Potential for Treatment of Neurodegenerative Diseases with Natural Products or Synthetic Compounds that Stabilize Microtubules

2020 ◽  
Vol 26 (35) ◽  
pp. 4362-4372
Author(s):  
John H. Miller ◽  
Viswanath Das
Keyword(s):  
Natural Products ◽  
Neurodegenerative Diseases ◽  
In Vivo Models ◽  
Synthetic Compounds ◽  
Stabilizing Agents ◽  
Animal Models Of Disease ◽  
Model Studies ◽  
Models Of Disease

No effective therapeutics to treat neurodegenerative diseases exist, despite significant attempts to find drugs that can reduce or rescue the debilitating symptoms of tauopathies such as Alzheimer’s disease, Parkinson’s disease, frontotemporal dementia, amyotrophic lateral sclerosis, or Pick’s disease. A number of in vitro and in vivo models exist for studying neurodegenerative diseases, including cell models employing induced-pluripotent stem cells, cerebral organoids, and animal models of disease. Recent research has focused on microtubulestabilizing agents, either natural products or synthetic compounds that can prevent the axonal destruction caused by tau protein pathologies. Although promising results have come from animal model studies using brainpenetrant natural product microtubule-stabilizing agents, such as paclitaxel analogs that can access the brain, epothilones B and D, and other synthetic compounds such as davunetide or the triazolopyrimidines, early clinical trials in humans have been disappointing. This review aims to summarize the research that has been carried out in this area and discuss the potential for the future development of an effective microtubule stabilizing drug to treat neurodegenerative disease.

scholarly journals Shiga Toxin Subtypes Display Dramatic Differences in Potency

2011 ◽  
Vol 79 (3) ◽  
pp. 1329-1337 ◽  
Author(s):  
Cynthia A. Fuller ◽  
Christine A. Pellino ◽  
Michael J. Flagler ◽  
Jane E. Strasser ◽  
Alison A. Weiss
Keyword(s):  
Shiga Toxin ◽  
Vero Cells ◽  
Epidemiologic Studies ◽  
Systemic Complications ◽  
Animal Models Of Disease ◽  
Uremic Syndrome ◽  
Models Of Disease ◽  
Relative Potencies

ABSTRACTPurified Shiga toxin (Stx) alone is capable of producing systemic complications, including hemolytic-uremic syndrome (HUS), in animal models of disease. Stx includes two major antigenic forms (Stx1 and Stx2), with minor variants of Stx2 (Stx2a to -h). Stx2a is more potent than Stx1. Epidemiologic studies suggest that Stx2 subtypes also differ in potency, but these differences have not been well documented for purified toxin. The relative potencies of five purified Stx2 subtypes, Stx2a, Stx2b, Stx2c, Stx2d, and activated (elastase-cleaved) Stx2d, were studiedin vitroby examining protein synthesis inhibition using Vero monkey kidney cells and inhibition of metabolic activity (reduction of resazurin to fluorescent resorufin) using primary human renal proximal tubule epithelial cells (RPTECs). In both RPTECs and Vero cells, Stx2a, Stx2d, and elastase-cleaved Stx2d were at least 25 times more potent than Stx2b and Stx2c.In vivopotency in mice was also assessed. Stx2b and Stx2c had potencies similar to that of Stx1, while Stx2a, Stx2d, and elastase-cleaved Stx2d were 40 to 400 times more potent than Stx1.

scholarly journals A Novel Small Molecule Inhibits Intrahepatocellular Accumulation of Z-Variant Alpha 1-Antitrypsin In Vitro and In Vivo

Cells ◽  
2019 ◽  
Vol 8 (12) ◽  
pp. 1586 ◽  
Author(s):  
Xiaojuan Zhang ◽  
Kien Pham ◽  
Danmeng Li ◽  
Ryan J. Schutte ◽  
David Hernandez Gonzalo ◽  
...  
Keyword(s):  
Liver Disease ◽  
Cell Model ◽  
Curative Therapy ◽  
Animal Models Of Disease ◽  
Antitrypsin Deficiency ◽  
Alpha 1 Antitrypsin Deficiency ◽  
Alpha 1 Antitrypsin ◽  
Models Of Disease

