Displaying all 13 publications

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  1. Lactobacillus Spp.-Enhanced Memory is Strain-Dependent and Associated, in Part, with Amyloidogenic and anti-Oxidant/Oxidative Stress Interplay in Amyloid Beta Precursor Protein Transgenic Mice
    Ahmad Alwi NA, Lim SM, Mani V, Ramasamy K
    J Diet Suppl, 2023;20(5):717-734.
    PMID: 35876040 DOI: 10.1080/19390211.2022.2103608
    This study explored mechanisms underpinning enhanced memory in amyloid precursor protein (APP) transgenic mice (male; 10-12 months; n = 6/group) supplemented with Lactobacillus plantarum LAB12 (LAB12)/Lactobacillus casei Shirota (LcS). Morris Water Maze test was performed before brains were harvested for gene expression and biochemical studies. LAB-supplemented mice exhibited reduced escape latency and distance but significant increased time spent in platform zone. This was associated with downregulated beta-site APP cleaving enzyme-1 (BACE1) mRNA and significant reduced nitric oxide in brains. LAB12 also significantly increased glutathione. The LAB-enhanced memory is strain-dependent and could be mediated, in part, through amyloidogenic pathway and anti-oxidant/oxidative stress interplay.
    Matched MeSH terms: Aspartic Acid Endopeptidases/genetics; Aspartic Acid Endopeptidases/metabolism
  2. Enhancement of β-secretase inhibition and antioxidant activities of tempeh, a fermented soybean cake through enrichment of bioactive aglycones
    Ahmad A, Ramasamy K, Majeed AB, Mani V
    Pharm Biol, 2015 May;53(5):758-66.
    PMID: 25756802 DOI: 10.3109/13880209.2014.942791
    Soybean and its fermented products are the most common source of isoflavones in human food.
    Matched MeSH terms: Aspartic Acid Endopeptidases/antagonists & inhibitors*; Aspartic Acid Endopeptidases/metabolism
  3. Fulltext Amino acid sequence and structural comparison of BACE1 and BACE2 using evolutionary trace method
    Mirsafian H, Mat Ripen A, Merican AF, Bin Mohamad S
    ScientificWorldJournal, 2014;2014:482463.
    PMID: 25254246 DOI: 10.1155/2014/482463
    Beta-amyloid precursor protein cleavage enzyme 1 (BACE1) and beta-amyloid precursor protein cleavage enzyme 2 (BACE2), members of aspartyl protease family, are close homologues and have high similarity in their protein crystal structures. However, their enzymatic properties differ leading to disparate clinical consequences. In order to identify the residues that are responsible for such differences, we used evolutionary trace (ET) method to compare the amino acid conservation patterns of BACE1 and BACE2 in several mammalian species. We found that, in BACE1 and BACE2 structures, most of the ligand binding sites are conserved which indicate their enzymatic property of aspartyl protease family members. The other conserved residues are more or less randomly localized in other parts of the structures. Four group-specific residues were identified at the ligand binding site of BACE1 and BACE2. We postulated that these residues would be essential for selectivity of BACE1 and BACE2 biological functions and could be sites of interest for the design of selective inhibitors targeting either BACE1 or BACE2.
    Matched MeSH terms: Aspartic Acid Endopeptidases/genetics*; Aspartic Acid Endopeptidases/metabolism; Aspartic Acid Endopeptidases/chemistry
  4. Purification and comparison of intracellular proteinase A in Candida spp. isolates from Malaysian and Iranian patients and infected mice
    Amri Saroukolaei S, Pei Pei C, Shokri H, Asadi F
    J Mycol Med, 2012 Jun;22(2):149-59.
    PMID: 23518017 DOI: 10.1016/j.mycmed.2012.01.002
    To compare the specific intracellular proteinase A activity in clinical isolates of Candida species isolated from Iranian and Malaysian patients, the blood and kidneys of mice infected by Candida cells isolated from these human patients.
