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  1. Fulltext Development and validation of a bioanalytical method for quantification of 2,6-bis-(4-hydroxy-3-methoxybenzylidene)-cyclohexanone (BHMC) in rat plasma
    Lee YZ, Ming-Tatt L, Lajis NH, Sulaiman MR, Israf DA, Tham CL
    Molecules, 2012 Dec 07;17(12):14555-64.
    PMID: 23222902 DOI: 10.3390/molecules171214555
    A sensitive and accurate high performance liquid chromatography with ultraviolet/visible light detection (HPLC-UV/VIS) method for the quantification of 2,6-bis-(4-hydroxy-3-methoxybenzylidene)-cyclohexanone (BHMC) in rat plasma was developed and validated. BHMC and the internal standard, harmaline, were extracted from plasma samples by a simple liquid-liquid extraction using 95% ethyl acetate and 5% methanol. Plasma concentration of BHMC and internal standard were analyzed by reversed phase chromatography using a C₁₈ column (150 × 4.6 mm I.D., particle size 5 µm) and elution with a gradient mobile phase of water and methanol at a flow rate of 1.0 mL/min. Detection of BHMC and internal standard was done at a wavelength of 380 nm. The limit of quantification was 0.02 µg/mL. The calibration curves was linear (R² > 0.999) over the concentration range of 0.02-2.5 µg/mL. Intra- and inter-day precision were less than 2% coefficient of variation. The validated method was then applied to a pharmacokinetic study in rats by intravenous administration of BHMC at a single dose of 10 mg/kg. Pharmacokinetic parameters such as half-life, maximum plasma concentration, volume of distribution, clearance and elimination rate constant for BHMC were calculated.
  2. Pharmacokinetic and anti-colon cancer properties of curcumin-containing chitosan-pectinate composite nanoparticles
    Alkhader E, Roberts CJ, Rosli R, Yuen KH, Seow EK, Lee YZ, et al.
    J Biomater Sci Polym Ed, 2018 12;29(18):2281-2298.
    PMID: 30376409 DOI: 10.1080/09205063.2018.1541500
    Curcumin, the active ingredient of the rhizome curcuma longa has been extensively studied as an anticancer agent for various types of tumours. However, its efficacy as an anticancer agent is restricted due to poor absorption from the gastrointestinal tract, rapid metabolism and degradation in acidic medium. In the present study, we encapsulated curcumin in chitosan-pectinate nanoparticulate system (CUR-CS-PEC-NPs) for deployment of curcumin to the colon, whereby curcumin is protected against degradative effects in the upper digestive tract, and hence, maintaining its anticancer properties until colon arrival. The CUR-CS-PEC-NPs was taken up by HT-29 colorectal cancer cells which ultimately resulted in a significant reduction in cancer cell propagation. The anti-proliferative effect of the encapsulated curcumin was similar to that of free curcumin at equivalent doses which confirms that the encapsulation process did not impede the anticancer activity of curcumin. The oral bioavailability (Cmax, and AUC) of curcumin in CUR-CS-PEC-NPs was enhanced significantly by 4-folds after 6 hours of treatment compared to free curcumin. Furthermore, the clearance of curcumin from the CUR-CS-PEC-NPs was lower compared to free curcumin. These findings point to the potential application of the CUR-CS-PEC-NPs in the oral delivery of curcumin in the treatment of colon cancer.
  3. Fulltext The geranyl acetophenone tHGA attenuates human bronchial smooth muscle proliferation via inhibition of AKT phosphorylation
    Yap HM, Lee YZ, Harith HH, Tham CL, Cheema MS, Shaari K, et al.
    Sci Rep, 2018 11 09;8(1):16640.
    PMID: 30413753 DOI: 10.1038/s41598-018-34847-0
    Increased airway smooth muscle (ASM) mass is a prominent hallmark of airway remodeling in asthma. Inhaled corticosteroids and long-acting beta2-agonists remain the mainstay of asthma therapy, however are not curative and ineffective in attenuating airway remodeling. The geranyl acetophenone 2,4,6-trihydroxy-3-geranyl acetophenone (tHGA), an in-house synthetic non-steroidal compound, attenuates airway hyperresponsiveness and remodeling in murine models of asthma. The effect of tHGA upon human ASM proliferation, migration and survival in response to growth factors was assessed and its molecular target was determined. Following serum starvation and induction with growth factors, proliferation and migration of human bronchial smooth muscle cells (hBSMCs) treated with tHGA were significantly inhibited without any significant effects upon cell survival. tHGA caused arrest of hBSMC proliferation at the G1 phase of the cell cycle with downregulation of cell cycle proteins, cyclin D1 and diminished degradation of cyclin-dependent kinase inhibitor (CKI), p27Kip1. The inhibitory effect of tHGA was demonstrated to be related to its direct inhibition of AKT phosphorylation, as well as inhibition of JNK and STAT3 signal transduction. Our findings highlight the anti-remodeling potential of this drug lead in chronic airway disease.
  4. Fulltext Formulation and In Vivo Evaluation of a Solid Self-Emulsifying Drug Delivery System Using Oily Liquid Tocotrienols as Model Active Substance
    Lee YZ, Seow EK, Lim SC, Yuen KH, Abdul Karim Khan N
    Pharmaceutics, 2021 Oct 25;13(11).
    PMID: 34834191 DOI: 10.3390/pharmaceutics13111777