Alpha 1-antitrypsin deficiency (AATD) is the most common genetic cause of liver disease in children and is associated with early-onset chronic liver disease in adults. AATD associated liver injury is caused by hepatotoxic retention of polymerized mutant alpha 1-antitrypsin molecules within the endoplasmic reticulum. Currently, there is no curative therapy for AATD. In this study, we selected small molecules with the potential to bind mutant alpha 1-antitrypsin (Z-variant) to inhibit its accumulation in hepatocytes. We used molecular docking to select candidate compounds that were validated in cell and animal models of disease. A crystal structure of polymerized alpha 1-antitrypsin molecule was used as the basis for docking 139,735 compounds. Effects of the top scoring compounds were investigated in a cell model that stably expresses Z-variant alpha 1-antitrypsin and in PiZ mice expressing Z-variant human alpha 1-antitrypsin (Z-hAAT), encoded by SERPINA1*E342K. 4′,′5-(Methylenedioxy)-2-nitrocinnamic acid was predicted to bind cleaved alpha 1-antitrypsin at the polymerization interface, and observed to co-localize with Z-hAAT, increase Z-hAAT degradation, inhibit intracellular accumulation of Z-hAAT, and alleviate liver fibrosis.

Microvesiculation and Disease

2013 ◽  
Vol 41 (1) ◽  
pp. 237-240 ◽  
Author(s):  
Jameel M. Inal ◽  
Una Fairbrother ◽  
Sheelagh Heugh
Keyword(s):  
Infectious Disease ◽  
Extracellular Vesicles ◽  
Immune Cell ◽  
In Vivo Models ◽  
Cell Functions ◽  
Models Of Disease ◽  
New Treatments ◽  
Acute Myeloid

The important roles of extracellular vesicles in the pathogenesis of various diseases are rapidly being elucidated. As important vehicles of intercellular communication, extracellular vesicles, which comprise microvesicles and exosomes, are revealing important roles in cancer tumorigenesis and metastases and in the spread of infectious disease. The September 2012 Focused Meeting ‘Microvesiculation and Disease’ brought together researchers working on extracellular vesicles. The papers in this issue of Biochemical Society Transactions review work in areas including HIV infection, kidney disease, hypoxia-mediated tumorigenesis and down-regulation of immune cell functions in acute myeloid leukaemia by tumour-derived exosomes. In all cases, microvesicles and exosomes have been demonstrated to be important factors leading to the pathophysiology of disease or indeed as therapeutic vehicles in possible new treatments. The aim was, having enhanced our molecular understanding of the contribution of microvesicles and exosomes to disease in vitro, to begin to apply this knowledge to in vivo models of disease.

scholarly journals Expanding the Fluorine Chemistry of Living Systems Using Engineered Polyketide Synthase Pathways

Science ◽  
2013 ◽  
Vol 341 (6150) ◽  
pp. 1089-1094 ◽  
Author(s):  
Mark C. Walker ◽  
Benjamin W. Thuronyi ◽  
Louise K. Charkoudian ◽  
Brian Lowry ◽  
Chaitan Khosla ◽  
...  
Keyword(s):  
Natural Products ◽  
Synthetic Biology ◽  
Natural Product ◽  
Polyketide Synthase ◽  
Building Blocks ◽  
Living Systems ◽  
Synthetic Compounds ◽  
Fluorinated Building Blocks

Organofluorines represent a rapidly expanding proportion of molecules that are used in pharmaceuticals, diagnostics, agrochemicals, and materials. Despite the prevalence of fluorine in synthetic compounds, the known biological scope is limited to a single pathway that produces fluoroacetate. Here, we demonstrate that this pathway can be exploited as a source of fluorinated building blocks for introduction of fluorine into natural-product scaffolds. Specifically, we have constructed pathways involving two polyketide synthase systems, and we show that fluoroacetate can be used to incorporate fluorine into the polyketide backbone in vitro. We further show that fluorine can be inserted site-selectively and introduced into polyketide products in vivo. These results highlight the prospects for the production of complex fluorinated natural products using synthetic biology.

scholarly journals Phytosterols: Potential Metabolic Modulators in Neurodegenerative Diseases

2021 ◽  
Vol 22 (22) ◽  
pp. 12255
Author(s):  
Niti Sharma ◽  
Mario A. Tan ◽  
Seong Soo A. An
Keyword(s):  
Natural Products ◽  
Neurodegenerative Diseases ◽  
Plant Species ◽  
Biological Activities ◽  
Herbal Medicines ◽  
Pharmacological Activities ◽  
Isolated Structures ◽  
Biological And Pharmacological Activities

