Multi-functional neuroprotective activity of neohesperidin dihydrochalcone: a novel scaffold for Alzheimer's disease therapeutics identified <i>via</i> drug repurposing screening

Chakraborty, Sandipan; Rakshit, Jyotirmoy; Bandyopadhyay, Jaya; Basu, Soumalee

doi:10.1039/c8nj00853a

Cited by 13 publications

(5 citation statements)

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“…Myricetin can inhibit the proliferation and migration of many types of tumor cells [26], and the pharmacological effects of Baicalin include anti-atherosclerosis, protection against myocardial ischemia-reperfusion injury, protection of cardiomyocytes and endothelial cells, inhibition of myocardial remodeling, and other properties [27]. Neohesperidin dihydrochalcone, a flavonoid derivative (vitamin P), has the effect of protecting the liver and inhibiting gastric acid secretion [28]. Others, such as chlorogenic acid, p-coumaric acid, and rosmarinic acid, also have significant pharmacological effects regarding immune regulation, inhibition of tumors, and prevention of cardiovascular diseases [29][30][31].…”

Section: Discussionmentioning

confidence: 99%

Evaluation of In Vitro Bio-Activities Effects of WST (Wushanshencha)

Liu

Zhang³

et al. 2019

Applied Sciences

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As a traditional Chinese drink, tea is favored for its rich flavor and its medicinal functionality. In this study, the in vitro bioactivities of Wushanshencha (WST; a local tea from Chongqing, China), which is processed mainly from the leaves of the wild Malus hupehensis (Pamp.) Rehd.). We assessed the scavenging capacity of tea extracts on 1, 1-diphenyl-2-picrylhydrazyl (DPPH); 2, 2′-azino-bis (3-ethylbenzthiazoline-6- sulphonic acid) diammonium salt (ABTS); and hydroxyl (OH) free radicals, and demonstrate the high antioxidant activity and dose-dependent relationship of these extracts. We also detail the anti-mutagenic effect of these tea extracts against the Salmonella typhimurium TA98 strain induced by the 2, 7-diaminofluorene (2, 7-AF) mutagen and the TA100 strain induced by the N-methyl-N′-nitro- N- nitrosoguanidine (MNNG) mutagen at concentrations of 1.25 and 2.50 mg/plate, respectively, with the high-dose groups showing better results. We investigated the anticancer mechanisms of WST extracts (40, 100, and 160 μg/mL) in HepG2 human hepatoma cells via 3-(4, 5-dimethyl-2-thiazolyl)-2, 5-diphenyl-2-H-tetrazolium bromide (MTT) assay and quantitative real-time reverse transcription-polymerase chain reaction (RT-qPCR). The results showed that the proliferation of HepG2 cells was significantly inhibited in a dose-dependent manner by the tea extracts. Moreover, apoptosis in HepG2 cells was induced via upregulation of Caspase-3, Caspase-7, Caspase-8, Caspase-9, p21, p53, and Bax as well as downregulation of Bcl-2 apoptosis-associated factors, as assessed via mRNA expression levels after treating with WST extracts. The expression of inflammation-related factors, e.g., NF-κB, and Cox-2, was significantly downregulated by the WST extracts, demonstrating its inflammatory properties. Together, these observations indicated that WST extracts have anti-inflammatory and anti-cancer properties. In addition, high-performance liquid chromatography (HPLC) analysis showed that WST extracts contained chlorogenic acid, 4-hydroxycinnamic acid, isoquercitrin, taxifolin, quercitrin, rosmarinic acid, myricetin, baicalin, neosperidin dihydrochalcone, and quercetin. As such, WST appears to be an effectively functional drink, due to its rich functional components and anti-cancer activity.

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Section: Discussionmentioning

confidence: 99%

Evaluation of In Vitro Bio-Activities Effects of WST (Wushanshencha)

Liu

Zhang³

et al. 2019

Applied Sciences

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“…After incubation, 2 μL of bromophenol blue dye (0.25% in 50% glycerol) was added. The reaction mixtures obtained were loaded on agarose gel (0.8% in Tris/borate/ethylenediaminetetraacetic acid (EDTA) (TBE) buffer), and electrophoresis was carried out at 90 V for 1 h, followed by staining with ethidium bromide . Various forms (supercoiled, open-circular, and linear) of pBR322 were visualized and quantified using a gel documentation system (AlphaImager Mini, ProteinSimple).…”

Section: Experimental Sectionmentioning

confidence: 99%

Donepezil-Inspired Multitargeting Indanone Derivatives as Effective Anti-Alzheimer’s Agents

Singh

Thakur

Kumar

et al. 2022

ACS Chem. Neurosci.

