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p-Coumaric acid attenuates the effects of Aβ42 in vitro and in a Drosophila Alzheimer's disease model

Tan FHP, Najimudin N, Watanabe N, Shamsuddin S, Azzam G

Behav Brain Res, 2023 Aug 24;452:114568.
PMID: 37414223 DOI: 10.1016/j.bbr.2023.114568

Alzheimer's disease (AD) is the most common neurodegenerative condition in civilizations worldwide. The distinctive occurrence of amyloid-beta (Aβ) accumulation into insoluble fibrils is part of the disease pathophysiology with Aβ42 being the most toxic and aggressive Aβ species. The polyphenol, p-Coumaric acid (pCA), has been known to boost a number of therapeutic benefits. Here, pCA's potential to counteract the negative effects of Aβ42 was investigated. First, pCA was confirmed to reduce Aβ42 fibrillation using an in vitro activity assay. The compound was next examined on Aβ42-exposed PC12 neuronal cells and was found to significantly decrease Aβ42-induced cell mortality. pCA was then examined using an AD Drosophila melanogaster model. Feeding of pCA partially reversed the rough eye phenotype, significantly lengthened AD Drosophila's lifespan, and significantly enhanced the majority of the AD Drosophila's mobility in a sex-dependent manner. The findings of this study suggest that pCA may have therapeutic benefits for AD.
Fulltext Creation of chimeric human/rabbit APOBEC1 with HIV-1 restriction and DNA mutation activities

Ikeda T, Ong EB, Watanabe N, Sakaguchi N, Maeda K, Koito A

Sci Rep, 2016;6:19035.
PMID: 26738439 DOI: 10.1038/srep19035

APOBEC1 (A1) proteins from lagomorphs and rodents have deaminase-dependent restriction activity against HIV-1, whereas human A1 exerts a negligible effect. To investigate these differences in the restriction of HIV-1 by A1 proteins, a series of chimeric proteins combining rabbit and human A1s was constructed. Homology models of the A1s indicated that their activities derive from functional domains that likely act in tandem through a dimeric interface. The C-terminal region containing the leucine-rich motif and the dimerization domains of rabbit A1 is important for its anti-HIV-1 activity. The A1 chimeras with strong anti-HIV-1 activity were incorporated into virions more efficiently than those without anti-HIV-1 activity, and exhibited potent DNA-mutator activity. Therefore, the C-terminal region of rabbit A1 is involved in both its packaging into the HIV-1 virion and its deamination activity against both viral cDNA and genomic RNA. This study identifies the novel molecular mechanism underlying the target specificity of A1.
Fulltext Identification of small molecule inhibitors of p27(Kip1) ubiquitination by high-throughput screening

Ooi LC, Watanabe N, Futamura Y, Sulaiman SF, Darah I, Osada H

Cancer Sci, 2013 Nov;104(11):1461-7.
PMID: 23910095 DOI: 10.1111/cas.12246

Dysregulation of p27(Kip1) due to proteolysis that involves the ubiquitin ligase (SCF) complex with S-phase kinase-associated protein 2 (Skp2) as the substrate-recognition component (SCF(Skp2)) frequently results in tumorigenesis. In this report, we developed a high-throughput screening system to identify small-molecule inhibitors of p27(Kip1) degradation. This system was established by tagging Skp2 with fluorescent monomeric Azami Green (mAG) and CDK subunit 1 (Cks1) (mAGSkp2-Cks1) to bind to p27(Kip1) phosphopeptides. We identified two compounds that inhibited the interaction between mAGSkp2-Cks1 and p27(Kip1): linichlorin A and gentian violet. Further studies have shown that the compounds inhibit the ubiquitination of p27(Kip1) in vitro as well as p27(Kip1) degradation in HeLa cells. Notably, both compounds exhibited preferential antiproliferative activity against HeLa and tsFT210 cells compared with NIH3T3 cells and delayed the G1 phase progression in tsFT210 cells. Our approach indicates a potential strategy for restoring p27(Kip1) levels in human cancers.
Comparison of microplate- and bottle-based methods to age yeast for chronological life span assays

Kwong MMY, Lee JW, Samian MR, Watanabe N, Osada H, Ong EBB

J Microbiol Methods, 2019 12;167:105743.
PMID: 31629019 DOI: 10.1016/j.mimet.2019.105743