Phytosterols constitute a class of natural products that are an important component of diet and have vast applications in foods, cosmetics, and herbal medicines. With many and diverse isolated structures in nature, they exhibit a broad range of biological and pharmacological activities. Among over 200 types of phytosterols, stigmasterol and β-sitosterol were ubiquitous in many plant species, exhibiting important aspects of activities related to neurodegenerative diseases. Hence, this mini-review presented an overview of the reported studies on selected phytosterols related to neurodegenerative diseases. It covered the major phytosterols based on biosynthetic considerations, including other phytosterols with significant in vitro and in vivo biological activities.

scholarly journals The Role of the Gut-Brain Axis in Neurodegenerative Diseases and Relevance of the Canine Model: A Review

2019 ◽  
Author(s):  
Yoko Ambrosini ◽  
Dana Borcherding ◽  
Anumantha Kanthasamy ◽  
Hyun Jung Kim ◽  
Albert Jergens ◽  
...  
Keyword(s):  
Animal Models ◽  
Neurodegenerative Diseases ◽  
Gut Microbiome ◽  
Individual Variability ◽  
Future Research ◽  
In Vivo Models ◽  
Advantages And Disadvantages ◽  
Amyloid A

Identifying appropriate animal models is critical in developing translatable in vitro and in vivo systems for therapeutic development and investigating disease pathophysiology. These animal models should have direct biological and translational relevance to the underlying disease they are supposed to mimic. Aging dogs naturally develop a cognitive decline in many aspects including learning and memory, but also exhibit human-like individual variability in the aging process. Neurodegenerative processes that can be observed in both human and canine brains include the progressive accumulation of β-amyloid (Aβ) found as diffuse plaques in the prefrontal cortex, including the gyrus proreus, the hippocampus, and in the cerebral vasculature. A growing body of epidemiological data shows that human patients with neurodegenerative diseases have concurrent intestinal lesions, and histopathological changes in the gastrointestinal (GI) tract occurs decades that evolve before neurodegenerative changes. Gut microbiome alterations also have been observed in many neurodegenerative diseases including Alzheimer’s and Parkinson’s diseases, and inflammatory CNS diseases. Interestingly, only recently has the dog gut microbiome been recognized to more closely resemble in composition and in functional overlap with the human gut microbiome as compared to rodent models. This article aims to review the physiology of the gut-brain axis (GBA), and its involvement with neurodegenerative diseases in dogs and humans. Additionally, we outline the advantages and disadvantages of traditional in vitro and in vivo models and discuss future research directions investigating major human neurodegenerative diseases such as Alzheimer’s and Parkinson’s diseases using dogs.

scholarly journals Neuroprotective and Cognitive Enhancement Potentials of Baicalin: A Review

2018 ◽  
Vol 8 (6) ◽  
pp. 104 ◽  
Author(s):  
Kandhasamy Sowndhararajan ◽  
Ponnuvel Deepa ◽  
Minju Kim ◽  
Se Park ◽  
Songmun Kim
Keyword(s):  
Neurodegenerative Diseases ◽  
Molecular Mechanisms ◽  
Cognitive Enhancement ◽  
Neuroprotective Effect ◽  
Neuroprotective Agents ◽  
Chinese Medicinal Herb ◽  
In Vivo Models ◽  
Flavonoid Compounds

Neurodegenerative diseases are a heterogeneous group of disorders that are characterized by the gradual loss of neurons. The development of effective neuroprotective agents to prevent and control neurodegenerative diseases is specifically important. Recently, there has been an increasing interest in selecting flavonoid compounds as potential neuroprotective agents, owing to their high effectiveness with low side effects. Baicalin is one of the important flavonoid compounds, which is mainly isolated from the root of Scutellaria baicalensis Georgi (an important Chinese medicinal herb). In recent years, a number of studies have shown that baicalin has a potent neuroprotective effect in various in vitro and in vivo models of neuronal injury. In particular, baicalin effectively prevents neurodegenerative diseases through various pharmacological mechanisms, including antioxidative stress, anti-excitotoxicity, anti-apoptotic, anti-inflammatory, stimulating neurogenesis, promoting the expression of neuronal protective factors, etc. This review mainly focuses on the neuroprotective and cognitive enhancement effects of baicalin. The aim of the present review is to compile all information in relation to the neuroprotective and cognitive enhancement effects of baicalin and its molecular mechanisms of action in various in vitro and in vivo experimental models.