    Self-emulsifying drug delivery systems (SEDDS) can improve the oral bioavailability of poorly water-soluble drugs. Solid self-emulsifying drug delivery systems (s-SEDDS) offer several advantages including improved drug stability, ease of administration, and production. Most compounds employed in developing s-SEDDS are solid in nature, with a high amount of surfactants added. The aim of this study was to develop an s-SEDDS using a tocotrienol-rich fraction (TRF) as the model liquid active substance via a simple adsorption method. The solid formulation was developed using magnesium aluminosilicate as the carrier with 70% TRF and 30% surfactants (poloxamer and Labrasol®). The formulation showed good self-emulsification efficiency with stable emulsion formed, excellent powder flowability, and small emulsion droplet size of 210-277 nm. The s-SEDDS with combined surfactants (poloxamer and Labrasol®) showed a faster absorption rate compared to preparations with only a single surfactant and enhanced oral bioavailability (3.4-3.8 times higher) compared to the non-self-emulsifying oily preparation when administered at a fasted state in rats. In conclusion, an s-SEDDS containing a high amount of TRF was successfully developed. It may serve as a useful alternative to a liquid product with enhanced oral bioavailability and the added advantage of being a solid dosage form.
  5. Fulltext Blockade of Eosinophil-Induced Bronchial Epithelial-Mesenchymal Transition with a Geranyl Acetophenone in a Coculture Model
    Lee YZ, Yap HM, Shaari K, Tham CL, Sulaiman MR, Israf DA
    Front Pharmacol, 2017;8:837.
    PMID: 29201006 DOI: 10.3389/fphar.2017.00837
    Epithelial-mesenchymal transition (EMT) is currently recognized as the main cellular event that contributes to airway remodeling. Eosinophils can induce EMT in airway epithelial cells via increased transforming growth factor (TGF)-β production. We assessed the effect of synthetic 2,4,6-trihydroxy-3-geranyl acetophenone (tHGA) upon eosinophil-induced EMT in a cellular model. The human eosinophil cell line EoL-1 was used to induce EMT in BEAS-2B human bronchial epithelial cells. The induction of EMT was dose-dependently suppressed following tHGA treatment in which the epithelial morphology and E-cadherin expression were not altered. Protein and mRNA expression of vimentin, collagen I and fibronectin in eosinophil-induced epithelial cells were also significantly suppressed by tHGA treatment. Following pathway analysis, we showed that tHGA suppressed eosinophil-induced activator protein-1-mediated TGF-β production by targeting c-Jun N-terminal kinase and phosphoinositide 3-kinase signaling pathways. These findings corroborated previous findings on the ability of tHGA to inhibit experimental murine airway remodeling.
  6. An orally active geranyl acetophenone attenuates airway remodeling in a murine model of chronic asthma
    Lee YZ, Shaari K, Cheema MS, Tham CL, Sulaiman MR, Israf DA
    Eur J Pharmacol, 2017 Feb 15;797:53-64.
    PMID: 28089919 DOI: 10.1016/j.ejphar.2017.01.011
    2,4,6-Trihydroxy-3-geranyl acetophenone (tHGA) is a synthetic compound that is naturally found in Melicope ptelefolia. We had previously demonstrated that parenteral administration of tHGA reduces pulmonary inflammation in OVA-sensitized mice. In this study, we evaluated the effect of orally administered tHGA upon airway remodeling in a murine model of chronic asthma. Female BALB/C mice were sensitized intraperitoneally with ovalbumin (OVA) on day 0, 7 and 14, followed by aerosolized 1% OVA 3 times per week for 6 weeks. Control groups were sensitized with saline. OVA sensitized animals were either treated orally with vehicle (saline with 1% DMSO and Tween 80), tHGA (80, 40, 20mg/kg) or zileuton (30mg/kg) 1h prior to each aerosolized OVA sensitization. On day 61, mice underwent methacholine challenge to determine airway hyperresponsiveness prior to collection of bronchoalveolar lavage (BAL) fluid and lung samples. BAL fluid inflammatory cell counts and cytokine concentrations were evaluated while histological analysis and extracellular matrix protein concentrations were determined on collected lung samples. Oral tHGA treatment attenuated airway hyperresponsiveness and inhibited airway remodeling in a dose-dependent fashion. tHGA's effect on airway remodeling could be attributed to the reduction of inflammatory cell infiltration and decreased expression of cytokines associated with airway remodeling. Oral administration of tHGA attenuates airway hyperresponsiveness and remodeling in OVA-induced BALB/c mice. tHGA is an interesting compound that should be evaluated further for its possible role as an alternative non-steroidal pharmacological approach in the management of asthma.
  7. Factors influencing pharmacists and pharmaceutical scientists' membership in professional organisations: an international survey
    Sullivan L, Ho JN, Lee YZ, Khalid GM, Sandhu AK, Meilianti S, et al.
    J Pharm Policy Pract, 2023 Sep 25;16(1):105.
    PMID: 37749646 DOI: 10.1186/s40545-023-00620-6
    BACKGROUND: Professional organisations exist as international or national organisations, with each country establishing at least one national professional association. There remains a knowledge gap about factors that influence professional organisational involvement of pharmacists and pharmaceutical scientists. This study aims to explore the motivators and barriers of pharmacy professionals holding organisation membership from a global perspective.