This study compared the chronological life span and survival of Saccharomyces cerevisiae aged in a microplate or bottle, under different aeration and calorie restriction conditions. Our data shows that limited aeration in the microplate-aged culture contributed to slower outgrowth but extended yeast CLS compared to the bottle-aged culture.
Fulltext Identification of Tropical Plant Extracts That Extend Yeast Chronological Life Span

Kwong MMY, Lee JW, Samian MR, Wahab HA, Watanabe N, Ong EBB

Cells, 2021 10 11;10(10).
PMID: 34685698 DOI: 10.3390/cells10102718

Certain plant extracts (PEs) contain bioactive compounds that have antioxidant and lifespan-extending activities on organisms. These PEs play different roles in cellular processes, such as enhancing stress resistance and modulating longevity-defined signaling pathways that contribute to longevity. Here, we report the discovery of PEs that extended chronological life span (CLS) in budding yeast from a screen of 222 PEs. We identified two PEs, the leaf extracts of Manihot esculenta and Wodyetia bifurcata that extended CLS in a dose-dependent manner. The CLS-extending PEs also conferred oxidative stress tolerance, suggesting that these PEs might extend yeast CLS through the upregulation of stress response pathways.
Ethyl caffeate ameliorated amyloid-beta42 protein-associated toxicity in PC12 cells and Drosophila melanogaster

Tan FHP, Hadri NAB, Najimudin N, Watanabe N, Azzam G

Geriatr Gerontol Int, 2021 Dec;21(12):1125-1130.
PMID: 34699118 DOI: 10.1111/ggi.14296

AIM: Alzheimer's disease (AD) is the most pervasive neurodegenerative disorder in societies globally. Till now, the mechanism behind this disease is still equivocal. Amyloid-beta42 protein (Aβ42), the most toxic and aggressive Aβ species, is the main focus of this study. The naturally occurring ethyl caffeate (EC) is associated with various medicinal properties. Here, EC was tested for its protective properties against Aβ42's toxic effects.
METHODS: As treatment of Aβ42 has been shown to cause neuronal cell death, EC was first screened with Aβ42-incubated PC12 neuronal cells. Next, the compound was tested on the Drosophila melanogaster AD model using the rough eye phenotype assay, lifespan assay and negative geotaxis assay.
RESULTS: EC ameliorated PC12 cells from cell death linked to Aβ42 exposure. Using Drosophila expressing human Aβ42, feeding of EC was able to partially rescue the rough eye phenotype, lengthen the lifespan of AD Drosophila and enhanced the mobility of middle-aged AD Drosophila.
CONCLUSION: Overall, the results of this study showed that EC might possess therapeutic properties for AD. Geriatr Gerontol Int 2021; 21: 1125-1130.
Alleviatory effects of Danshen, Salvianolic acid A and Salvianolic acid B on PC12 neuronal cells and Drosophila melanogaster model of Alzheimer's disease

Tan FHP, Ting ACJ, Leow BG, Najimudin N, Watanabe N, Azzam G

J Ethnopharmacol, 2021 Oct 28;279:114389.
PMID: 34217797 DOI: 10.1016/j.jep.2021.114389