    Matched MeSH terms: Aspartic Acid Endopeptidases/isolation & purification*; Aspartic Acid Endopeptidases/metabolism
  5. Fulltext Inhibition of hyphae formation and SIR2 expression in Candida albicans treated with fresh Allium sativum (garlic) extract
    Low CF, Chong PP, Yong PV, Lim CS, Ahmad Z, Othman F
    J Appl Microbiol, 2008 Dec;105(6):2169-77.
    PMID: 19120662 DOI: 10.1111/j.1365-2672.2008.03912.x
    The aims of the present study were to determine whether Allium sativum (garlic) extract has any effect on the morphology transformation of Candida albicans, and to investigate whether it could alter the gene expression level of SIR2, a morphogenetic control gene and SAP4, a gene encoding secreted aspartyl proteinase.
    Matched MeSH terms: Aspartic Acid Endopeptidases/genetics; Aspartic Acid Endopeptidases/metabolism
  6. Fulltext γ-Secretase Inhibitors and Modulators Induce Distinct Conformational Changes in the Active Sites of γ-Secretase and Signal Peptide Peptidase
    Gertsik N, Chau DM, Li YM
    ACS Chem. Biol., 2015 Aug 21;10(8):1925-31.
    PMID: 26030233 DOI: 10.1021/acschembio.5b00321
    γ-Secretase inhibitors (GSIs) and modulators (GSMs) are at the frontline of cancer and Alzheimer's disease research, respectively. While both are therapeutically promising, not much is known about their interactions with proteins other than γ-secretase. Signal peptide peptidase (SPP), like γ-secretase, is a multispan transmembrane aspartyl protease that catalyzes regulated intramembrane proteolysis. We used active site-directed photophore walking probes to study the effects of different GSIs and GSMs on the active sites of γ-secretase and SPP and found that nontransition state GSIs inhibit labeling of γ-secretase by activity-based probes but enhance labeling of SPP. The opposite is true of GSMs, which have little effect on the labeling of γ-secretase but diminish labeling of SPP. These results demonstrate that GSIs and GSMs are altering the structure of not only γ-secretase but also SPP, leading to potential changes in enzyme activity and specificity that may impact the clinical outcomes of these molecules.
    Matched MeSH terms: Aspartic Acid Endopeptidases/chemistry*
  7. Protective effects of total alkaloidal extract from Murraya koenigii leaves on experimentally induced dementia
    Mani V, Ramasamy K, Ahmad A, Parle M, Shah SA, Majeed AB
    Food Chem Toxicol, 2012 Mar;50(3-4):1036-44.
    PMID: 22142688 DOI: 10.1016/j.fct.2011.11.037
    Dementia is a syndrome of gradual onset and continuous decline of higher cognitive functioning. It is a common disorder in older persons and has become more prevalent today. The fresh leaves of Murraya koenigii are often added to various dishes in Asian countries due to the delicious taste and flavor that they impart. These leaves have also been proven to have health benefits. In the present study, the effect of total alkaloidal extract from M. koenigii leaves (MKA) on cognitive functions and brain cholinesterase activity in mice were determined. In vitro β-secretase 1 (BACE1) inhibitory activity was also evaluated. The total alkaloidal extract was administered orally in three doses (10, 20 and 30 mg/kg) for 15 days to different groups of young and aged mice. Elevated plus maze and passive avoidance apparatus served as the exteroceptive behavioral models for testing memory. Diazepam-, scopolamine-, and ageing-induced amnesia served as the interoceptive behavioral models. MKA (20 and 30 mg/kg, p.o.) showed significant improvement in memory scores of young and aged mice. Furthermore, the same doses of MKA reversed the amnesia induced by scopolamine (0.4 mg/kg, i.p.) and diazepam (1 mg/kg, i.p.). Interestingly, the brain cholinesterase activity was also reduced significantly by total alkaloidal extract of M. koenigii leaves. The IC50 value of MKA against BACE1 was 1.7 μg/mL. In conclusion, this study indicates MKA to be a useful remedy in the management of Alzheimer's disease and dementia.
