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Gene expression analysis in MCF-7 breast cancer cells treated with recombinant bromelain

Fouz N, Amid A, Hashim YZ

Appl Biochem Biotechnol, 2014 Aug;173(7):1618-39.
PMID: 24928548 DOI: 10.1007/s12010-014-0947-6

The contributing molecular pathways underlying the pathogenesis of breast cancer need to be better characterized. The principle of our study was to better understand the genetic mechanism of oncogenesis for human breast cancer and to discover new possible tumor markers for use in clinical practice. We used complimentary DNA (cDNA) microarrays to compare gene expression profiles of treated Michigan Cancer Foundation-7 (MCF-7) with recombinant bromelain and untreated MCF-7. SpringGene analysis was carried out of differential expression followed by Ingenuity Pathway Analysis (IPA), to understand the underlying consequence in developing disease and disorders. We identified 1,102 known genes differentially expressed to a significant degree (p<0.001) changed between the treatment. Within this gene set, 20 genes were significantly changed between treated cells and the control cells with cutoff fold change of more than 1.5. These genes are RNA-binding motif, single-stranded interacting protein 1 (RBMS1), ribosomal protein L29 (RPL29), glutathione S-transferase mu 2 (GSTM2), C15orf32, Akt3, B cell translocation gene 1 (BTG1), C6orf62, C7orf60, kinesin-associated protein 3 (KIFAP3), FBXO11, AT-rich interactive domain 4A (ARID4A), COPS2, TBPL1|SLC2A12, TMEM59, SNORD46, glioma tumor suppressor candidate region gene 2 (GLTSCR2), and LRRFIP. Our observation on gene expression indicated that recombinant bromelain produces a unique signature affecting different pathways, specific for each congener. The microarray results give a molecular mechanistic insight and functional effects, following recombinant bromelain treatment. The extent of changes in genes is related to and involved significantly in gap junction signaling, amyloid processing, cell cycle regulation by BTG family proteins, and breast cancer regulation by stathmin1 that play major roles.
Cytokinetic study of MCF-7 cells treated with commercial and recombinant bromelain

Fouz N, Amid A, Hashim YZ

Asian Pac J Cancer Prev, 2014 Jan;14(11):6709-14.
PMID: 24377593

BACKGROUND: Breast cancer is a leading cause of death in women. The available chemotherapy drugs have been associated with many side effects. Bromelain has novel medicinal qualities including anti-inflammatory, anti-thrombotic, fibrinolytic and anti-cancer functions. Commercially available bromelain is obtained through tedious methods; therefore, recombinant bromelain may provide a cheaper and simpler choice with similar quality.
MATERIALS AND METHODS: This study aimed to assess the effects of commercial and recombinant bromelain on the cytokinetic behavior of MCF-7 breast cancer cells and their potential as therapeutic alternatives in cancer treatment. Cytotoxic activities of commercial and recombinant bromelain were determined using (sulforhodamine) SRB assay. Next, cell viability assays were conducted to determine effects of commercial and recombinant bromelain on MCF-7 cell cytokinetic behavior. Finally, the established growth kinetic data were used to modify a model that predicts the effects of commercial and recombinant bromelain on MCF-7 cells.
RESULTS: Commercial and recombinant bromelain exerted strong effects towards decreasing the cell viability of MCF-7 cells with IC50 values of 5.13 μg/mL and 6.25 μg/mL, respectively, compared to taxol with an IC50 value of 0.063 μg/mL. The present results indicate that commercial and recombinant bromelain both have anti-proliferative activity, reduced the number of cell generations from 3.92 to 2.81 for commercial bromelain and to 2.86 for recombinant bromelain, while with taxol reduction was to 3.12. Microscopic observation of bromelain-treated MCF-7 cells demonstrated detachment. Inhibition activity was verified with growth rates decreased dynamically from 0.009 h-1 to 0.0059 h-1 for commercial bromelain and to 0.0063 h-1 for recombinant bromelain.
CONCLUSIONS: Commercial and recombinant bromelain both affect cytokinetics of MCF-7 cells by decreasing cell viability, demonstrating similar strength to taxol.
Fulltext Screening of anticancer activity from agarwood essential oil

