scholarly journals Roles of Cannabidiol in Reversing Proteinopathies

2020 ◽  
Author(s):  
Raju Dash ◽  
Md. Chayan Ali ◽  
Israt Jahan ◽  
Yeasmin Akter Munni ◽  
Sarmistha Mitra ◽  
...  
Keyword(s):  
Neurodegenerative Diseases ◽  
Neurological Disorders ◽  
Protein Misfolding ◽  
Cannabis Sativa ◽  
Protein Homeostasis ◽  
Compelling Evidence ◽  
The Past ◽  
Clearing System ◽  
Central Nervous Systems ◽  
Preclinical And Clinical Studies

Cannabidiol is a well-known non-psychotropic phytocannabinoid from Cannabis sativa, which exerts a broad range of neuropharmacological activities in the central nervous systems. Over the past years, compelling evidence from preclinical and clinical studies support therapeutic potentials of cannabidiol in various neurological disorders, including neurodegenerative diseases. Neurodegenerative diseases are characterized by the accumulation of misfolded or aggregated protein due to the defective protein homeostasis or proteostasis network, termed as proteinopathies. Because of its role in the protein homeostasis network, cannabidiol could be a potent molecule to revert not only age-associated neurodegeneration but also other protein misfolding disorders. In this review, we discuss the potentiality of cannabidiol as a pharmacological modulator of the proteostasis network, highlighting its neuroprotective and aggregates clearing system inducing potentials in the neurodegenerative diseases.

scholarly journals Misfolded protein aggregation and altered cellular pathways in neurodegenerative diseases

STEMedicine ◽  
2020 ◽  
Vol 1 (4) ◽  
pp. e63
Author(s):  
Huifang Li ◽  
Zhenghong Yu ◽  
Wei Zhang
Keyword(s):  
Neurodegenerative Diseases ◽  
Neurological Disorders ◽  
Cell Types ◽  
World Health ◽  
Protein Homeostasis ◽  
Sensory Impairments ◽  
Cellular Pathways ◽  
Health Organization ◽  
Nonhuman Species ◽  
Human Death

Neurodegenerative diseases are estimated by the World Health Organization to be the second leading cause of human death by 2050. They actually are a group of chronic neurological disorders leading to motor, cognitive and sensory impairments in both human and nonhuman species. Despite different in clinical manifestation, prevalence, risk factors, cell types injured and genes hijacked, neurodegenerative disorders are usually associated with the misfolding and aggregation of a distinct protein that accumulates in diverse cellular locations including the nucleus, cytoplasm, plasma membrane and extracellular space. Here we intend to give an overview of the characters and features of several pathogenic protein aggregates in disease brains, and introduce some general signaling pathways involved in protein homeostasis with emphasis on their puzzling roles under the degenerative conditions.

scholarly journals Proteostasis Disturbances and Inflammation in Neurodegenerative Diseases

Cells ◽  
2020 ◽  
Vol 9 (10) ◽  
pp. 2183
Author(s):  
Tuuli-Maria Sonninen ◽  
Gundars Goldsteins ◽  
Nihay Laham-Karam ◽  
Jari Koistinaho ◽  
Šárka Lehtonen
Keyword(s):  
Neurodegenerative Diseases ◽  
Protein Misfolding ◽  
Inflammatory Responses ◽  
Biological Response ◽  
Protein Damage ◽  
Protein Homeostasis ◽  
Cellular Functions ◽  
Regenerative Capacity ◽  
Age Related ◽  
Lateral Sclerosis

Protein homeostasis (proteostasis) disturbances and inflammation are evident in normal aging and some age-related neurodegenerative diseases. While the proteostasis network maintains the integrity of intracellular and extracellular functional proteins, inflammation is a biological response to harmful stimuli. Cellular stress conditions can cause protein damage, thus exacerbating protein misfolding and leading to an eventual overload of the degradation system. The regulation of proteostasis network is particularly important in postmitotic neurons due to their limited regenerative capacity. Therefore, maintaining balanced protein synthesis, handling unfolding, refolding, and degrading misfolded proteins are essential to preserve all cellular functions in the central nervous sysytem. Failing proteostasis may trigger inflammatory responses in glial cells, and the consequent release of inflammatory mediators may lead to disturbances in proteostasis. Here, we review the mechanisms of proteostasis and inflammatory response, emphasizing their role in the pathological hallmarks of neurodegenerative diseases such as Alzheimer’s disease, Parkinson’s disease, and amyotrophic lateral sclerosis. Furthermore, we discuss the interplay between proteostatic stress and excessive immune response that activates inflammation and leads to dysfunctional proteostasis.

