we have investigated the ability of various leukemic cells to activate complement. Lymphocytes from patients with chronic lymphocytic leukemia (CLL) activated the alternative pathway, but cells from patients with other forms of leukemia or normal lymphocytes did not do so. The amount of C3 deposited on the CLL cells was significantly higher in patients with organomegaly (i.e., splenomegaly and/or hepatomegaly). Activation of complement by CLL cells as assessed by C3 deposition on the membrane occurred both in vivo and in vitro and was not related to the N- acetylneuraminic acid content of the membrane.

scholarly journals Graphene oxide inhibits hIAPP amyloid fibrillation and toxicity in insulin-producing NIT-1 cells

2016 ◽  
Vol 18 (1) ◽  
pp. 94-100 ◽  
Author(s):  
Praveen Nedumpully-Govindan ◽  
Esteban N. Gurzov ◽  
Pengyu Chen ◽  
Emily H. Pilkington ◽  
William J. Stanley ◽  
...  
Keyword(s):  
Graphene Oxide ◽  
Computational Modeling ◽  
Molecular Mechanism ◽  
Multidisciplinary Approach ◽  
Biophysical Characterization ◽  
Toxicity Studies ◽  
Amyloid Fibrillation

Using a multidisciplinary approach combining computational modeling, biophysical characterization, and in vitro toxicity studies, the anti-amyloid effect of graphene oxide and its molecular mechanism is investigated.

scholarly journals Rat brain microsomal gangliosides. Accessibility to a neuraminidase preparation and the possible existence of different pools in relation to their biosynthesis

1974 ◽  
Vol 138 (2) ◽  
pp. 291-298 ◽  
Author(s):  
H. J. F. Maccioni ◽  
A. Arce ◽  
C. Landa ◽  
R. Caputto
Keyword(s):  
Rat Brain ◽  
Chemical Structure ◽  
Proper Position ◽  
Neuraminidase Treatment ◽  
Acetylneuraminic Acid ◽  
Microsomal Membranes ◽  
Labelling Experiment ◽  
Labile N ◽  
The Right

1. Treatment of rat brain microsomal membranes with a neuraminidase preparation from Clostridium perfringens resulted in an almost complete conversion of polysialogangliosides into monosialogangliosides. 2. Neuraminidase treatment of the membranes did not increase the incorporation of N-[3H]acetylneuraminic acid from CMP-N-[3H]acetylneuraminic acid into the gangliosidic fraction, indicating that a monosialoganglioside is an acceptor of N-acetylneuraminic acid in these membranes only if, in addition to having the right chemical structure, it is in a proper position, probably in relation to the endogenous sialyltransferases. 3. These experiments also indicated that no independent turnover of the neuraminidase-labile N-acetylneuraminyl groups of gangliosides occurred in vitro. 4. N-[3H]Acetylneuraminic acid from endogenous polysialogangliosides labelled in vitro was released by neuraminidase at a slower rate than N-acetylneuraminic acid from unlabelled gangliosides of the same membranes. From this it was concluded that recently synthesized polysialogangliosides (completed in vitro) are in the membranes in a position less accessible to neuraminidase than are those synthesized earlier which were present in the membranes at the start of the labelling experiment.

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