Hashim YZ, Phirdaous A, Azura A

Pharmacognosy Res, 2014 Jul;6(3):191-4.
PMID: 25002797 DOI: 10.4103/0974-8490.132593

Agarwood is a priceless non-timber forest product from Aquilaria species belonging to the Thymelaeaceae family. As a result of a defence mechanism to fend off pathogens, Aquilaria species develop agarwood or resin which can be used for incense, perfumery, and traditional medicines. Evidences from ethnopharmacological practices showed that Aquilaria spp. have been traditionally used in the Ayurvedic practice and Chinese medicine to treat various diseases particularly the inflammatory-associated diseases. There have been no reports on traditional use of agarwood towards cancer treatment. However, this is most probably due to the fact that cancer nomenclature is used in modern medicine to describe the diseases associated with unregulated cell growth in which inflammation and body pain are involved.
Microarray and quantitative PCR analysis of gene expression profiles in response to treatment with tomato leaf extract in mcf-7 breast cancer cells

Amid A, Wan Chik WD, Jamal P, Hashim YZ

Asian Pac J Cancer Prev, 2012;13(12):6319-25.
PMID: 23464452

We previously found cytotoxic effects of tomato leaf extract (TLE) on the MCF-7 breast cancer cell line. The aim of this study was to ascertain the molecular mechanisms associated with the usage of TLE as an anticancer agent by microarray analysis using mRNA from MCF-7 breast cancer cells after treatment with TLE for 1 hr and 48 hrs. Approximately 991 genes out of the 30,000 genes in the human genome were significantly (p<0.05) changed after the treatment. Within this gene set, 88 were significantly changed between the TLE treated cells and the untreated MCF-7 cells (control cells) with a cut-off fold change >2.00. In order to focus on genes that were involved in cancer cell growth, only twenty-nine genes were selected, either down-regulated or up-regulated after treatment with TLE. Microarray assay results were confirmed by analyzing 10 of the most up and down regulated genes related to cancer cells progression using real-time PCR. Treatment with TLE induced significant up-regulation in the expression of the CRYAB, PIM1, BTG1, CYR61, HIF1-α and CEBP-β genes after 1 hr and 48 hrs, whereas the TXNIP and THBS1 genes were up-regulated after 1 hr of treatment but down-regulated after 48 hrs. In addition both the HMG1L1 and HIST2H3D genes were down-regulated after 1 hr and 48 hrs of treatment. These results demonstrate the potent activity of TLE as an anticancer agent.
Aquilaria spp. (agarwood) as source of health beneficial compounds: A review of traditional use, phytochemistry and pharmacology

Hashim YZ, Kerr PG, Abbas P, Mohd Salleh H

J Ethnopharmacol, 2016 Aug 02;189:331-60.
PMID: 27343768 DOI: 10.1016/j.jep.2016.06.055

