scholarly journals Bisavenathramide Analogues as Nrf2 Inductors and Neuroprotectors in In Vitro Models of Oxidative Stress and Hyperphosphorylation

Antioxidants ◽  
2021 ◽  
Vol 10 (6) ◽  
pp. 941
Author(s):  
Ángel Cores ◽  
Sheila Abril ◽  
Patrycja Michalska ◽  
Pablo Duarte ◽  
Ana I. Olives ◽  
...  
Keyword(s):  
Oxidative Stress ◽  
Neurodegenerative Diseases ◽  
Common Factor ◽  
Natural Antioxidants ◽  
Antioxidant Response ◽  
In Vitro Models ◽  
Primary Amines ◽  
Three Component Reaction ◽  
Low Cytotoxicity

Oxidative stress is crucial to the outbreak and advancement of neurodegenerative diseases and is a common factor to many of them. We describe the synthesis of a library of derivatives of the 4-arylmethylen-2-pyrrolin-5-one framework by sequential application of a three-component reaction of primary amines, β-dicarbonyl compounds, and α-haloketones and a Knoevenagel condensation. These compounds can be viewed as cyclic amides of caffeic and ferulic acids, and are also structurally related to the bisavenanthramide family of natural antioxidants. Most members of the library showed low cytotoxicity and good activity as inductors of Nrf2, a transcription factor that acts as the master regulator of the antioxidant response associated with activation of the antioxidant response element (ARE). Nrf2-dependent protein expression was also proved by the significant increase in the levels of the HMOX1 and NQO1 proteins. Some compounds exerted neuroprotective properties in oxidative stress situations, such as rotenone/oligomycin-induced toxicity, and also against protein hyperphosphorylation induced by the phosphatase inhibitor okadaic acid. Compound 3i, which can be considered a good candidate for further hit-to-lead development against neurodegenerative diseases due to its well-balanced multitarget profile, was further characterized by proving its ability to reduce phosphorylated Tau levels.

scholarly journals Curcumin-Piperlongumine Hybrids with a Multitarget Profile Elicit Neuroprotection in In Vitro Models of Oxidative Stress and Hyperphosphorylation

Antioxidants ◽  
2021 ◽  
Vol 11 (1) ◽  
pp. 28
Author(s):  
Ángel Cores ◽  
Noelia Carmona-Zafra ◽  
Olmo Martín-Cámara ◽  
Juan Domingo Sánchez ◽  
Pablo Duarte ◽  
...  
Keyword(s):  
Oral Absorption ◽  
Mitochondrial Respiratory Chain ◽  
Antioxidant Response ◽  
In Vitro Models ◽  
Primary Amines ◽  
Structural Fragment ◽  
Cellular Models ◽  
Three Component Reaction ◽  
Low Toxicity

Curcumin shows a broad spectrum of activities of relevance in the treatment of Alzheimer’s disease (AD); however, it is poorly absorbed and is also chemically and metabolically unstable, leading to a very low oral bioavailability. A small library of hybrid compounds designed as curcumin analogues and incorporating the key structural fragment of piperlongumine, a natural neuroinflammation inhibitor, were synthesized by a two-step route that combines a three-component reaction between primary amines, β-ketoesters and α-haloesters and a base-promoted acylation with cinnamoyl chlorides. These compounds were predicted to have good oral absorption and CNS permeation, had good scavenging properties in the in vitro DPPH experiment and in a cellular assay based on the oxidation of dichlorofluorescin to a fluorescent species. The compounds showed low toxicity in two cellular models, were potent inductors of the Nrf2-ARE phase II antioxidant response, inhibited PHF6 peptide aggregation, closely related to Tau protein aggregation and were active against the LPS-induced inflammatory response. They also afforded neuroprotection against an oxidative insult induced by inhibition of the mitochondrial respiratory chain with the rotenone-oligomycin A combination and against Tau hyperphosphorylation induced by the phosphatase inhibitor okadaic acid. This multitarget pharmacological profile is highly promising in the development of treatments for AD and provides a good hit structure for future optimization efforts.

