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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 Uncovering the Microbiota of Bagworm Metisa plana (Lepidoptera: Psychidae) in Oil Palm Plantations in Malaysia

Ting A, Abidin CMRZ, Hamid NH, Azzam G, Salim H

Trop Life Sci Res, 2023 Mar;34(1):185-218.
PMID: 37065800 DOI: 10.21315/tlsr2023.34.1.11

Bagworm Metisa plana is one of the major pests in Malaysia's oil palm plantation, with infestation resulting in huge economical loss. Currently, the microbial profile of the bagworm has yet to be study. Understanding the biology of the pest such as the bacterial community is crucial as bacteria associated with insects often provide benefits to the insect, giving the insect host a better chance of survival. Here, 16S amplicon sequencing was used to identify the bacteria community of M. plana. Additionally, two comparisons were made, the bacterial communities between two larval stages (early instar stage and late instar stage) from outbreak area; the bacterial communities of late instar stage larvae from non-outbreak between outbreak areas. From this study, it was found that the bacterial community of M. plana consisted of Proteobacteria, Actinobacteria, Bacterioidetes, Firmicutes and other minor phyla, with Proteobacteria being the most dominant phylum. Furthermore, bacterial genera of M. plana consisted of Pantoea, Curtobacterium, Pseudomonas, Massilia and other minor genera, with Pantoea being the most dominant. It was also found that the alpha and beta diversity in both comparisons were not significantly different. We present our data as a first insight towards the bacterial community of M. plana, paving a way towards understanding the biology of the bagworm M. plana.
The molecular mechanisms of probiotic strains in improving ageing bone and muscle of d-galactose-induced ageing rats

Hor YY, Ooi CH, Lew LC, Jaafar MH, Lau AS, Lee BK, et al.

J Appl Microbiol, 2021 Apr;130(4):1307-1322.
PMID: 32638482 DOI: 10.1111/jam.14776

AIM: The aim of this study was to evaluate the molecular mechanisms of Lactobacillus strains in improving ageing of the musculoskeletal system.
METHODS AND RESULTS: The anti-ageing mechanism of three probiotics strains Lactobacillus fermentum DR9, Lactobacillus paracasei OFS 0291 and L. helveticus OFS 1515 were evaluated on gastrocnemius muscle and tibia of d-galactose-induced ageing rats. Upon senescence induction, aged rats demonstrated reduced antioxidative genes CAT and SOD expression in both bone and muscle compared to the young rats (P
Fulltext Systematic identification and characterization of Aedes aegypti long noncoding RNAs (lncRNAs)

Azlan A, Obeidat SM, Yunus MA, Azzam G

Sci Rep, 2019 08 21;9(1):12147.
PMID: 31434910 DOI: 10.1038/s41598-019-47506-9

Long noncoding RNAs (lncRNAs) play diverse roles in biological processes. Aedes aegypti (Ae. aegypti), a blood-sucking mosquito, is the principal vector responsible for replication and transmission of arboviruses including dengue, Zika, and Chikungunya virus. Systematic identification and developmental characterisation of Ae. aegypti lncRNAs are still limited. We performed genome-wide identification of lncRNAs, followed by developmental profiling of lncRNA in Ae. aegypti. We identified a total of 4,689 novel lncRNA transcripts, of which 2,064, 2,076, and 549 were intergenic, intronic, and antisense respectively. Ae. aegypti lncRNAs share many characteristics with other species including low expression, low GC content, short in length, and low conservation. Besides, the expression of Ae. aegypti lncRNAs tend to be correlated with neighbouring and antisense protein-coding genes. A subset of lncRNAs shows evidence of maternal inheritance; hence, suggesting potential role of lncRNAs in early-stage embryos. Additionally, lncRNAs show higher tendency to be expressed in developmental and temporal specific manner. The results from this study provide foundation for future investigation on the function of Ae. aegypti lncRNAs.
Fulltext SARS-CoV-2 genomic surveillance in Malaysia: displacement of B.1.617.2 with AY lineages as the dominant Delta variants and the introduction of Omicron during the fourth epidemic wave

Azami NAM, Perera D, Thayan R, AbuBakar S, Sam IC, Salleh MZ, et al.