ETHNOPHARMACOLOGICAL RELEVANCE: Aquilaria spp. (agarwood) has been a part of Ayurvedic and Traditional Chinese Medicine for centuries. Agarwood has also been used as a traditional medicine in Southeast Asian countries, Bangladesh and Tibet. Its common uses include the treatment of joint pain, inflammatory-related ailments, and diarrhoea, as well as a stimulant, sedative and cardioprotective agent. In this paper, we aim to provide an overview of the phytochemistry, ethnomedicinal use, pharmacological activities and safety of plant materials from Aquilaria spp. as an evidence base to further appraise its potential use as a source of health beneficial compounds.
MATERIALS AND METHODS: Literature abstracts and full text articles from journals, books, reports and electronic searches (Google Scholar, Elsevier, PubMed, Read Cube, Scopus, Springer, and Web of Science), as well as from other relevant websites, are surveyed, analysed and included in this review.
RESULTS: A literature survey of agarwood plant materials showed that they contain sesquiterpenes, 2(-2-phenylethyl)-4H-chromen-4-one derivatives, genkwanins, mangiferins, iriflophenones, cucurbitacins, terpenoids and phenolic acids. The crude extracts and some of the isolated compounds exhibit anti-allergic, anti-inflammatory, anti-diabetic, anti-cancer, anti-oxidant, anti-ischemic, anti-microbial, hepatoprotective, laxative, and mosquitocidal properties and effects on the central nervous system. Agarwood plant materials are considered to be safe based on the doses tested. However, the toxicity and safety of the materials, including the smoke from agarwood incense burning, should be further investigated. Future research should be directed towards the bio-guided isolation of bioactive compounds with proper chemical characterisation and investigations of the underlying mechanisms towards drug discovery.
CONCLUSIONS: The traditional medicinal use of agarwood plant materials has provided clues to their pharmacological properties. Indeed, agarwood contains a plethora of bioactive compounds that now elegantly support their use in traditional medicine. As wild agarwood trees are critically endangered and vulnerable, sustainable agricultural and forestry practices are necessary for the further development and utilization of agarwood as a source of health beneficial compounds.
Effects of season and storage period on accumulation of individual carotenoids in pumpkin flesh (Cucurbita moschata)

Jaswir I, Shahidan N, Othman R, Has-Yun Hashim YZ, Octavianti F, bin Salleh MN

J Oleo Sci, 2014;63(8):761-7.
PMID: 25007748

Carotenoids are antioxidants with pharmaceutical potential. The major carotenoids important to humans are α-carotene, β-carotene, lycopene, lutein, zeaxanthin, and β-cryptoxanthin. Some of the biological functions and actions of these individual carotenoids are quite similar to each other, whereas others are specific. Besides genotype and location, other environmental effects such as temperature, light, mineral uptake, and pH have been found affect carotenoid development in plant tissues and organs. Therefore, this research investigated the effects of the season and storage periods during postharvest handling on the accumulation of carotenoid in pumpkin. This study shows that long-term storage of pumpkins resulted in the accumulation of lutein and β-carotene with a slight decrease in zeaxanthin. The amounts of β-carotene ranged from 174.583±2.105 mg/100g to 692.871±22.019 mg/100g, lutein from 19.841±9.693 mg/100g to 59.481±1.645 mg/100g, and zeaxanthin from not detected to 2.709±0.118 mg/100g. The pumpkins were collected three times in a year; they differed in that zeaxanthin was present only in the first season, while the amounts of β-carotene and lutein were the highest in the second and third seasons, respectively. By identifying the key factors among the postharvest handling conditions that control specific carotenoid accumulations, a greater understanding of how to enhance the nutritional values of pumpkin and other crops will be gained. Postharvest storage conditions can markedly enhance and influence the levels of zeaxanthin, lutein, and β-carotene in pumpkin. This study describes how the magnitudes of these effects depend on the storage period and season.
Fulltext Comparing BRIN-BD11 culture producing insulin using different type of microcarriers

Mel M, Karim MI, Yusuf SA, Hashim YZ, Ahmad Nor Y

Cytotechnology, 2010 Oct;62(5):423-30.
PMID: 20953703 DOI: 10.1007/s10616-010-9294-9