    Matched MeSH terms: Aspartic Acid Endopeptidases/antagonists & inhibitors
  8. Fulltext Pulsatile stretch as a novel modulator of amyloid precursor protein processing and associated inflammatory markers in human cerebral endothelial cells
    Gangoda SVS, Avadhanam B, Jufri NF, Sohn EH, Butlin M, Gupta V, et al.
    Sci Rep, 2018 01 26;8(1):1689.
    PMID: 29374229 DOI: 10.1038/s41598-018-20117-6
    Amyloid β (Aβ) deposition is a hallmark of Alzheimer's disease (AD). Vascular modifications, including altered brain endothelial cell function and structural viability of the blood-brain barrier due to vascular pulsatility, are implicated in AD pathology. Pulsatility of phenomena in the cerebral vasculature are often not considered in in vitro models of the blood-brain barrier. We demonstrate, for the first time, that pulsatile stretch of brain vascular endothelial cells modulates amyloid precursor protein (APP) expression and the APP processing enzyme, β-secretase 1, eventuating increased-Aβ generation and secretion. Concurrent modulation of intercellular adhesion molecule 1 and endothelial nitric oxide synthase (eNOS) signaling (expression and phosphorylation of eNOS) in response to pulsatile stretch indicates parallel activation of endothelial inflammatory pathways. These findings mechanistically support vascular pulsatility contributing towards cerebral Aβ levels.
    Matched MeSH terms: Aspartic Acid Endopeptidases/analysis
  9. Fulltext Extraction, purification and characterisation of a milk-clotting protease from ‘kesinai’ (Streblus asper Lour.) leaves
    Pagthinathan, M., Ghazali, H.M., Yazid, A.M., Foo, H.L.
    International Food Research Journal, 2019;26(3):913-922.
    MyJurnal
    Extracts from ‘kesinai’ (Streblus asper) leaves were investigated as a potential source of enzymes that can serve as an alternative to calf rennet in cheese making. Different types of extraction buffers were investigated namely sodium acetate buffer (pH 4.2-5.0), phosphate buffer (pH 6.0-7.0) and Tris-HCl buffer (pH 7.0-9.0). Finally, the milk-clotting enzyme was extracted using 100 mM Tris-HCl buffer (pH 7.4) with and without 5.0 mg/mL polyvinylpyrrolidone, 0.015 mL/mL Triton X-100 and 2 mM sodium metabisulphite. Purification was carried out using acetone precipitation, and ion-exchange and size-exclusion chromatographic techniques. Results showed that 100 mM Tris-HCl buffer (pH 7.4) was the most efficient extraction buffer among the buffers used in the extraction study. After the final purification step of size-exclusion chromatography, the enzyme was purified 3.3-fold with 42.3% of recovery. The enzyme showed an optimum temperature and pH at 60°C and pH 7.4, respectively. The enzyme was stable up to 70°C for one hour and the partially purified enzyme retained 83% and 96% of its original activity at pH 6.0 and 8.0, respectively. The molecular weight of the partially enzyme was estimated to be 75.8 kDa on SDS-PAGE. The milk-clotting activity of ‘kesinai’ enzyme was found to be lower than that of commercial Mucor rennet.
    Matched MeSH terms: Aspartic Acid Endopeptidases
  10. Fulltext Multitargeted Molecular Docking and Dynamic Simulation Studies of Bioactive Compounds from Rosmarinus officinalis against Alzheimer's Disease
    Mirza FJ, Zahid S, Amber S, Sumera, Jabeen H, Asim N, et al.
    Molecules, 2022 Oct 25;27(21).
