Displaying publications 81 - 98 of 98 in total

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  1. A semisynthetic diterpenoid lactone inhibits NF-κB signalling to ameliorate inflammation and airway hyperresponsiveness in a mouse asthma model
    Lim JC, Goh FY, Sagineedu SR, Yong AC, Sidik SM, Lajis NH, et al.
    Toxicol Appl Pharmacol, 2016 07 01;302:10-22.
    PMID: 27089844 DOI: 10.1016/j.taap.2016.04.004
    Andrographolide (AGP) and 14-deoxy-11,12-didehydroandrographolide (DDAG), two main diterpenoid constituents of Andrographis paniculata were previously shown to ameliorate asthmatic symptoms in a mouse model. However, due to inadequacies of both compounds in terms of drug-likeness, DDAG analogues were semisynthesised for assessment of their anti-asthma activity. A selected analogue, 3,19-diacetyl-14-deoxy-11,12-didehydroandrographolide (SRS27), was tested for inhibitory activity of NF-κB activation in TNF-α-induced A549 cells and was subsequently evaluated in a mouse model of ovalbumin (OVA)-induced asthma. Female BALB/c mice, 6-8weeks old were sensitized on days 0 and 14, and challenged on days 22, 23 and 24 with OVA. Compound or vehicle (3% dimethyl sulfoxide) was administered intraperitoneally 1h before and 11h after each OVA aerosol challenge. On day 25, pulmonary eosinophilia, airway hyperresponsiveness, mucus hypersecretion, inflammatory cytokines such as IL-4, -5 and -13 in BAL fluid, gene expression of inflammatory mediators such as 5-LOX, E-selectin, VCAM-1, CCL5, TNF-α, AMCase, Ym2, YKL-40, Muc5ac, CCL2 and iNOS in animal lung tissues, and serum IgE were determined. SRS27 at 30μM was found to suppress NF-κB nuclear translocation in A549 cells. In the ovalbumin-induced mouse asthma model, SRS27 at 3mg/kg displayed a substantial decrease in pulmonary eosinophilia, BAL fluid inflammatory cytokines level, serum IgE production, mucus hypersecretion and gene expression of inflammatory mediators in lung tissues. SRS27 is the first known DDAG analogue effective in ameliorating inflammation and airway hyperresponsiveness in the ovalbumin-induced mouse asthma model.
  2. Beneficial effects of TQRF and TQ nano- and conventional emulsions on memory deficit, lipid peroxidation, total antioxidant status, antioxidants genes expression and soluble Aβ levels in high fat-cholesterol diet-induced rats
    Ismail N, Ismail M, Azmi NH, Bakar MFA, Yida Z, Stanslas J, et al.
    Chem Biol Interact, 2017 Sep 25;275:61-73.
    PMID: 28734741 DOI: 10.1016/j.cbi.2017.07.014
    The study determined the effect of thymoquinone rich fraction (TQRF) and thymoquinone (TQ) in the forms of nano- and conventional emulsions on learning and memory, lipid peroxidation, total antioxidant status, antioxidants genes expression and soluble β-amyloid (Aβ) levels in rats fed with a high fat-cholesterol diet (HFCD). The TQRF was extracted from Nigella sativa seeds using a supercritical fluid extraction system and prepared into nanoemulsion, which later named as TQRF nanoemulsion (TQRFNE). Meanwhile, TQ was acquired commercially and prepared into thymoquinone nanoemulsion (TQNE). The TQRF and TQ conventional emulsions (CE), named as TQRFCE and TQCE, respectively were studied for comparison. Statin (simvastatin) and non-statin (probucol) cholesterol-lowering agents, and a mild-to-severe Alzheimer's disease drug (donepezil) were served as control drugs. The Sprague Dawley rats were fed with HFCD for 6 months, and treated with the intervention groups via oral gavage daily for the last 3 months. As a result, HFCD-fed rats exhibited hypercholesterolaemia, accompanied by memory deficit, increment of lipid peroxidation and soluble Aβ levels, decrement of total antioxidant status and down-regulation of antioxidants genes expression levels. TQRFNE demonstrated comparable effects to the other intervention groups and control drugs in serum biomarkers as well as in the learning and memory test. Somehow, TQRFNE was more prominent than those intervention groups and control drugs in brain biomarkers concomitant to gene and protein expression levels. Supplementation of TQRFNE into an HFCD thus could ameliorate memory deficit, lipid peroxidation and soluble Aβ levels as well as improving the total antioxidant status and antioxidants genes expression levels.
  3. In silico and saturation transfer difference NMR approaches to unravel the binding mode of an andrographolide derivative to K-Ras oncoprotein
    Quah SY, Tan MS, Ho KL, Manan NA, Gorfe AA, Deb PK, et al.