Emerging Potential of Naturally Occurring Autophagy Modulators Against Neurodegeneration

2020 ◽  
Vol 26 (7) ◽  
pp. 772-779 ◽  
Author(s):  
Md. Ataur Rahman ◽  
Md Rezanur Rahman ◽  
Toyfiquz Zaman ◽  
Md. Sahab Uddin ◽  
Rokibul Islam ◽  
...  
Keyword(s):  
Natural Products ◽  
Neurodegenerative Diseases ◽  
Biological Activities ◽  
Naturally Occurring ◽  
Living Organisms ◽  
Therapeutic Assistance ◽  
Lateral Sclerosis ◽  
Made In

Background: Naturally-occurring products derived from living organisms have been shown to modulate various pharmacological and biological activities. Natural products protect against various diseases, which could be used for therapeutic assistance. Autophagy, a lysosome-mediated self-digestion pathway, has been implicated in a range of pathophysiological conditions and has recently gained attention for its role in several neurodegenerative diseases. Methods: In this current review, we emphasized the recent progress made in our understanding of the molecular mechanism of autophagy in different cellular and mouse models using naturally-occurring autophagy modulators for the management of several neurodegenerative diseases. Results: Accumulating evidence has revealed that a wide variety of natural compounds such as alkaloids, polyphenols, terpenoids, xanthonoids, flavonoids, lignans, disaccharides, glycolipoproteins, and saponins are involved in the modulation of the autophagy signaling pathway. These natural products have been used to treat various neurodegenerative diseases such as Alzheimer’s disease, Parkinson’s disease, Huntington’s disease, Amyotrophic lateral sclerosis, spinocerebellar ataxia, neuroblastoma, and glioblastoma. Although a number of synthetic autophagy regulators have been recognized as encouraging neurodegenerative therapeutic candidates, natural autophagy- regulating compounds have been of further interest as potential disease therapeutics, as they cause insignificant side effects. Conclusion: Existing in vitro and in vivo data are promising and highlight that naturally-occurring autophagyregulating compounds play an important role in the prevention and treatment of neurodegenerative disorders.

scholarly journals Cytoprotective and Neurotrophic Effects of Octadecaneuropeptide (ODN) in in vitro and in vivo Models of Neurodegenerative Diseases

2020 ◽  
Vol 11 ◽  
Author(s):  
Olfa Masmoudi-Kouki ◽  
Amira Namsi ◽  
Yosra Hamdi ◽  
Seyma Bahdoudi ◽  
Ikram Ghouili ◽  
...  
Keyword(s):  
Neurodegenerative Diseases ◽  
In Vivo Models

scholarly journals Structural Modifications Yield Novel Insights Into the Intriguing Pharmacodynamic Potential of Anti-inflammatory Nitro-Fatty Acids

2021 ◽  
Vol 12 ◽  
Author(s):  
Nadine Hellmuth ◽  
Camilla Brat ◽  
Omar Awad ◽  
Sven George ◽  
Astrid Kahnt ◽  
...  
Keyword(s):  
Fatty Acids ◽  
Biological Effects ◽  
Covalent Modification ◽  
Related Factor ◽  
Nuclear Factor ◽  
Animal Models Of Disease ◽  
Anti Inflammatory ◽  
Models Of Disease

Endogenous nitro-fatty acids (NFA) are potent electrophilic lipid mediators that exert biological effects in vitro and in vivo via selective covalent modification of thiol-containing target proteins. The cytoprotective, anti-inflammatory, and anti-tumorigenic effects of NFA in animal models of disease caused by targeted protein nitroalkylation are a valuable basis for the development of future anti-phlogistic and anti-neoplastic drugs. Considering the complexity of diseases and accompanying comorbidities there is an urgent need for clinically effective multifunctional drugs. NFA are composed of a fatty acid backbone containing a nitroalkene moiety triggering Michael addition reactions. However, less is known about the target-specific structure–activity relationships and selectivities comparing different NFA targets. Therefore, we analyzed 15 NFA derivatives and compared them with the lead structure 9-nitro-oleic acid (9NOA) in terms of their effect on NF-κB (nuclear factor kappa B) signaling inhibition, induction of Nrf-2 (nuclear factor erythroid 2-related factor 2) gene expression, sEH (soluble epoxide hydrolase), LO (lipoxygenase), and COX-2 (cyclooxygenase-2) inhibition, and their cytotoxic effects on colorectal cancer cells. Minor modifications of the Michael acceptor position and variation of the chain length led to drugs showing increased target preference or enhanced multi-targeting, partly with higher potency than 9NOA. This study is a significant step forward to better understanding the biology of NFA and their enormous potential as scaffolds for designing future anti-inflammatory drugs.

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