scholarly journals Regulation of Age-Related Protein Toxicity

2021 ◽  
Vol 9 ◽  
Author(s):  
Anita Pras ◽  
Ellen A. A. Nollen
Keyword(s):  
Protein Misfolding ◽  
Model Organisms ◽  
Amyloid Formation ◽  
Protein Homeostasis ◽  
Control Mechanisms ◽  
Toxic Protein ◽  
The Past ◽  
Age Related ◽  
Protein Misfolding And Aggregation ◽  
Protein Toxicity

Proteome damage plays a major role in aging and age-related neurodegenerative diseases. Under healthy conditions, molecular quality control mechanisms prevent toxic protein misfolding and aggregation. These mechanisms include molecular chaperones for protein folding, spatial compartmentalization for sequestration, and degradation pathways for the removal of harmful proteins. These mechanisms decline with age, resulting in the accumulation of aggregation-prone proteins that are harmful to cells. In the past decades, a variety of fast- and slow-aging model organisms have been used to investigate the biological mechanisms that accelerate or prevent such protein toxicity. In this review, we describe the most important mechanisms that are required for maintaining a healthy proteome. We describe how these mechanisms decline during aging and lead to toxic protein misassembly, aggregation, and amyloid formation. In addition, we discuss how optimized protein homeostasis mechanisms in long-living animals contribute to prolonging their lifespan. This knowledge might help us to develop interventions in the protein homeostasis network that delay aging and age-related pathologies.

Microbial Genetic Screens for Monitoring Protein Misfolding Associated with Neurodegeneration: Tools for Identifying Disease-Relevant Genes and for Screening Synthetic and Natural Compound Libraries for the Discovery of Potential Therapeutics

2018 ◽  
Vol 24 (19) ◽  
pp. 2055-2075 ◽  
Author(s):  
Kalliopi Kostelidou ◽  
Ilias Matis ◽  
Georgios Skretas
Keyword(s):  
Protein Misfolding ◽  
Socioeconomic Impact ◽  
Genetic Screens ◽  
Subsequent Formation ◽  
The Past ◽  
Compound Libraries ◽  
Selection Systems ◽  
Cellular Factors ◽  
Effective Drugs ◽  
Potential Therapeutics

Neurodegenerative Diseases (ND) are a major threat to the aging population and the lack of a single preventive or disease-modifying agent only serves to increase their impact. In the past few years, protein misfolding and the subsequent formation of neurotoxic oligomeric/aggregated protein species have emerged as a unifying theme underlying the pathology of these complex diseases. Recently developed microbial genetic screens and selection systems for monitoring ND-associated protein misfolding have allowed the establishment of highthroughput assays for the identification of cellular factors and processes that are important mediators of NDassociated proteotoxicities. In addition, such systems have facilitated the discovery of synthetic and natural compounds with the ability to rescue the misfolding and the associated pathogenic effects of aggregation-prone proteins associated with NDs. This review outlines such available systems in bacteria and yeast, whose usage will likely accelerate the pre-clinical discovery process for effective drugs against a variety of NDs with high socioeconomic impact.

Purines and Pyrimidines: Metabolism, Function and Potential as therapeutic options in neurodegenerative diseases

2020 ◽  
Vol 21 ◽  
Author(s):  
Debanjan Kundu ◽  
Vikash Kumar Dubey
Keyword(s):  
Neurodegenerative Diseases ◽  
Neurodegenerative Disorders ◽  
Protein Misfolding ◽  
Molecular Mechanisms ◽  
Treatment Regimens ◽  
Loss Of Balance ◽  
Current Scenario ◽  
Unexplored Area ◽  
Molecular Origin ◽  
Purines And Pyrimidines