Int J Infect Dis, 2022 Dec;125:216-226.
PMID: 36336246 DOI: 10.1016/j.ijid.2022.10.044

OBJECTIVES: This study reported SARS-CoV-2 whole genome sequencing results from June 2021 to January 2022 from seven genome sequencing centers in Malaysia as part of the national surveillance program.
METHODS: COVID-19 samples that tested positive by reverse transcription polymerase chain reaction and with cycle threshold values <30 were obtained throughout Malaysia. Sequencing of SARS-CoV-2 complete genomes was performed using Illumina, Oxford Nanopore, or Ion Torrent platforms. A total of 6163 SARS-CoV-2 complete genome sequences were generated over the surveillance period. All sequences were submitted to the Global Initiative on Sharing All Influenza Data database.
RESULTS: From June 2021 to January 2022, Malaysia experienced the fourth wave of COVID-19 dominated by the Delta variant of concern, including the original B.1.617.2 lineage and descendant AY lineages. The B.1.617.2 lineage was identified as the early dominant circulating strain throughout the country but over time, was displaced by AY.59 and AY.79 lineages in Peninsular (west) Malaysia, and the AY.23 lineage in east Malaysia. In December 2021, pilgrims returning from Saudi Arabia facilitated the introduction and spread of the BA.1 lineage (Omicron variant of concern) in the country.
CONCLUSION: The changing trends of circulating SARS-CoV-2 lineages were identified, with differences observed between west and east Malaysia. This initiative highlighted the importance of leveraging research expertise in the country to facilitate pandemic response and preparedness.
MicroRNA regulation of CTP synthase and cytoophidium in Drosophila melanogaster

Dzaki N, Woo WK, Thangadurai S, Azzam G

Exp Cell Res, 2019 12 15;385(2):111688.
PMID: 31678212 DOI: 10.1016/j.yexcr.2019.111688

CTPsyn is a crucial metabolic enzyme which synthesizes CTP nucleotides. It has the extraordinary ability to compartmentalize into filaments termed cytoophidia. Though the structure is evolutionarily conserved across kingdoms, the mechanisms behind their formation remain unknown. MicroRNAs (miRNAs) are short single-stranded RNA capable of directing mRNA silencing and degradation. D. melanogaster has a high total gene count to miRNA gene number ratio, alluding to the possibility that CTPsyn too may come under their regulation. A thorough miRNA overexpression involving 123 miRNAs was conducted, followed by CTPsyn-specific staining upon cytoophidia-rich egg chambers. This revealed a small group of candidates which confer either a lengthening or truncating effect on cytoophidia, suggesting they may play a role in regulating CTPsyn. MiR-975 and miR-1014 are both cytoophidia-elongating, whereas miR-190 and miR-932 are cytoophidia-shortening. Though target prediction shows that miR-975 and miR-932 do indeed have binding sites on CTPsyn mRNA, in vitro assays instead revealed a low probability of this being true, instead indicating that the effects asserted by overexpressed miRNAs indirectly reach CTPsyn and its cytoophidia through the actions of middling elements. In silico target prediction and qPCR quantification indicated that, at least for miR-932 and miR-1014, these undetermined elements may be players in fat metabolism. This is the first study to thoroughly investigate miRNAs in connection to CTPsyn expression and activity in any species. The findings presented could serve as a basis for further queries into not only the fundamental aspects of the enzyme's regulation, but may uncover new facets of closely related pathways as well.
Lactobacillus sp. improved microbiota and metabolite profiles of aging rats

Hor YY, Lew LC, Jaafar MH, Lau AS, Ong JS, Kato T, et al.