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In continuous efforts to develop anti-Alzheimer’s agents, we rationally designed and synthesized a series of multitargeting molecules by incorporating the essential molecular features of the standard drug donepezil. Among the series, compound 4b showed multitargeting properties to act as an anti-Alzheimer’s agent, which is better tolerable in vivo than donepezil. Acetylcholinesterase (AChE) inhibition data showed that compound 4b inhibits the enzyme with a half-maximal inhibitory concentration (IC50) value of 0.78 μM and also showed DNA protection, which was confirmed through the DNA nicking assay, suggesting the protective effect of 4b against oxidative DNA damage. Compound 4b also showed 53.04% inhibition against Aβ1–42 aggregations, which was found comparable to that of the standard compound curcumin. Molecular dynamics simulations were performed to check the stability of compound 4b with the enzyme AChE, which showed that the enzyme–ligand complex is stable enough to block the hydrolysis of acetylcholine in the brain. Its higher LD50 cutoff value (50 mg/kg) in comparison to donepezil (LD50: 25 mg/kg) made it safer, suggesting that it can be used in further clinical experiments. To evaluate its anti-Alzheimer property, a mice model with melamine-induced cognitive dysfunction was used, and Morris water maze and Rotarod tests were performed. A significant improvement in memory was observed after the treatment with compound 4b and donepezil. The study postulated that the introduction of important structural features of donepezil (dimethoxyindanone moiety as ring-A) embarked with terminal aromatic ether (ring-B and ring-C) made 4b a multitargeting molecule that offers a way for developing alternative therapeutics in the future against Alzheimer’s disease (AD).

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“…These hits have been further rescreened using two BACE1 conformations using ensemble docking and then by a separately developed 2-D QSAR for BACE1 inhibition. This multitier screening increases the chances of true hit discovery, and three flavonoids, hesperidin, neohesperidin dihydrochalcone, and narirutin have been identified and experimentally verified. − Steady-state and time-resolved fluorescence spectroscopies have been used to shed light on the ligand recognition mechanism. The intrinsic protein fluorescence continuously increases with the gradual addition of flavonoids (Figure ).…”

Section: Bace1 Flexibility: a Grand Challenge In Computational Hit Di...mentioning

confidence: 99%

Scope of β-Secretase (BACE1)-Targeted Therapy in Alzheimer’s Disease: Emphasizing the Flavonoid Based Natural Scaffold for BACE1 Inhibition

Das

Sengupta

Chakraborty

2020

ACS Chem. Neurosci.

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Alzheimer’s disease (AD) is a progressive neurodegenerative disease and the most common form of dementia in the world. Studies report the presence of extracellular amyloid plaques consisting of β-amyloid peptide and intracellular tangles consisting of hyperphosphorylated tau proteins as the histopathological indicators of AD. The process of β-amyloid peptide generation by sequential cleavage of amyloid precursor protein by β-secretase (BACE1) and γ-secretase, followed by its aggregation to form amyloid plaques, is the mechanistic basis of the amyloid hypothesis. Other popular hypotheses related to the pathogenesis of AD include the tau hypothesis and the oxidative stress hypothesis. Various targets of the amyloid cascade are now in prime focus to develop drugs for AD. Many BACE1 inhibitors, β-amyloid aggregation inhibitors, and Aβ clearance strategies using monoclonal antibodies are in various stages of clinical trials. This review provides an in-depth evaluation of the role of BACE1 in disease pathogenesis and also highlights the therapeutic approaches developed to find more potent but less toxic inhibitors for BACE1, particularly emphasizing the natural scaffold as a nontoxic lead for BACE1 inhibition. Cellular targets and signaling cascades involving BACE1 have been highlighted to understand the physiological role of BACE1. This knowledge is extremely crucial to understand the toxicity evaluations for BACE1-targeted therapy. We have particularly highlighted the scope of flavonoids as a new generation of nontoxic BACE1 inhibitory scaffolds. The structure–activity relationship of BACE1 inhibition for this group of compounds has been highlighted to provide a guideline to design more selective highly potent inhibitors. The review aims to provide a holistic overview of BACE1-targeted therapy for AD that paves the way for future drug development.

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Multi-functional neuroprotective activity of neohesperidin dihydrochalcone: a novel scaffold for Alzheimer's disease therapeutics identified via drug repurposing screening

Abstract: Multi-target screening identifies neohesperidin dihydrochalcone for Alzheimer's disease therapeutics, which exhibits strong BACE1 and amyloid aggregation inhibition along with antioxidant activity.

Cited by 13 publications

References 83 publications

Evaluation of In Vitro Bio-Activities Effects of WST (Wushanshencha)

Evaluation of In Vitro Bio-Activities Effects of WST (Wushanshencha)

Donepezil-Inspired Multitargeting Indanone Derivatives as Effective Anti-Alzheimer’s Agents

Scope of β-Secretase (BACE1)-Targeted Therapy in Alzheimer’s Disease: Emphasizing the Flavonoid Based Natural Scaffold for BACE1 Inhibition

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