    METHODS: An online questionnaire was developed and disseminated between May and July 2021. The survey was open to all pharmacists and pharmaceutical scientists. The survey consisted of four sections; demographic information, questions about professional organisations, about the International Pharmaceutical Federation (FIP) and its impact on the members. Data were analysed descriptively.

    RESULTS: A total of 1033 complete survey responses were received and included in the analysis. Of all respondents, 761 (73.7%) respondents were current members of a professional organisation and 272 (26.3%) were not members of any professional organisation. Overall, findings demonstrated networking, education, training and professional development opportunities as the main interests and anticipated activities, while the lack of clarity or need to join organisation, time, and financial constraints as the main barriers of pharmacy professionals holding membership. The majority of FIP members are satisfied with current FIP activities, and anticipate further networking opportunities, educational resources and grants made available to members.

    CONCLUSIONS: Understanding the perceptions and needs, as well as factors that influence engagement of pharmacists and pharmaceutical scientists is the key to enhancing membership. Professional organisations are highly encouraged to strengthen and target activities according to the identified motivators and barriers.

  8. House dust mite allergy in Malaysia: review of research gaps in the current scenario and the way forward
    Lee YZ, Kow ASF, Jacquet A, Lee MT, Tham CL
    Exp Appl Acarol, 2023 Dec;91(4):509-539.
    PMID: 37995026 DOI: 10.1007/s10493-023-00857-5
    The prevalence of house dust mite (HDM) allergy, especially in Asian countries with rapid urbanization, has been increasing. House dust mites thrive in places with relatively high humidity. With the combination of climate change, naturally high humidity, and urbanization, tropical countries like Malaysia are becoming a hotspot for HDM allergy fast. With a previously reported sensitization rate of between 60 and 80%, it is a worrying trend for Malaysia. However, due to incomplete and out-of-date data, as seen by the limited study coverage in the past, these numbers do not paint a complete picture of the true HDM allergy scene in Malaysia. This review briefly discusses the HDM fauna, the HDM sensitization rate, the common diagnosis and therapeutic tools for HDM allergy in Malaysia, and makes suggestions for possible improvements in the future. This review also highlights the need of more comprehensive population-based prevalence studies to be done in Malaysia, encompassing the three main HDMs-Dermatophagoides pteronyssinus, Dermatophagoides farinae, and Blomia tropicalis-as the lack of up-to-date studies failed to give a clearer picture on the current scenario of HDM allergy in Malaysia. Future studies will be beneficial to the nation in preparing a better blueprint for the management and treatment of HDM allergy.
  9. Fulltext Anthropometric indices, but not birth weight, are associated with high blood pressure risk among Malay adolescents in Kuala Lumpur
    Poh BK, Ang YN, Yeo GS, Lee YZ, Lee ST, Chia JSM, et al.
    Dialogues Health, 2022 Dec;1:100006.
    PMID: 38515871 DOI: 10.1016/j.dialog.2022.100006
    BACKGROUND: With the high prevalence of hypertension, it is important to determine its predictors early. The aim of this study was to determine the association between blood pressure with anthropometric indices and birth weight among a population of Malay adolescents in Kuala Lumpur.

    DESIGN AND METHODS: This cross-sectional study was carried out among 254 primary and secondary school adolescents aged 10 to 16 years. Anthropometric measurements and blood pressure were determined through standardized protocols, while participants' birth weight was obtained from birth certificate. Body mass index (BMI), waist-to-hip ratio (WHR), waist-to-height ratio (WHtR) and a body shape index (ABSI) were calculated.