Pharmacol Res, 2019 08;146:104312.
PMID: 31207344 DOI: 10.1016/j.phrs.2019.104312

Aging is closely associated with altered gut function and composition, in which elderly were reported with reduced gut microbiota diversity and increased incidence of age-related diseases. Probiotics have been shown to exert beneficial health-promoting effects through modulation of intestinal microflora biodiversity, thus the effects of probiotics administration on D-galactose (D-gal) senescence-induced rat were evaluated based on the changes in gut microbiota and metabolomic profiles. Upon senescence induction, the ratio of Firmicutes/ Bacteroidetes was significantly lowered, while treatment with Lactobacillus helveticus OFS 1515 and L. fermentum DR9 increased the ratio at the phylum level (P
Lactobacillus probiotics improved the gut microbiota profile of a Drosophila melanogaster Alzheimer's disease model and alleviated neurodegeneration in the eye

Tan FHP, Liu G, Lau SA, Jaafar MH, Park YH, Azzam G, et al.

Benef Microbes, 2020 Feb 19;11(1):79-89.
PMID: 32066253 DOI: 10.3920/BM2019.0086

Alzheimer's disease (AD) is a progressive disease and one of the most common forms of neurodegenerative disorders. Emerging evidence is supporting the use of various strategies that modulate gut microbiota to exert neurological and psychological changes. This includes the utilisation of probiotics as a natural and dietary intervention for brain health. Here, we showed the potential AD-reversal effects of Lactobacillus probiotics through feeding to our Drosophila melanogaster AD model. The administration of Lactobacillus strains was able to rescue the rough eye phenotype (REP) seen in AD-induced Drosophila, with a more prominent effect observed upon the administration of Lactobacillus plantarum DR7 (DR7). Furthermore, we analysed the gut microbiota of the AD-induced Drosophila and found elevated levels of Wolbachia. The administration of DR7 restored the gut microbiota diversity of AD-induced Drosophila with a significant reduction in Wolbachia's relative abundance, accompanied by an increase of Stenotrophomonas and Acetobacter. Through functional predictive analyses, Wolbachia was predicted to be positively correlated with neurodegenerative disorders, such as Parkinson's, Huntington's and Alzheimer's diseases, while Stenotrophomonas was negatively correlated with these neurodegenerative disorders. Altogether, our data exhibited DR7's ability to ameliorate the AD effects in our AD-induced Drosophila. Thus, we propose that Wolbachia be used as a potential biomarker for AD.
Lactobacillus plantarum DR7 improved brain health in aging rats via the serotonin, inflammatory and apoptosis pathways

Zaydi AI, Lew LC, Hor YY, Jaafar MH, Chuah LO, Yap KP, et al.

Benef Microbes, 2020 Dec 02;11(8):753-766.
PMID: 33245015 DOI: 10.3920/BM2019.0200

Aging processes affect the brain in many ways, ranging from cellular to functional levels which lead to cognitive decline and increased oxidative stress. The aim of this study was to investigate the potentials of Lactobacillus plantarum DR7 on brain health including cognitive and memory functions during aging and the impacts of high fat diet during a 12-week period. Male Sprague-Dawley rats were separated into six groups: (1) young animals on normal diet (ND, (2) young animals on a high fat diet (HFD), (3) aged animals on ND, (4) aged animals on HFD, (5) aged animals on HFD and L. plantarum DR7 (109 cfu/day) and (6) aged animals receiving HFD and lovastatin. To induce ageing, all rats in group 3 to 6 were injected sub-cutaneously at 600 mg/kg/day of D-galactose daily. The administration of DR7 has reduced anxiety accompanied by enhanced memory during behavioural assessments in aged-HFD rats (P<0.05). Hippocampal concentration of all three pro-inflammatory cytokines were increased during aging but reduced upon administration of both statin and DR7. Expressions of hippocampal neurotransmitters and apoptosis genes showed reduced expressions of indoleamine dioxygenase and P53 accompanied by increased expression of TPH1 in aged- HFD rats administered with DR7, indicating potential effects of DR7 along the pathways of serotonin and oxidative senescence. This study provided an insight into potentials of L. plantarum DR7 as a prospective dietary strategy to improve cognitive functions during aging. This study provided an insight into potentials of L. plantarum DR7 as a prospective dietary strategy to improve cognitive functions during aging.
Fulltext Lactobacillus Strains Alleviated Hyperlipidemia and Liver Steatosis in Aging Rats via Activation of AMPK

Lew LC, Hor YY, Jaafar MH, Lau AS, Lee BK, Chuah LO, et al.