Determination of Parameters of Oxidative Stress in vitro Models of Neurodegenerative Diseases-A Review

2018 ◽  
Vol 13 (2) ◽  
pp. 100-109 ◽  
Author(s):  
Chistiane Mendes Feitosa ◽  
George Laylson da Silva Oliveira ◽  
Antonio do Nascimento Cavalcante ◽  
Soane Kaline Morais Chaves ◽  
Mahendra Rai
Keyword(s):  
Oxidative Stress ◽  
Neurodegenerative Diseases ◽  
In Vitro Models ◽  
Determination Of Parameters

scholarly journals The Potential Use of Plant Natural Products and Plant Extracts with Antioxidant Properties for the Prevention/Treatment of Neurodegenerative Diseases: In Vitro, In Vivo and Clinical Trials

Molecules ◽  
2018 ◽  
Vol 23 (12) ◽  
pp. 3283 ◽  
Author(s):  
Franziska Pohl ◽  
Paul Kong Thoo Lin
Keyword(s):  
Oxidative Stress ◽  
Clinical Trials ◽  
Neurodegenerative Diseases ◽  
Neurological Disorders ◽  
Natural Antioxidants ◽  
Natural Extracts ◽  
The Impact ◽  
Potential Use

Neurodegenerative disorders, including Alzheimer’s disease, Parkinson’s disease and Huntington’s disease, present a major health issue and financial burden for health care systems around the world. The impact of these diseases will further increase over the next decades due to increasing life expectancies. No cure is currently available for the treatment of these conditions; only drugs, which merely alleviate the symptoms. Oxidative stress has long been associated with neurodegeneration, whether as a cause or as part of the downstream results caused by other factors. Thus, the use of antioxidants to counter cellular oxidative stress within the nervous system has been suggested as a potential treatment option for neurological disorders. Over the last decade, significant research has focused on the potential use of natural antioxidants to target oxidative stress. However, clinical trial results have lacked success for the treatment of patients with neurological disorders. The knowledge that natural extracts show other positive molecular activities in addition to antioxidant activity, however, has led to further research of natural extracts for their potential use as prevention or treatment/management of neurodegenerative diseases. This review will cover several in vitro and in vivo research studies, as well as clinical trials, and highlight the potential of natural antioxidants.

scholarly journals 1,5-Benzodiazepin-2(3H)-ones: In Vitro Evaluation as Antiparkinsonian Agents

Antioxidants ◽  
2021 ◽  
Vol 10 (10) ◽  
pp. 1584
Author(s):  
Ana Ortíz de Zárate ◽  
Marta Pérez-Torralba ◽  
Iñigo Bonet Isidro ◽  
Concepción López ◽  
Rosa M. Claramunt ◽  
...  
Keyword(s):  
Oxidative Stress ◽  
Cell Line ◽  
Antioxidant Properties ◽  
Neuronal Cell ◽  
In Vitro Models ◽  
Glutathione Synthetase ◽  
Human Neuroblastoma ◽  
Antioxidant Power ◽  
Low Cytotoxicity

A new series of twenty-three 1,5-benzodiazepin-2(3H)-ones were synthesized and evaluated in the 2,2′-azino-bis(3-ethylbenzothiazoline-6-sulfonic acid (ABTS), ferric reducing antioxidant power (FRAP), and 2,2-diphenyl-1-picrylhydrazyl (DPPH) assays as a new chemotype with antioxidant and good drug-like properties. All of the derivatives showed low cytotoxicity in comparison to curcumin against the human neuroblastoma SH-SY5Y and the human hepatoma HepG2 cell lines. Experimental solubility in bio-relevant media showed a good relationship with melting points in this series. Five compounds with the best antioxidant properties showed neuroprotectant activity against H2O2-induced oxidative stress in the SH-SY5Y cell line. From them, derivatives 4-phenyl-1H-1,5-benzodiazepin-2(3H)-one (18) and 4-(3,4,5-trimethoxyphenyl)-1H-1,5-benzodiazepin-2(3H)-one (20) yielded good neuroprotection activity in the same neuronal cell line under 6-OHD and MPP+ insults as in vitro models of mitochondrial dysfunction and oxidative stress in Parkinson’s disease (PD). Both compounds also demonstrated a significant reduction of intracellular Reactive Oxygen Species (ROS) and superoxide levels, in parallel with a good improvement of the Mitochondrial Membrane Potential (ΔΨm). Compared with curcumin, compound 18 better reduced lipid peroxidation levels, malondialdehyde (MDA), in SH-SY5Y cells under oxidative stress pressure and recovered intracellular glutathione synthetase (GSH) levels. Apoptosis and caspase-3 levels of SH-SY5Y under H2O2 pressure were also reduced after treatment with 18. Neuroprotection in neuron-like differentiated SH-SY5Y cells was also achieved with 18. In summary, this family of 1,5-benzodiazepin-2-ones with an interesting antioxidant and drug-like profile, with low cytotoxic and good neuroprotectant activity, constitutes a new promising chemical class with high potential for the development of new therapeutic agents against PD.