This research was conducted to examine the growth profile, growth kinetics, and insulin-secretory responsiveness of BRIN-BD11 cells grown in optimized medium on different types of microcarriers (MCs). Comparisons were made on modified polystyrene (Hillex(®) II) and crosslinked polystyrene Plastic Plus (PP) from Solohill Engineering. The cell line producing insulin was cultured in a 25 cm(2) T-flask as control while MCs based culture was implemented in a stirred tank bioreactor with 1 L working volume. For each culture type, the viable cell number, glucose, lactate, glutamate, and insulin concentrations were measured and compared. Maximum viable cell number was obtained at 1.47 × 10(5) cell/mL for PP microcarrier (PPMCs) culture, 1.35 × 10(5) cell/mL Hillex(®) II (HIIMCs) culture and 0.95 × 10(5) cell/mL for T-flask culture, respectively. The highest insulin concentration has been produced in PPMCs culture (5.31 mg/L) compared to HIIMCs culture (2.01 mg/L) and T-flask culture (1.99 mg/L). Therefore overall observation suggested that PPMCs was likely preferred to be used for BRIN-BD11 cell culture as compared with Hillex(®) II MCs.
Fulltext Metabolomics profiling of extracellular metabolites in CHO-K1 cells cultured in different types of growth media

Mohmad-Saberi SE, Hashim YZ, Mel M, Amid A, Ahmad-Raus R, Packeer-Mohamed V

Cytotechnology, 2013 Aug;65(4):577-86.
PMID: 23179090 DOI: 10.1007/s10616-012-9508-4

An efficient mammalian cell system for producing bioproducts should retain high cell viability and efficient use of energy sources rendering the need to understand the effects of various variables on the cell system. In this study, global metabolite (metabolomics) analysis approach was used to try and understand the relationships between types of media used, culture growth behavior and productivity. CHO-KI cells producing IGF-1 were obtained from ATCC and grown in T-flask (37 °C, 5 % CO2) until 70-80 % confluent in RPMI 1640 and Ham's F12, respectively. Samples were taken at 8-hourly intervals for routine cell counting, biochemical responses, insulin like growth factor-1 (IGF-1) protein concentration and global metabolite analysis (gas chromatography mass spectrometry, GCMS). Conditioned media from each time point were spun down before injection into GCMS. Data from GCMS were then transferred to SIMCA-P + Version 12 for chemometric evaluation using principal component analysis. The results showed that while routine analysis gave only subtle differences between the media, global metabolite analysis was able to clearly separate the culture based on growth media with growth phases as confounding factor. Different types of media also appeared to affect IGF-1 production. Asparagine was found to be indicative of healthiness of cells and production of high IGF-1. Meanwhile identification of ornithine and lysine in death phase was found to be associated with apoptosis and oversupplied nutrient respectively. Using the biomarkers revealed in the study, several bioprocessing strategies including medium improvement and in-time downstream processing can be potentially implemented to achieve efficient CHO culture system.
Virgin olive oil phenolics extract inhibit invasion of HT115 human colon cancer cells in vitro and in vivo

Hashim YZ, Worthington J, Allsopp P, Ternan NG, Brown EM, McCann MJ, et al.

Food Funct, 2014 Jul 25;5(7):1513-9.
PMID: 24836598 DOI: 10.1039/c4fo00090k

The decreased cancer risk associated with consumption of olive oil may be due to the presence of phenolics which can modulate pathways including apoptosis and invasion that are relevant to carcinogenesis. We have previously shown that a virgin olive oil phenolics extract (OVP) inhibited invasion of HT115 colon cancer cells in vitro. In the current study we assessed the in vitro effects of OVP (25 μg mL(-1)) on HT115 cell migration, spreading and integrin expression. Furthermore, the anti-metastatic activity of OVP - at a dose equivalent to 25 mg per kg per day for 2, 8 or 10 weeks - was assessed in a Severe Combined ImmunoDeficiency (SCID) Balb-c mouse model. After 24 h OVP did not inhibit cell migration but significantly reduced cell spreading on fibronectin (65% of control; p < 0.05) and expression of a range of α and β integrins was modulated. In vivo, OVP by gavage significantly (p < 0.05) decreased not only tumour volume but also the number of metastases in SCID Balb-c mice. Collectively, the data suggest that - possibly through modulation of integrin expression - OVP decreases invasion in vitro and also inhibits metastasis in vivo.