Int J Mol Sci, 2020 Aug 16;21(16).
PMID: 32824277 DOI: 10.3390/ijms21165872

In this study, we hypothesized that different strains of Lactobacillus can alleviate hyperlipidemia and liver steatosis via activation of 5' adenosine monophosphate-activated protein kinase (AMPK), an enzyme that is involved in cellular energy homeostasis, in aged rats. Male rats were fed with a high-fat diet (HFD) and injected with D-galactose daily over 12 weeks to induce aging. Treatments included (n = 6) (i) normal diet (ND), (ii) HFD, (iii) HFD-statin (lovastatin 2 mg/kg/day), (iv) HFD-Lactobacillus fermentum DR9 (10 log CFU/day), (v) HFD-Lactobacillus plantarum DR7 (10 log CFU/day), and (vi) HFD-Lactobacillus reuteri 8513d (10 log CFU/day). Rats administered with statin, DR9, and 8513d reduced serum total cholesterol levels after eight weeks (p < 0.05), while the administration of DR7 reduced serum triglycerides level after 12 weeks (p < 0.05) as compared to the HFD control. A more prominent effect was observed from the administration of DR7, where positive effects were observed, ranging from hepatic gene expressions to liver histology as compared to the control (p < 0.05); downregulation of hepatic lipid synthesis and β-oxidation gene stearoyl-CoA desaturase 1 (SCD1), upregulation of hepatic sterol excretion genes of ATP-binding cassette subfamily G member 5 and 8 (ABCG5 and ABCG8), lesser degree of liver steatosis, and upregulation of hepatic energy metabolisms genes AMPKα1 and AMPKα2. Taken altogether, this study illustrated that the administration of selected Lactobacillus strains led to improved lipid profiles via activation of energy and lipid metabolisms, suggesting the potentials of Lactobacillus as a promising natural intervention for alleviation of cardiovascular and liver diseases.
Lactobacilli modulated AMPK activity and prevented telomere shortening in ageing rats

Lew LC, Hor YY, Jaafar MH, Lau ASY, Ong JS, Chuah LO, et al.

Benef Microbes, 2019 Dec 09;10(8):883-892.
PMID: 31965837 DOI: 10.3920/BM2019.0058

This study aimed to evaluate the anti-ageing effects of different strains of lactobacilli putative probiotics on an ageing rat model as induced by D-galactose and a high fat diet. Male Sprague-Dawley rats were fed with high fat diet (54% kcal fat) and injected with D-galactose daily for 12 weeks to induce ageing. The effects of putative probiotic strains on age-related impairment such as telomere length, plasma lipid peroxidation, hepatic 5'adenosine monophosphate-activated protein kinase (AMPK) expression, as well as endurance performance were evaluated. Administration of statin, Lactobacillus plantarum DR7 (LP-DR7), Lactobacillus fermentum DR9 (LF-DR9), and Lactobacillus reuteri 8513d (LR-8513d) significantly reduced the shortening of telomere and increased the expression of AMPK subunit-α1 (P<0.05). Plasma lipid peroxidation was lower (P<0.05) in groups administered with statin and LF-DR9 as compared to the control. AMPK subunit-α2 was elevated in rats administered with LP-DR7 as compared to the control (P<0.05). Using an in vivo ageing rat model, the current study has illustrated the potentials of lactobacilli putative probiotics in alleviation of age-related impairment in a strain-dependent manner.
Lactic acid bacteria feeding reversed the malformed eye structures and ameliorated gut microbiota profiles of Drosophila melanogaster Alzheimer's disease model

Liu G, Tan FH, Lau SA, Jaafar MH, Chung FY, Azzam G, et al.