ETHNOPHARMACOLOGICAL RELEVANCE: Danshen water extract (DWE), obtained from the Salvia miltiorrhiza Bunge (Family Lamiaceae) root, is usually employed in Chinese traditional medicine as treatment to cardiovascular ailments and cerebrovascular diseases. Intriguingly, the extract was also found to contain vast beneficial properties in Alzheimer's disease (AD) treatment.
AIM OF THE STUDY: Alzheimer's disease is the most significant type of neurodegenerative disorder plaguing societies globally. Its pathogenesis encompasses the hallmark aggregation of amyloid-beta (Aβ). Of all the Aβ oligomers formed in the brain, Aβ42 is the most toxic and aggressive. Despite this, the mechanism behind this disease remains elusive. In this study, DWE, and its major components, Salvianolic acid A (SalA) and Salvianolic acid B (SalB) were tested for their abilities to attenuate Aβ42's toxic effects.
METHODS: The composition of DWE was determined via Ultra-Performance Liquid Chromatography (UPLC). DWE, SalA and SalB were first verified for their capability to diminish Aβ42 fibrillation using an in vitro activity assay. Since Aβ42 aggregation results in neuronal degeneration, the potential Aβ42 inhibitors were next evaluated on Aβ42-exposed PC12 neuronal cells. The Drosophila melanogaster AD model was then employed to determine the effects of DWE, SalA and SalB.
RESULTS: DWE, SalA and SalB were shown to be able to reduce fibrillation of Aβ42. When tested on PC12 neuronal cells, DWE, SalA and SalB ameliorated cells from cell death associated with Aβ42 exposure. Next, DWE and its components were tested on the Drosophila melanogaster AD model and their rescue effects were further characterized. The UPLC analysis showed that SalA and SalB were present in the brains and bodies of Drosophila after DWE feeding. When human Aβ42 was expressed, the AD Drosophila exhibited degenerated eye structures known as the rough eye phenotype (REP), reduced lifespan and deteriorated locomotor ability. Administration of DWE, SalA and SalB partially reverted the REP, increased the age of AD Drosophila and improved most of the mobility of AD Drosophila.
CONCLUSION: Collectively, DWE and its components may have therapeutic potential for AD patients and possibly other forms of brain diseases.
3-[[(3S)-1,2,3,4-Tetrahydroisoquinoline-3-Carbonyl]Amino]Propanoic Acid (THICAPA) Is Protective Against Aβ42-Induced Toxicity In Vitro and in an Alzheimer's Disease Drosophila

Tan FHP, Ting ACJ, Najimudin N, Watanabe N, Shamsuddin S, Zainuddin A, et al.

J Gerontol A Biol Sci Med Sci, 2023 Oct 28;78(11):1944-1952.
PMID: 37453137 DOI: 10.1093/gerona/glad169

Alzheimer's disease (AD) is the most prevalent type of dementia globally. The accumulation of amyloid-beta (Aβ) extracellular senile plaques in the brain is one of the hallmark mechanisms found in AD. Aβ42 is the most damaging and aggressively aggregating Aβ isomer produced in the brain. Although Aβ42 has been extensively researched as a crucial peptide connected to the development of the characteristic amyloid fibrils in AD, the specifics of its pathophysiology are still unknown. Therefore, the main objective was to identify novel compounds that could potentially mitigate the negative effects of Aβ42. 3-[[(3S)-1,2,3,4-Tetrahydroisoquinoline-3-carbonyl]amino]propanoic acid (THICAPA) was identified as a ligand for Aβ42 and for reducing fibrillary Aβ42 aggregation. THICAPA also improved cell viability when administered to PC12 neuronal cells that were exposed to Aβ42. Additionally, this compound diminished Aβ42 toxicity in the current AD Drosophila model by rescuing the rough eye phenotype, prolonging the life span, and enhancing motor functions. Through next-generation RNA-sequencing, immune response pathways were downregulated in response to THICAPA treatment. Thus, this study suggests THICAPA as a possible disease-modifying treatment for AD.
Fulltext Niosomes in cancer treatment: A focus on curcumin encapsulation

Bashkeran T, Kamaruddin AH, Ngo TX, Suda K, Umakoshi H, Watanabe N, et al.

Heliyon, 2023 Aug;9(8):e18710.
PMID: 37593605 DOI: 10.1016/j.heliyon.2023.e18710

Curcumin is widely used as a therapeutic drug for cancer treatment. However, its limited absorption and rapid excretion are the major therapeutic limitations to its clinical use. Using niosomes as a curcumin delivery system is a cheap, easy, and less toxic strategy for enhancing the absorption of curcumin by cells and delaying its excretion. Thus, there is a vital need to explore curcumin niosomes to configure the curcumin to suitably serve and aid current pharmacokinetics in treatments for cancer. To date, no comprehensive review has focused on the cytotoxic effects of curcumin niosomes on malignant cells. Thus, this review provides a critical analysis of the curcumin niosomes in cancer treatment, formulations of curcumin niosomes, characterizations of curcumin niosomes, and factors influencing their performance. The findings from this review article can strongly accelerate the understanding of curcumin niosomes and pave a brighter direction towards advances in the pharmaceutical, biotechnology, and medical industries.
Fulltext Screening of selected ageing-related proteins that extend chronological life span in yeast Saccharomyces cerevisiae

Lee JW, Ong TG, Samian MR, Teh AH, Watanabe N, Osada H, et al.