    Future Med Chem, 2020 09;12(18):1611-1631.
    PMID: 32892640 DOI: 10.4155/fmc-2020-0104
    Background: Andrographolide and its benzylidene derivatives, SRJ09 and SRJ23, potentially bind oncogenic K-Ras to exert anticancer activity. Their molecular interactions with K-Ras oncoproteins that lead to effective biological activity are of major interest. Methods & results: In silico docking and molecular dynamics simulation were performed using Glide and Desmond, respectively; while saturation transfer difference NMR was performed using GDP-bound K-RasG12V. SRJ23 was found to bind strongly and selectively to K-RasG12V, by anchoring to a binding pocket (namely p2) principally via hydrogen bond and hydrophobic interactions. The saturation transfer difference NMR analysis revealed the proximity of protons of functional moieties in SRJ23 to K-RasG12V, suggesting positive binding. Conclusion: SRJ23 binds strongly and interacts stably with K-RasG12V to exhibit its inhibitory activity.
  4. Microarray-based identification of differentially expressed genes associated with andrographolide derivatives-induced resistance in colon and prostate cancer cell lines
    Quah SY, Wong CC, Wong HC, Ho KL, Abdul Manan N, Deb PK, et al.
    Toxicol Appl Pharmacol, 2021 08 15;425:115605.
    PMID: 34087331 DOI: 10.1016/j.taap.2021.115605
    Chemoresistance poses a major hurdle to cancer treatments. Andrographolide-derived SRJ09 and SRJ23 were reported to exhibit potent, selective inhibitory activities against colon and prostate cancer cells, respectively. In this study, previously developed resistant colon (HCT-116rst09) and prostate (PC-3rst23) cancer cell lines were used to elucidate the molecular mechanisms contributing to chemoresistance. Cytotoxic effects of SRJ09 and SRJ23 on both parental and resistant cells were investigated. Cell cycle distributions in HCT-116rst09 cells following SRJ09 treatment were analysed using flow cytometry. Whole-genome microarray analysis was performed on both parental and resistant cells to obtain differential gene expression profiles. Microarray data were subjected to protein-protein interaction network, functional enrichment, and pathway analyses. Reverse transcription-polymerase chain reaction (RT-PCR) was used to validate the changes in expression levels of selected genes. Besides morphological changes, HCT-116rst09 cells showed 7.0-fold resistance to SRJ09 while PC-3rst23 cells displayed a 5.5-fold resistance to SRJ23, as compared with their respective parental cells. G0/G1-phase cell cycle arrest was observed in HCT-116rst09 cells upon SRJ09 treatment. Collectively, 77 and 21 genes were found differentially modulated in HCT-116rst09 and PC-3rst23 cells, respectively. Subsequent bioinformatics analysis revealed several genes associated with FGFR4 and PI3K pathways, and cancer stemness, were chemoresistance mediators in HCT-116rst09 cells. RT-PCR confirmed the HMOX1 upregulation and ATG12 downregulation protected the PC-3rst23 cells from SRJ23 cytotoxicity. In conclusion, acquired chemoresistance to SRJ09 and SRJ23 in colon and prostate cancer cells, respectively, could be attributed to the alterations in the expression of genes such as those related to PI3K and autophagy pathways.
  5. Fulltext Hypoxia-Induced Neuroinflammation in Alzheimer's Disease: Potential Neuroprotective Effects of Centella asiatica
    Hambali A, Kumar J, Hashim NFM, Maniam S, Mehat MZ, Cheema MS, et al.
    Front Physiol, 2021;12:712317.
    PMID: 34721056 DOI: 10.3389/fphys.2021.712317
    Alzheimer's disease (AD) is a neurodegenerative disorder that is characterised by the presence of extracellular beta-amyloid fibrillary plaques and intraneuronal neurofibrillary tau tangles in the brain. Recurring failures of drug candidates targeting these pathways have prompted research in AD multifactorial pathogenesis, including the role of neuroinflammation. Triggered by various factors, such as hypoxia, neuroinflammation is strongly linked to AD susceptibility and/or progression to dementia. Chronic hypoxia induces neuroinflammation by activating microglia, the resident immune cells in the brain, along with an increased in reactive oxygen species and pro-inflammatory cytokines, features that are common to many degenerative central nervous system (CNS) disorders. Hence, interests are emerging on therapeutic agents and plant derivatives for AD that target the hypoxia-neuroinflammation pathway. Centella asiatica is one of the natural products reported to show neuroprotective effects in various models of CNS diseases. Here, we review the complex hypoxia-induced neuroinflammation in the pathogenesis of AD and the potential application of Centella asiatica as a therapeutic agent in AD or dementia.