J Appl Microbiol, 2020 Jul 08.
PMID: 32640111 DOI: 10.1111/jam.14773

AIMS: To utilize transgenic GMR-Aβ42 Drosophila melanogaster as a model to evaluate potential Alzheimer's disease (AD)-reversal effects via the administration of lactic acid bacteria (LAB) strains, and associations of LAB with changes in gut microbiota profiles.
METHODS AND RESULTS: Wild-type flies (Oregon-R) were crossed with glass multimer reporter-GAL4 (GMR-GAL4) to produce GMR-OreR (Control), while UAS-Aβ42 (#33769) were crossed with GMR-GAL4 to produce transgenic Drosophila line that expressed Aβ42 (GMR-Aβ42). Feed containing seven different LAB strains (Lactobacillus paracasei 0291, Lactobacillus helveticus 1515, Lactobacillus reuteri 30242, L. reuteri 8513d, Lactobacillus fermentum 8312, Lactobacillus casei Y, Lactobacillus sakei Probio65) were given to GMR-Aβ42 respectively, while feed without LAB strains were given to control and transgenic GMR-Aβ42.nf Drosophila lines. The morphology of the eyes was viewed with scanning electron microscopy (SEM). The changes in gut microbiota profiles associated with LAB were analysed using 16s high throughput sequencing. Malformation of eye structures in transgenic GMR-Aβ42 Drosophila were reversed upon the administration of LAB strains, with more prevalent effects from L. sakei Probio65 and L. paracasei 0291. The GMR-Aβ42.nf group showed dominance of Wolbachia in the gut, a genus that was almost absent in the normal control group (P
Identification and characterization of long noncoding RNAs and their association with acquisition of blood meal in Culex quinquefasciatus

Azlan A, Halim MA, Mohamad F, Azzam G

Insect Sci, 2021 Aug;28(4):917-928.
PMID: 32621332 DOI: 10.1111/1744-7917.12847

The Southern house mosquito, Culex quinquefasciatus (Cx. quinquefasciatus) is an important vector that transmit multiple diseases including West Nile encephalitis, Japanese encephalitis, St. Louis encephalitis and lymphatic filariasis. Long noncoding RNAs (lncRNAs) involve in many biological processes such as development, infection, and virus-host interaction. However, there is no systematic identification and characterization of lncRNAs in Cx. quinquefasciatus. Here, we report the first lncRNA identification in Cx. quinquefasciatus. By using 31 public RNA-seq datasets, a total of 4763 novel lncRNA transcripts were identified, of which 3591, 569, and 603 were intergenic, intronic, and antisense respectively. Examination of genomic features revealed that Cx. quinquefasciatus shared similar characteristics with other species such as short in length, low GC content, low sequence conservation, and low coding potential. Furthermore, compared to protein-coding genes, Cx. quinquefasciatus lncRNAs had lower expression values, and tended to be expressed in temporally specific fashion. In addition, weighted correlation network and functional annotation analyses showed that lncRNAs may have roles in blood meal acquisition of adult female Cx. quinquefasciatus mosquitoes. This study presents the first systematic identification and analysis of Cx. quinquefasciatus lncRNAs and their association with blood feeding. Results generated from this study will facilitate future investigation on the function of Cx. quinquefasciatus lncRNAs.
Fulltext Genome-wide identification of Aedes albopictus long noncoding RNAs and their association with dengue and Zika virus infection

Azlan A, Obeidat SM, Theva Das K, Yunus MA, Azzam G

PLoS Negl Trop Dis, 2021 01;15(1):e0008351.
PMID: 33481791 DOI: 10.1371/journal.pntd.0008351