    PMID: 36364071 DOI: 10.3390/molecules27217241
    Alzheimer's disease (AD) has been associated with the hallmark features of cholinergic dysfunction, amyloid beta (Aβ) aggregation and impaired synaptic transmission, which makes the associated proteins, such as β-site amyloid precursor protein cleaving enzyme 1 (BACE I), acetylcholine esterase (AChE) and synapsin I, II and III, major targets for therapeutic intervention. The present study investigated the therapeutic potential of three major phytochemicals of Rosmarinus officinalis, ursolic acid (UA), rosmarinic acid (RA) and carnosic acid (CA), based on their binding affinity with AD-associated proteins. Detailed docking studies were conducted using AutoDock vina followed by molecular dynamic (MD) simulations using Amber 20. The docking analysis of the selected molecules showed the binding energies of their interaction with the target proteins, while MD simulations comprising root mean square deviation (RMSD), root mean square fluctuation (RMSF) and molecular mechanics/generalized born surface area (MM/GBSA) binding free energy calculations were carried out to check the stability of bound complexes. The drug likeness and the pharmacokinetic properties of the selected molecules were also checked through the Lipinski filter and ADMETSAR analysis. All these bioactive compounds demonstrated strong binding affinity with AChE, BACE1 and synapsin I, II and III. The results showed UA and RA to be potential inhibitors of AChE and BACE1, exhibiting binding energies comparable to those of donepezil, used as a positive control. The drug likeness and pharmacokinetic properties of these compounds also demonstrated drug-like characteristics, indicating the need for further in vitro and in vivo investigations to ascertain their therapeutic potential for AD.
    Matched MeSH terms: Aspartic Acid Endopeptidases
  11. Fulltext Germinated Brown Rice Alters Aβ(1-42) Aggregation and Modulates Alzheimer's Disease-Related Genes in Differentiated Human SH-SY5Y Cells
    Azmi NH, Ismail M, Ismail N, Imam MU, Alitheen NB, Abdullah MA
    Evid Based Complement Alternat Med, 2015;2015:153684.
    PMID: 26858770 DOI: 10.1155/2015/153684
    The pathogenesis of Alzheimer's disease involves complex etiological factors, of which the deposition of beta-amyloid (Aβ) protein and oxidative stress have been strongly implicated. We explored the effects of H2O2, which is a precursor for highly reactive hydroxyl radicals, on neurotoxicity and genes related to AD on neuronal cells. Candidate bioactive compounds responsible for the effects were quantified using HPLC-DAD. Additionally, the effects of germinated brown rice (GBR) on the morphology of Aβ(1-42) were assessed by Transmission Electron Microscopy and its regulatory effects on gene expressions were explored. The results showed that GBR extract had several phenolic compounds and γ-oryzanol and altered the structure of Aβ(1-42) suggesting an antiamyloidogenic effect. GBR was also able to attenuate the oxidative effects of H2O2 as implied by reduced LDH release and intracellular ROS generation. Furthermore, gene expression analyses showed that the neuroprotective effects of GBR were partly mediated through transcriptional regulation of multiple genes including Presenilins, APP, BACE1, BACE2, ADAM10, Neprilysin, and LRP1. Our findings showed that GBR exhibited neuroprotective properties via transcriptional regulation of APP metabolism with potential impact on Aβ aggregation. These findings can have important implications for the management of neurodegenerative diseases like AD and are worth exploring further.
    Matched MeSH terms: Aspartic Acid Endopeptidases
  12. Thymoquinone-rich fraction nanoemulsion (TQRFNE) decreases Aβ40 and Aβ42 levels by modulating APP processing, up-regulating IDE and LRP1, and down-regulating BACE1 and RAGE in response to high fat/cholesterol diet-induced rats
    Ismail N, Ismail M, Azmi NH, Bakar MFA, Yida Z, Abdullah MA, et al.
    Biomed Pharmacother, 2017 Nov;95:780-788.