Targeting PPARalpha in Alzheimer's Disease

2018 ◽  
Vol 15 (4) ◽  
pp. 345-354 ◽  
Author(s):  
Barbara D'Orio ◽  
Anna Fracassi ◽  
Maria Paola Cerù ◽  
Sandra Moreno
Keyword(s):  
Oxidative Stress ◽  
Alzheimer’S Disease ◽  
Alzheimer's Disease ◽  
Molecular Mechanisms ◽  
Redox Homeostasis ◽  
Antioxidant Response ◽  
Peroxisome Proliferator ◽  
Prevailing Paradigm

Background: The molecular mechanisms underlying Alzheimer's disease (AD) are yet to be fully elucidated. The so-called “amyloid cascade hypothesis” has long been the prevailing paradigm for causation of disease, and is today being revisited in relation to other pathogenic pathways, such as oxidative stress, neuroinflammation and energy dysmetabolism. The peroxisome proliferator-activated receptors (PPARs) are expressed in the central nervous system (CNS) and regulate many physiological processes, such as energy metabolism, neurotransmission, redox homeostasis, autophagy and cell cycle. Among the three isotypes (α, β/δ, γ), PPARγ role is the most extensively studied, while information on α and β/δ are still scanty. However, recent in vitro and in vivo evidence point to PPARα as a promising therapeutic target in AD. Conclusion: This review provides an update on this topic, focussing on the effects of natural or synthetic agonists in modulating pathogenetic mechanisms at AD onset and during its progression. Ligandactivated PPARα inihibits amyloidogenic pathway, Tau hyperphosphorylation and neuroinflammation. Concomitantly, the receptor elicits an enzymatic antioxidant response to oxidative stress, ameliorates glucose and lipid dysmetabolism, and stimulates autophagy.

scholarly journals Oxidative Stress as a Possible Target in the Treatment of Toxoplasmosis: Perspectives and Ambiguities

2021 ◽  
Vol 22 (11) ◽  
pp. 5705
Author(s):  
Karolina Szewczyk-Golec ◽  
Marta Pawłowska ◽  
Roland Wesołowski ◽  
Marcin Wróblewski ◽  
Celestyna Mila-Kierzenkowska
Keyword(s):  
Oxidative Stress ◽  
Animal Studies ◽  
Treatment Options ◽  
Natural Antioxidants ◽  
Redox Status ◽  
Host Cells ◽  
Common Disease ◽  
Parasite Viability

Toxoplasma gondii is an apicomplexan parasite causing toxoplasmosis, a common disease, which is most typically asymptomatic. However, toxoplasmosis can be severe and even fatal in immunocompromised patients and fetuses. Available treatment options are limited, so there is a strong impetus to develop novel therapeutics. This review focuses on the role of oxidative stress in the pathophysiology and treatment of T. gondii infection. Chemical compounds that modify redox status can reduce the parasite viability and thus be potential anti-Toxoplasma drugs. On the other hand, oxidative stress caused by the activation of the inflammatory response may have some deleterious consequences in host cells. In this respect, the potential use of natural antioxidants is worth considering, including melatonin and some vitamins, as possible novel anti-Toxoplasma therapeutics. Results of in vitro and animal studies are promising. However, supplementation with some antioxidants was found to promote the increase in parasitemia, and the disease was then characterized by a milder course. Undoubtedly, research in this area may have a significant impact on the future prospects of toxoplasmosis therapy.

scholarly journals In vitro Antioxidant Potentials of Ethanol Extract of Unripe and Ripe Dennetia tripetala Fruits

2019 ◽  
pp. 1-8
Author(s):  
E. I. Akpakpan ◽  
E. N. Onyeike ◽  
C. U. Ogunka-Nnoka
Keyword(s):  
Vitamin C ◽  
Competitive Inhibition ◽  
Reducing Power ◽  
Ethanol Extract ◽  
Natural Antioxidants ◽  
In Vitro Models ◽  
Scavenging Activity ◽  
Fruit Extract ◽  
Ic50 Values

Dennettia tripetala fruit is a popular Nigerian fruit from the family of plant known as Annonaceae. The whole fruit (flesh and seed) is usually consumed as snacks and it is oftentimes consumed with local gin (ufofop in Ibibio or kaikai in Igbo) or added to dishes as spice due to its peculiar strong pepperish taste and sweet aroma. The present study is aimed at evaluating the antioxidant potentials of ethanol extract of ripe and unripe D. tripetala (DT) fruit in vitro. The antioxidant activity of the ethanol extract of DT was evaluated spectrophotometrically using various in vitro models like 1, 1-diphenyl-2-picryl-hydrazyl (DPPH) and hydrogen peroxide scavenging activity; metal chelating activity and reducing power. Vitamin C was used as the standard antioxidant.Unripe and ripe DT fruits, as well as vitamin C showed a competitive inhibition of DPPH and H2O2 free radicals. As concentration of the extracts increased from 20 to100 µg/mL, the % scavenging activity for vitamin C increased from 87.86 ± 0.11 to 90.66 ± 0.07 and for ripe DT fruits from 15.15 ± 0.24 to 25.52 ± 0.23, while for unripe, fruits values increased from 12.09 ± 0.35 to 23.06 ± 0.12. The IC50 values was highest in unripe (549.23) followed by ripe (276.63) and lowest in vitamin C (12.92) indicating that vitamin C was the best scavenger of DPPH radical. Similar trend was obtained for H2O2 scavenging activity as well as reducing power. Unripe DT fruit extract was more potent at chelating metal ions (IC50 was 95.38), followed by the standard ascorbic acid with IC50 of 97.03 and was lowest in ripe DT fruit extract with IC50 value of 124.66. Unripe and ripe DT are potent antioxidants in nature and may be used to supplement our diets as rich sources of natural antioxidants for health protection.