Abstract:: Various neurodegenerative disorders have molecular origin but some common molecular mechanisms. In the current scenario, there are very few treatment regimens present for advanced neurodegenerative diseases. In this context, there is an urgent need for alternate options in the form of natural compounds with an ameliorating effect on patients. There have been individual scattered experiments trying to identify potential values of various intracellular metabolites. Purines and Pyrimidines, which are vital molecules governing various aspects of cellular biochemical reactions, have been long sought as crucial candidates for the same, but there are still many questions that go unanswered. Some critical functions of these molecules associated with neuromodulation activities have been identified. They are also known to play a role in foetal neurodevelopment, but there is a lacuna in understanding their mechanisms. In this review, we have tried to assemble and identify the importance of purines and pyrimidines, connecting them with the prevalence of neurodegenerative diseases. The leading cause of this class of diseases is protein misfolding and the formation of amyloids. A direct correlation between loss of balance in cellular homeostasis and amyloidosis is yet an unexplored area. This review aims at bringing the current literature available under one umbrella serving as a foundation for further extensive research in this field of drug development in neurodegenerative diseases.

Conformation as the Therapeutic Target for Neurodegenerative Diseases

2017 ◽  
Vol 14 (4) ◽  
pp. 393-402 ◽  
Author(s):  
Rajaraman Krishnan ◽  
Franz Hefti ◽  
Haim Tsubery ◽  
Michal Lulu ◽  
Ming Proschitsky ◽  
...  
Keyword(s):  
Monoclonal Antibodies ◽  
Neurodegenerative Diseases ◽  
Protein Misfolding ◽  
Specific Binding ◽  
Drug Candidate ◽  
High Affinity ◽  
Novel Approach ◽  
Multiple Protein ◽  
Clinical Benefits ◽  
Effective Drugs

Therapeutic strategies that target pathways of protein misfolding and the toxicity of intermediates along these pathways are mainly at discovery and early development stages, with the exception of monoclonal antibodies that have mainly failed to produce convincing clinical benefits in late stage trials. The clinical failures represent potentially critical lessons for future neurodegenerative disease drug development. More effective drugs may be achieved by pursuing the following two strategies. First, conformational targeting of aggregates of misfolded proteins, rather than less specific binding that includes monomer subunits, which vastly outnumber the toxic targets. Second, since neurodegenerative diseases frequently include more than one potential protein pathology, generic targeting of aggregates by shape might also be a crucial feature of a drug candidate. Incorporating both of these critical features into a viable drug candidate along with high affinity binding has not been achieved with small molecule approaches or with antibody fragments. Monoclonal antibodies developed so far are not broadly acting through conformational recognition. Using GAIM (General Amyloid Interaction Motif) represents a novel approach that incorporates high affinity conformational recognition for multiple protein assemblies, as well as recognition of an array of assemblies along the misfolding pathway between oligomers and fibers. A GAIM-Ig fusion, NPT088, is nearing clinical testing.

Neurological Disorders

2017 ◽  
Author(s):  
Margit L. Bleecker
Keyword(s):  
Carbon Monoxide ◽  
Neurological Disorders ◽  
Occupational Exposures ◽  
Signs And Symptoms ◽  
Dose Effect ◽  
Temporal Association ◽  
Biological Plausibility ◽  
Cognitive Domains ◽  
The Past ◽  
Neurologic Disorders

This chapter describes neurologic disorders related primarily to occupational exposures along with presenting signs and symptoms. Acute or subacute occupational exposure to high levels of neurotoxic compounds, which occurred in the past and resulted in unique presentations of neurological disorders, occur infrequently today. Sections include the evaluation of toxic neuropathies and the approach to neurobehavioral impairment along with the cognitive domains commonly affected with exposure to neurointoxicants. A section describes the approach to a patient with exposure to neurointoxicants that includes the need for a temporal association between exposure and effect, a dose-effect relationship, biological plausibility, and other causes eliminated Effects of selected neurotoxins are described, including carbon monoxide, lead, organic solvents, and manganese.

scholarly journals Green Tea Epigallocatechin-3-gallate (EGCG) Targeting Protein Misfolding in Drug Discovery for Neurodegenerative Diseases

Biomolecules ◽  
2021 ◽  
Vol 11 (5) ◽  
pp. 767
Author(s):  
Priscila Baltazar Gonçalves ◽  
Ana Carolina Rennó Sodero ◽  
Yraima Cordeiro
Keyword(s):  
Drug Discovery ◽  
Neurodegenerative Diseases ◽  
Green Tea ◽  
Protein Misfolding ◽  
Financial Burden ◽  
Scientific Evidence ◽  
Symptomatic Relief ◽  
Public Health Problem ◽  
Bioactive Compound ◽  
Common Cause