  6. A pilot study on the association between SLCO1B1 RS4363657 polymorphism and muscle adverse events in adults with newly diagnosed dyslipidaemia who were prescribed a statin: the Malaysian primary health care cohort
    C Thambiah S, Meor Anuar Shuhaili MFR, Chew BH, Samsudin IN, Abdul Rahman H, Stanslas J, et al.
    Biomarkers, 2019 Nov;24(7):659-665.
    PMID: 31342800 DOI: 10.1080/1354750X.2019.1648554
    Introduction: Statin, the first-line treatment for dyslipidaemia, may have suboptimal adherence due to its associated muscle adverse events. These data, however, remain limited. Aim: To determine the association of serum creatine kinase (CK) and SLCO1B1 rs4363657 polymorphism with statin-associated muscle adverse events (SAMAE) among dyslipidaemia participants.
    Methods: This was a prospective cohort study at government health clinics involving newly diagnosed adults with dyslipidaemia. SAMAE were recorded based on the patient's complaint after a month on statin. CK was taken at baseline and follow-up. Genetic profiling was performed for SLCO1B1 rs4363657 polymorphism.
    Results: Among 118 participants, majority were Malay (72%) males (61%) with a mean age of 49 ± 12.2 years old and prescribed lovastatin (61.9). There was a significant association between statin types (lovastatin and simvastatin) and SAMAE (p = 0.0327); no significant association noted between CK and SAMAE (p = 0.5637). The SLCO1B1 rs4363657 polymorphism was significantly associated SAMAE (p 
  7. The impact of cycleanine in cancer research: a computational study
    Nwaefulu ON, Al-Shar'i NA, Owolabi JO, Sagineedu SR, Woei LC, Wai LK, et al.
    J Mol Model, 2022 Oct 04;28(11):340.
    PMID: 36194315 DOI: 10.1007/s00894-022-05326-1
    Cancer is imposing a global health burden because of the steady increase in new cases. Moreover, current anticancer therapeutics are associated with many drawbacks, mainly the emergence of resistance and the severe adverse effects. Therefore, there is a continuous need for developing new anticancer agents with novel mechanisms of action and lower side effects. Natural products have been a rich source of anticancer medication. Cycleanine, a natural product, was reported to exert an antiproliferative effect on ovarian cancer cells by causing apoptosis through activation of caspases 3/7 and cleavage of poly (ADP-ribose) polymerase to form poly (ADP-ribose) polymerase-1 (PARP1). It is well-established that PARP1 is associated with carcinogenesis, and different PARP1 inhibitors are approved as anticancer drugs. In this study, the cytotoxic activity of cycleanine was computationally investigated to determine whether it is a PARP1 inhibitor or a caspase activator. Molecular docking and molecular dynamics (MD) simulations were utilized for this purpose. The results showed that cycleanine has a good binding affinity to PARP1; moreover, MD simulation showed that it forms a stable complex with the enzyme. Consequently, the results showed that cycleanine is a potential inhibitor of the PARP1 enzyme.
  8. Correlation of whole blood hydroxychloroquine concentration with cutaneous lupus erythematosus and factors associated with it: First multicenter, cross-sectional analysis in Malaysia
    Peh D, Wan Ahmad Kammal WSL, Beh PJ, Yong ACH, Tan WC, Lim AL, et al.
    J Dermatol, 2022 Jan 24.
    PMID: 35067938 DOI: 10.1111/1346-8138.16292
    Hydroxychloroquine (HCQ) is the first-line systemic treatment for cutaneous lupus erythematosus (CLE). Whole blood HCQ concentration (WBHCQ) was found to correlate with CLE severity among Caucasians. However, studies on Asians are scarce. We aim to explore the relationship of WBHCQ with CLE disease activity among multi-racial Malaysians and the factors associated with WBHCQ. A cross-sectional study targeting patients with CLE was conducted from 1 June till 30 November 2019. Disease activity was assessed using Cutaneous Lupus Erythematosus Disease Area and Severity Index - Activity Score (CLASI-AS). Blood was analyzed for WBHCQ concentration using a high-performance liquid chromatography technique. Statistical analysis was done using R studio version 1.2.1335. A total of 88 subjects (male : female, 4.5:1) with a median age of 41 years old were recruited. The median duration CLE was 5 years. The majority had acute cutaneous lupus (n = 45, 51.1%). The median WBHCQ was 946.8 ng/mL. Indians were found to have the highest WBHCQ (median ± interquartile range [IQR], 1515.4 ± 1494.8 ng/mL). Males had a lower WBHCQ (median ± IQR, 733.5 ± 573.8 ng/mL) than females (995.5 ± 925.1 ng/mL). However, no statistically significant association between race and sex with WBHCQ was demonstrable (p = 0.247, p = 0.066). No correlation was demonstrated between WBHCQ and CLASI-AS (r = -0.02, p = 0.851). A positive correlation was found between HCQ dosage (ideal bodyweight) and WBHCQ (r = 0.24, p = 0.027). No other factors were found associated with WBHCQ. Indians and females were observed to have higher WBCHQ; however, no significant correlation was identified. Further study is required to confirm the finding.