The Asian tiger mosquito, Aedes albopictus (Ae. albopictus), is an important vector that transmits arboviruses such as dengue (DENV), Zika (ZIKV) and Chikungunya virus (CHIKV). Long noncoding RNAs (lncRNAs) are known to regulate various biological processes. Knowledge on Ae. albopictus lncRNAs and their functional role in virus-host interactions are still limited. Here, we identified and characterized the lncRNAs in the genome of an arbovirus vector, Ae. albopictus, and evaluated their potential involvement in DENV and ZIKV infection. We used 148 public datasets, and identified a total of 10, 867 novel lncRNA transcripts, of which 5,809, 4,139, and 919 were intergenic, intronic and antisense respectively. The Ae. albopictus lncRNAs shared many characteristics with other species such as short length, low GC content, and low sequence conservation. RNA-sequencing of Ae. albopictus cells infected with DENV and ZIKV showed that the expression of lncRNAs was altered upon virus infection. Target prediction analysis revealed that Ae. albopictus lncRNAs may regulate the expression of genes involved in immunity and other metabolic and cellular processes. To verify the role of lncRNAs in virus infection, we generated mutations in lncRNA loci using CRISPR-Cas9, and discovered that two lncRNA loci mutations, namely XLOC_029733 (novel lncRNA transcript id: lncRNA_27639.2) and LOC115270134 (known lncRNA transcript id: XR_003899061.1) resulted in enhancement of DENV and ZIKV replication. The results presented here provide an important foundation for future studies of lncRNAs and their relationship with virus infection in Ae. albopictus.
Genome-wide identification and characterization of long intergenic noncoding RNAs in the regenerative flatworm Macrostomum lignano

Azlan A, Halim MA, Azzam G

Genomics, 2020 03;112(2):1273-1281.
PMID: 31381967 DOI: 10.1016/j.ygeno.2019.07.016

The free-living flatworm Macrostoma lignano (M. lignano) is an emerging model organism for aging and regeneration research. Long intergenic non-coding RNAs (lincRNAs) have important roles in many biological processes such as aging, stem cell maintenance and differentiation. However, to date, there is no systematic identification of lincRNAs in M. lignano. By using public RNA-seq data, we identified a total of 2547 lincRNA transcripts in M. lignano genome. We discovered that M. lignano lincRNAs shared many characteristics with other species such as shorter in length, lower GC content, and lower in expression compared to protein-coding genes. Unlike protein-coding genes, M. lignano lincRNAs showed higher tendency to be expressed in temporal and region-specific fashion. Additionally, co-expression network analysis and functional enrichment suggest that M. lignano lincRNAs have potential roles in regeneration. This study will provide important resources and pave the way for investigations on non-coding genes involved in aging and regeneration.
Fulltext Evaluation of reference genes at different developmental stages for quantitative real-time PCR in Aedes aegypti

Dzaki N, Ramli KN, Azlan A, Ishak IH, Azzam G

Sci Rep, 2017 03 16;7:43618.
PMID: 28300076 DOI: 10.1038/srep43618

The mosquito Aedes aegypti (Ae. aegypti) is the most notorious vector of illness-causing viruses such as Dengue, Chikugunya, and Zika. Although numerous genetic expression studies utilizing quantitative real-time PCR (qPCR) have been conducted with regards to Ae. aegypti, a panel of genes to be used suitably as references for the purpose of expression-level normalization within this epidemiologically important insect is presently lacking. Here, the usability of seven widely-utilized reference genes i.e. actin (ACT), eukaryotic elongation factor 1 alpha (eEF1α), alpha tubulin (α-tubulin), ribosomal proteins L8, L32 and S17 (RPL8, RPL32 and RPS17), and glyceraldeyde 3-phosphate dehydrogenase (GAPDH) were investigated. Expression patterns of the reference genes were observed in sixteen pre-determined developmental stages and in cell culture. Gene stability was inferred from qPCR data through three freely available algorithms i.e. BestKeeper, geNorm, and NormFinder. The consensus rankings generated from stability values provided by these programs suggest a combination of at least two genes for normalization. ACT and RPS17 are the most dependably expressed reference genes and therefore, we propose an ACT/RPS17 combination for normalization in all Ae. aegypti derived samples. GAPDH performed least desirably, and is thus not a recommended reference gene. This study emphasizes the importance of validating reference genes in Ae. aegypti for qPCR based research.
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.
Fulltext Effects of salvianolic acid A on β-amyloid mediated toxicity in Caenorhabditis elegans model of Alzheimer's disease