The potential to treat neurodegenerative diseases (NDs) of the major bioactive compound of green tea, epigallocatechin-3-gallate (EGCG), is well documented. Numerous findings now suggest that EGCG targets protein misfolding and aggregation, a common cause and pathological mechanism in many NDs. Several studies have shown that EGCG interacts with misfolded proteins such as amyloid beta-peptide (Aβ), linked to Alzheimer’s disease (AD), and α-synuclein, linked to Parkinson’s disease (PD). To date, NDs constitute a serious public health problem, causing a financial burden for health care systems worldwide. Although current treatments provide symptomatic relief, they do not stop or even slow the progression of these devastating disorders. Therefore, there is an urgent need to develop effective drugs for these incurable ailments. It is expected that targeting protein misfolding can serve as a therapeutic strategy for many NDs since protein misfolding is a common cause of neurodegeneration. In this context, EGCG may offer great potential opportunities in drug discovery for NDs. Therefore, this review critically discusses the role of EGCG in NDs drug discovery and provides updated information on the scientific evidence that EGCG can potentially be used to treat many of these fatal brain disorders.

scholarly journals The Past, Present and Future of Cannabis sativa Tissue Culture

Plants ◽  
2021 ◽  
Vol 10 (1) ◽  
pp. 185
Author(s):  
Adrian S. Monthony ◽  
Serena R. Page ◽  
Mohsen Hesami ◽  
Andrew Maxwell P. Jones
Keyword(s):  
Tissue Culture ◽  
Disease Virus ◽  
Cannabis Sativa ◽  
Clonal Plants ◽  
Future Directions ◽  
The Past ◽  
Recent Developments ◽  
History Of ◽  
Drug Type

The recent legalization of Cannabis sativa L. in many regions has revealed a need for effective propagation and biotechnologies for the species. Micropropagation affords researchers and producers methods to rapidly propagate insect-/disease-/virus-free clonal plants and store germplasm and forms the basis for other biotechnologies. Despite this need, research in the area is limited due to the long history of prohibitions and restrictions. Existing literature has multiple limitations: many publications use hemp as a proxy for drug-type Cannabis when it is well established that there is significant genotype specificity; studies using drug-type cultivars are predominantly optimized using a single cultivar; most protocols have not been replicated by independent groups, and some attempts demonstrate a lack of reproducibility across genotypes. Due to culture decline and other problems, the multiplication phase of micropropagation (Stage 2) has not been fully developed in many reports. This review will provide a brief background on the history and botany of Cannabis as well as a comprehensive and critical summary of Cannabis tissue culture. Special attention will be paid to current challenges faced by researchers, the limitations of existing Cannabis micropropagation studies, and recent developments and future directions of Cannabis tissue culture technologies.

scholarly journals Metronomic Chemotherapy: A Systematic Review of the Literature and Clinical Experience

2019 ◽  
Vol 2019 ◽  
pp. 1-31 ◽  
Author(s):  
Cem Simsek ◽  
Ece Esin ◽  
Suayib Yalcin
Keyword(s):  
Clinical Studies ◽  
Lower Cost ◽  
Metronomic Chemotherapy ◽  
Maximum Tolerated Dose ◽  
Cancer Management ◽  
The Past ◽  
Promising Therapeutic Approach ◽  
Treatment Models ◽  
Dose Dense ◽  
Preclinical And Clinical Studies

Metronomic chemotherapy, continuous and dose-dense administration of chemotherapeutic drugs with lowered doses, is being evaluated for substituting, augmenting, or appending conventional maximum tolerated dose regimens, with preclinical and clinical studies for the past few decades. To date, the principle mechanisms of its action include impeding tumoral angiogenesis and modulation of hosts’ immune system, affecting directly tumor cells, their progenitors, and neighboring stromal cells. Its better toxicity profile, lower cost, and easier use are main advantages over conventional therapies. The evidence of metronomic chemotherapy for personalized medicine is growing, starting with unfit elderly patients and also for palliative treatment. The literature reviewed in this article mainly demonstrates that metronomic chemotherapy is advantageous for selected patients and for certain types of malignancies, which make it a promising therapeutic approach for filling in the gaps. More clinical studies are needed to establish a solidified role for metronomic chemotherapy with other treatment models in modern cancer management.

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