scholarly journals Effect of Borrelia burgdorferi Outer Membrane Vesicles on Host Oxidative Stress Response

Antibiotics ◽  
2020 ◽  
Vol 9 (5) ◽  
pp. 275
Author(s):  
Keith Wawrzeniak ◽  
Gauri Gaur ◽  
Eva Sapi ◽  
Alireza G. Senejani
Keyword(s):  
Oxidative Stress ◽  
Borrelia Burgdorferi ◽  
Outer Membrane ◽  
Neuroblastoma Cells ◽  
Membrane Vesicles ◽  
Antioxidant Response ◽  
Outer Membrane Vesicles ◽  
Vitro Model ◽  
Superoxide Dismutase 2

Outer membrane vesicles (OMVs) are spherical bodies containing proteins and nucleic acids that are released by Gram-negative bacteria, including Borrelia burgdorferi, the causative agent of Lyme disease. The functional relationship between B. burgdorferi OMVs and host neuron homeostasis is not well understood. The objective of this study was to examine how B. burgdorferi OMVs impact the host cell environment. First, an in vitro model was established by co-culturing human BE2C neuroblastoma cells with B. burgdorferi B31. B. burgdorferi was able to invade BE2C cells within 24 h. Despite internalization, BE2C cell viability and levels of apoptosis remained unchanged, but resulted in dramatically increased production of MCP-1 and MCP-2 cytokines. Elevated secretion of MCP-1 has previously been associated with changes in oxidative stress. BE2C cell mitochondrial superoxides were reduced as early as 30 min after exposure to B. burgdorferi and OMVs. To rule out whether BE2C cell antioxidant response is the cause of decline in superoxides, superoxide dismutase 2 (SOD2) gene expression was assessed. SOD2 expression was reduced upon exposure to B. burgdorferi, suggesting that B. burgdorferi might be responsible for superoxide reduction. These results suggest that B. burgdorferi modulates cell antioxidant defense and immune system reaction in response to the bacterial infection. In summary, these results show that B. burgdorferi OMVs serve to directly counter superoxide production in BE2C neurons, thereby ‘priming’ the host environment to support B. burgdorferi colonization.

scholarly journals A Mechanistic Evaluation of Antioxidant Nutraceuticals on Their Potential against Age-Associated Neurodegenerative Diseases

Antioxidants ◽  
2020 ◽  
Vol 9 (10) ◽  
pp. 1019 ◽  
Author(s):  
Nur Zuliani Ramli ◽  
Mohamad Fairuz Yahaya ◽  
Ikuo Tooyama ◽  
Hanafi Ahmad Damanhuri
Keyword(s):  
Oxidative Stress ◽  
Natural Antioxidants ◽  
Green Tea Polyphenols ◽  
Food Sources ◽  
Gene Expressions ◽  
Neuroprotective Effects ◽  
Antioxidative Effects

Nutraceuticals have been extensively studied worldwide due to its neuroprotective effects in in vivo and in vitro studies, attributed by the antioxidative properties. Alzheimer (AD) and Parkinson disease (PD) are the two main neurodegenerative disorders that are discussed in this review. Both AD and PD share the similar involvement of oxidative stress in their pathophysiology. Nutraceuticals exert their antioxidative effects via direct scavenging of free radicals, prevent damage to biomolecules, indirectly stimulate the endogenous antioxidative enzymes and gene expressions, inhibit activation of pro-oxidant enzymes, and chelate metals. In addition, nutraceuticals can act as modulators of pro-survival, pro-apoptotic, and inflammatory signaling pathways. They have been shown to be effective particularly in preclinical stages, due to their multiple mechanisms of action in attenuating oxidative stress underlying AD and PD. Natural antioxidants from food sources and natural products such as resveratrol, curcumin, green tea polyphenols, and vitamin E are promising therapeutic agents in oxidative stress-mediated neurodegenerative disease as they have fewer adverse effects, more tolerable, cheaper, and sustainable for long term consumption.

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