Yuen CW,, Halim MA,, Najimudin N,, Azzam G,

Journal of Biomedical and Clinical Sciences, 2020;5(1):1-7.
MyJurnal

Alzheimer’s disease (AD) is a brain disease attributed to the accumulation of extracellular senile plaques comprising β-amyloid peptide (Aβ). In this study, a transgenic Caenorhabditis elegans (C. elegans) containing the human beta amyloid Aβ42 gene which exhibited paralysis when expressed, was used to study the anti-paralysis effect of salvianolic acid A. Various concentrations ranging from 1 μg/ml to 100 μg/ml of salvianolic acid A were tested which exhibited the highest effect on the worm at the concentration of 100 μg/ml. For anti-aggregation effect, 14 μg/ml of salvianolic acid A (within 4 mg/ml of Danshen) showed a significant level of inhibition of the formation of Aβ fibrils. An amount of 100 μg/ml of salvianolic acid A had the potential in reducing the reactive oxygen species (ROS) but did not totally obliterate the ROS production in the worms. Salvianolic acid A was found to delay the paralysis of the transgenic C. elegans, decrease Aβ42 aggregation and decrease Aβ-induced oxidative stress.
Fulltext Ectopic miR-975 induces CTP synthase directed cell proliferation and differentiation in Drosophila melanogaster

Woo WK, Dzaki N, Thangadurai S, Azzam G

Sci Rep, 2019 Apr 15;9(1):6096.
PMID: 30988367 DOI: 10.1038/s41598-019-42369-6

CTP synthase (CTPSyn) is an essential metabolic enzyme, synthesizing precursors required for nucleotides and phospholipids production. Previous studies have also shown that CTPSyn is elevated in various cancers. In many organisms, CTPSyn compartmentalizes into filaments called cytoophidia. In Drosophila melanogaster, only its isoform C (CTPSynIsoC) forms cytoophidia. In the fruit fly's testis, cytoophidia are normally seen in the transit amplification regions close to its apical tip, where the stem-cell niche is located, and development is at its most rapid. Here, we report that CTPSynIsoC overexpression causes the lengthening of cytoophidia throughout the entirety of the testicular body. A bulging apical tip is found in approximately 34% of males overexpressing CTPSynIsoC. Immunostaining shows that this bulged phenotype is most likely due to increased numbers of both germline cells and spermatocytes. Through a microRNA (miRNA) overexpression screen, we found that ectopic miR-975 concurrently increases both the expression levels of CTPSyn and the length of its cytoophidia. The bulging testes phenotype was also recovered at a penetration of approximately 20%. However, qPCR assays reveal that CTPSynIsoC and miR-975 overexpression each provokes a differential response in expression of a number of cancer-related genes, indicating that the shared CTPSyn upregulation seen in either case is likely the cause of observed testicular overgrowth. This study presents the first instance of consequences of miRNA-asserted regulation upon CTPSyn in D. melanogaster, and further reaffirms the enzyme's close ties to germline cells overgrowth.
Fulltext Drosophila melanogaster: Deciphering Alzheimer's Disease

Tan FHP, Azzam G

Malays J Med Sci, 2017 Mar;24(2):6-20.
PMID: 28894399 MyJurnal DOI: 10.21315/mjms2017.24.2.2

Alzheimer's disease (AD) is the most widespread neurodegenerative disorder worldwide. Its pathogenesis involves two hallmarks: aggregation of amyloid beta (Aβ) and occurrence of neurofibrillary tangles (NFTs). The mechanism behind the disease is still unknown. This has prompted the use of animal models to mirror the disease. The fruit fly, Drosophila melanogaster has garnered considerable attention as an organism to recapitulate human disorders. With the ability to monopolise a multitude of traditional and novel genetic tools, Drosophila is ideal for studying not only cellular aspects but also physiological and behavioural traits of human neurodegenerative diseases. Here, we discuss the use of the Drosophila model in understanding AD pathology and the insights gained in discovering drug therapies for AD.

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