    RESULTS: Boys had significantly higher weight, height, WC, WHtR and systolic blood pressure (SBP) than girls (p  +1SD had higher odds of being prehypertensive or hypertensive (aOR 8.97; 95% CI 3.16, 25.48), followed by participants with WC ≥ 90th percentile (aOR 6.31; 95% CI 2.48, 16.01) and participants with WHtR > 0.5 (aOR 5.10; 95% CI 2.05, 12.69). Multiple linear regression showed BMI was positively associated with both SBP and DBP. No significant association was found between birth weight and BP.

    CONCLUSION: BMI had the best predictive ability for SBP and DBP. These findings strongly emphasize the importance of primary prevention of hypertension in adolescents, especially among those with high BMI.

  10. Cellular Traction Force Holds the Potential as a Drug Testing Readout for In Vitro Cancer Metastasis
    Liew HY, Liew XH, Lin WX, Lee YZ, Ong YS, Ogawa S, et al.
    Cell Mol Bioeng, 2024 Jun;17(3):203-217.
    PMID: 39050509 DOI: 10.1007/s12195-024-00811-4
    INTRODUCTION: Metastasis is responsible for 90% of cancer-related deaths worldwide. However, the potential inhibitory effects of metastasis by various anticancer drugs have been left largely unexplored. Existing preclinical models primarily focus on antiproliferative agents on the primary tumor to halt the cancer growth but not in metastasis. Unlike primary tumors, metastasis requires cancer cells to exert sufficient cellular traction force through the actomyosin machinery to migrate away from the primary tumor site. Therefore, we seek to explore the potential of cellular traction force as a novel readout for screening drugs that target cancer metastasis.

    METHODS: In vitro models of invasive and non-invasive breast cancer were first established using MDA-MB-231 and MCF-7 cell lines, respectively. Cellular morphology was characterized, revealing spindle-like morphology in MDA-MB-231 and spherical morphology in MCF-7 cells. The baseline cellular traction force was quantified using the Traction force Microscopy technique. Cisplatin, a paradigm antimetastatic drug, and 5-Fluorouracil (5FU), a non-antimetastatic drug, were selected to evaluate the potential of cellular traction force as a drug testing readout for the in vitro cancer metastasis.

    RESULTS: MDA-MB-231 cells exhibited significantly higher baseline cellular traction force compared to MCF-7 cells. Treatment with Cisplatin, an antimetastatic drug, and 5-Fluorouracil (5FU), a non-antimetastatic drug, demonstrated distinct effects on cellular traction force in MDA-MB-231 but not in MCF-7 cells. These findings correlate with the invasive potential observed in the two models.

    CONCLUSION: Cellular traction force emerges as a promising metric for evaluating drug efficacy in inhibiting cancer metastasis using in vitro models. This approach could enhance the screening and development of novel anti-metastatic therapies, addressing a critical gap in current anticancer drug research.

  11. Oral and topical administration of a geranyl acetophenone attenuates DNCB-induced atopic dermatitis-like skin lesions in BALB/c mice
    Mohd Kasim VNK, Lee YZ, Bakrin IH, Hussain MK, Israf DA, Shaari K, et al.
    Sci Rep, 2024 Jul 31;14(1):17623.
    PMID: 39085287 DOI: 10.1038/s41598-024-66601-0
    Atopic dermatitis (AD) is a chronic, allergic inflammatory skin disorder that lacks a definite cure. Using a mouse DNCB-induced AD-like skin lesions model, this study evaluated the potential therapeutic utility of tHGA as an oral and topical treatment for AD. Male BALB/c mice were sensitised and challenged with 1% and 0.5% DNCB on their shaved dorsal skin. Mice in the treatment group were administered tHGA (20, 40, and 80 mg/kg) orally three times per week for 2 weeks, or tHGA (0.2%, 1%, and 5%) topically once daily for 12 days. On day 34, the mice were euthanized, and blood and dorsal skin samples were obtained for analysis. All doses of orally and topically administered tHGA significantly improved scratching, epidermal thickness, blood eosinophilia and mast cell infiltration. There was a minor discrepancy between the two routes of administration, with orally treated tHGA showing significant reductions in Scoring of Atopic Dermatitis (SCORAD), tissue eosinophil infiltration, serum IgE and skin IL-4 levels with treatment of 40 and 80 mg/kg tHGA, whereas topically applied tHGA showed significant reductions in all dosages. These findings suggest that tHGA exhibited therapeutic potential for AD as both oral and topical treatment ameliorates AD-like symptoms in the murine model.
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