    PMID: 28892789 DOI: 10.1016/j.biopha.2017.08.074
    Though the causes of Alzheimer's disease (AD) are yet to be understood, much evidence has suggested that excessive amyloid-β (Aβ) accumulation due to abnormal amyloid-β precursor protein (APP) processing and Aβ metabolism are crucial processes towards AD pathogenesis. Hence, approaches aiming at APP processing and Aβ metabolism are currently being actively pursued for the management of AD. Studies suggest that high cholesterol and a high fat diet have harmful effects on cognitive function and may instigate the commencement of AD pathogenesis. Despite the neuropharmacological attributes of black cumin seed (Nigella sativa) extracts and its main active compound, thymoquinone (TQ), limited records are available in relation to AD research. Nanoemulsion (NE) is exploited as drug delivery systems due to their capacity of solubilising non-polar active compounds and is widely examined for brain targeting. Herewith, the effects of thymoquinone-rich fraction nanoemulsion (TQRFNE), thymoquinone nanoemulsion (TQNE) and their counterparts' conventional emulsion in response to high fat/cholesterol diet (HFCD)-induced rats were investigated. Particularly, the Aβ generation; APP processing, β-secretase 1 (BACE1), γ-secretases of presenilin 1 (PSEN1) and presenilin 2 (PSEN2), Aβ degradation; insulin degrading enzyme (IDE), Aβ transportation; low density lipoprotein receptor-related protein 1 (LRP1) and receptor for advanced glycation end products (RAGE) were measured in brain tissues. TQRFNE reduced the brain Aβ fragment length 1-40 and 1-42 (Aβ40 and Aβ42) levels, which would attenuate the AD pathogenesis. This reduction could be due to the modulation of β- and γ-secretase enzyme activity, and the Aβ degradation and transportation in/out of the brain. The findings show the mechanistic actions of TQRFNE in response to high fat and high cholesterol diet associated to Aβ generation, degradation and transportation in the rat's brain tissue.
    Matched MeSH terms: Aspartic Acid Endopeptidases/metabolism*
  13. Fulltext BACE1 inhibitory activity of fungal endophytic extracts from Malaysian medicinal plants
    Harun A, James RM, Lim SM, Abdul Majeed AB, Cole AL, Ramasamy K
    BMC Complement Altern Med, 2011 Sep 24;11:79.
    PMID: 21943123 DOI: 10.1186/1472-6882-11-79
    BACKGROUND: BACE1 was found to be the major β-secretase in neurons and its appearance and activity were found to be elevated in the brains of AD patients. Fungal endophytic extracts for BACE1 inhibitory activity and cytotoxicity against PC-12 (a rat pheochromocytoma with neuronal properties) and WRL68 (a non-tumorigenic human hepatic) were investigated.

    METHODS: Endophytes were isolated from plants collected from Kuala Pilah, Negeri Sembilan and the National Park, Pahang and the extracts were tested for BACE1 inhibition. For investigation of biological activity, the pure endophytic cultures were cultivated for 14 days on PDA plates at 28°C and underwent semipolar extraction with ethyl acetate.

    RESULTS: Of 212 endophytic extracts (1000 μg/ml), 29 exhibited more than 90% inhibition of BACE1 in the preliminary screening. Four extracts from isolates HAB16R13, HAB16R14, HAB16R18 and HAB8R24 identified as Cytospora rhizophorae were the most active with IC(50(BACE1)) values of less than 3.0 μg/ml. The most active extract HAB16R13 was shown to non-competitively inhibit BACE1 with K(i) value of 10.0 μg/ml. HAB16R13 was considered non-potent against PC-12 and WRL68 (IC(50(CT))) of 60.0 and 40.0 μg/ml, respectively).

    CONCLUSIONS: This first report on endophytic fungal extract with good BACE1 inhibitory activity demonstrates that more extensive study is required to uncover the potential of endophytes.

    Matched MeSH terms: Aspartic Acid Endopeptidases/antagonists & inhibitors*
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