Sci Rep, 2021 Dec 17;11(1):24148.
PMID: 34921163 DOI: 10.1038/s41598-021-03490-7

Ageing-related proteins play various roles such as regulating cellular ageing, countering oxidative stress, and modulating signal transduction pathways amongst many others. Hundreds of ageing-related proteins have been identified, however the functions of most of these ageing-related proteins are not known. Here, we report the identification of proteins that extended yeast chronological life span (CLS) from a screen of ageing-related proteins. Three of the CLS-extending proteins, Ptc4, Zwf1, and Sme1, contributed to an overall higher survival percentage and shorter doubling time of yeast growth compared to the control. The CLS-extending proteins contributed to thermal and oxidative stress responses differently, suggesting different mechanisms of actions. The overexpression of Ptc4 or Zwf1 also promoted rapid cell proliferation during yeast growth, suggesting their involvement in cell division or growth pathways.
In Silico Investigation of a HIV-1 Vpr Inhibitor Binding Site: Potential for Virtual Screening and anti-HIV Drug Design

Choi SB, Choong YS, Saito A, Wahab HA, Najimudin N, Watanabe N, et al.

Mol Inform, 2014 Dec;33(11-12):742-8.
PMID: 27485420 DOI: 10.1002/minf.201400080

Present HIV antiviral therapy only targets structural proteins of HIV, but evidence shows that the targeting of accessory proteins will expand our options in combating HIV. HIV-1 Vpr, a multifunctional accessory protein involved in viral infection, replication and pathogenesis, is a potential target. Previously, we have shown that phenyl coumarin compounds can inhibit the growth arrest activity of Vpr in host cells and predicted that the inhibitors' binding site is a hydrophobic pocket on Vpr. To investigate our prediction of the inhibitors' binding site, we docked the coumarin inhibitors into the predicted hydrophobic binding pocket on a built model of Vpr and observed a linear trend between their calculated binding energies and prior experimentally determined potencies. Subsequently, to analyze the inhibitor-protein binding interactions in detail, we built homology models of Vpr mutants and performed docking studies on these models too. The results revealed that structural changes on the binding pocket that were caused by the mutations affected inhibitor binding. Overall, this study showed that the binding energies of the docked molecules are good indicators of the activity of the inhibitors. Thus, the model can be used in virtual screening to identify other Vpr inhibitors and for designing more potent inhibitors.
Chemical-Induced Inhibition of Blue Light-Mediated Seedling Development Caused by Disruption of Upstream Signal Transduction Involving Cryptochromes in Arabidopsis thaliana

Ong WD, Okubo-Kurihara E, Kurihara Y, Shimada S, Makita Y, Kawashima M, et al.

Plant Cell Physiol, 2017 01 01;58(1):95-105.
PMID: 28011868 DOI: 10.1093/pcp/pcw181

Plants have a remarkable ability to perceive and respond to various wavelengths of light and initiate regulation of different cascades of light signaling and molecular components. While the perception of red light and the mechanisms of its signaling involving phytochromes are largely known, knowledge of the mechanisms of blue light signaling is still limited. Chemical genetics involves the use of diverse small active or synthetic molecules to evaluate biological processes. By combining chemicals and analyzing the effects they have on plant morphology, we identified a chemical, 3-bromo-7-nitroindazole (3B7N), that promotes hypocotyl elongation of wild-type Arabidopsis only under continuous blue light. Further evaluation with loss-of-function mutants confirmed that 3B7N inhibits photomorphogenesis through cryptochrome-mediated light signaling. Microarray analysis demonstrated that the effect of 3B7N treatment on gene expression in cry1cry2 is considerably smaller than that in the wild type, indicating that 3B7N specifically interrupts cryptochrome function in the control of seedling development in a light-dependent manner. We demonstrated that 3B7N directly binds to CRY1 protein using an in vitro binding assay. These results suggest that 3B7N is a novel chemical that directly inhibits plant cryptochrome function by physical binding. The application of 3B7N can be used on other plants to study further the blue light mechanism and the genetic control of cryptochromes in the growth and development of plant species.

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