  9. BsmI-ApaI-TaqI TAC (BAt) Haplotype of Vitamin D Receptor Gene Is Associated with Increased Risk of Major Depressive Disorder
    Lye MS, Tor YS, Tey YY, Shahabudin A, Loh SP, Ibrahim N, et al.
    J Mol Neurosci, 2021 May;71(5):981-990.
    PMID: 33034825 DOI: 10.1007/s12031-020-01719-0
    Heritability of major depressive disorder (MDD) is between 36 and 44%, suggesting that up to nearly half of the phenotypic variability is attributable to genes. A number of genetic polymorphisms have been shown to predispose certain individuals to depression. Of particular interest are the polymorphisms of the vitamin D receptor (VDR) gene. Although the VDR gene has been well characterized and a vast number of polymorphisms have been identified, the association between BsmI (rs1544410), ApaI (rs7975232) and TaqI (rs731236) single-nucleotide polymorphisms (SNPs), together with their haplotypes, and MDD risk have yet to be established. We conducted a matched case-control study with a total of 600 participants comprising 300 major depressive disorder (MDD) cases and 300 controls matched by age, gender and ethnicity in a 1:1 ratio, in four public hospitals in Kuala Lumpur and Selangor. Three adjacent SNPs of the VDR gene-BsmI (rs1544410), ApaI (rs7975232) and TaqI (rs731236)-were genotyped using polymerase chain reaction-restriction fragment length polymorphism (PCR-RFLP). Odds ratios and 95% confidence intervals (CIs) were obtained from conditional logistic regression using Stata 16. Linkage disequilibrium and haplotype association with MDD were analyzed using the online SNPStats program. None of the genotypes of the three SNPs was significantly associated with risk of developing MDD after adjusting for confounding factors. However, the TAC (BAt) haplotype was associated with increased odds of MDD (adjusted OR = 2.17, 95% CI = 1.30-3.61, p = 0.003) using CCT (baT) as reference haplotype. The findings suggest that the BsmI-ApaI-TaqI TAC (BAt) haplotype of the VDR gene increases susceptibility to MDD.
  10. Whole blood hydroxychloroquine: Does genetic polymorphism of cytochrome P450 enzymes have a role?
    Jatta N, Stanslas J, Yong ACH, Ho WC, Wan Ahmad Kammal WSL, Chua EW, et al.
    Clin Exp Med, 2023 Dec;23(8):4141-4152.
    PMID: 37480404 DOI: 10.1007/s10238-023-01142-w
    Systemic lupus erythematosus (SLE) is a chronic autoimmune disease with a wide range of clinical manifestations and multifactorial etiologies ranging from environmental to genetic. SLE is associated with dysregulated immunological reactions, with increased immune complex formation leading to end-organ damages such as lupus nephritis, cutaneous lupus, and musculoskeletal disorders. Lupus treatment aims to reduce disease activity, prevent organ damage, and improve long-term patient survival and quality of life. Antimalarial, hydroxychloroquine (HCQ) is used as a first-line systemic treatment for lupus. It has shown profound efficacy in lupus and its associated conditions. However, wide variation in terms of clinical response to this drug has been observed among this group of patients. This variability has limited the potential of HCQ to achieve absolute clinical benefits. Several factors, including genetic polymorphisms of cytochrome P450 enzymes, have been stipulated as key entities leading to this inter-individual variation. Thus, there is a need for more studies to understand the role of genetic polymorphisms in CYP450 enzymes in the clinical response to HCQ. Focusing on the role of genetic polymorphism on whole blood HCQ in lupus disorder, this review aims to highlight up-to-date pathophysiology of SLE, the mechanism of action of HCQ, and finally the role of genetic polymorphism of CYP450 enzymes on whole blood HCQ level as well as clinical response in lupus.
  11. The Standardized Extract of Centella asiatica and Its Fractions Exert Antioxidative and Anti-Neuroinflammatory Effects on Microglial Cells and Regulate the Nrf2/HO-1 Signaling Pathway
    Hambali A, Jusril NA, Md Hashim NF, Abd Manan N, Adam SK, Mehat MZ, et al.
    J Alzheimers Dis, 2024;99(s1):S119-S138.
    PMID: 38250772 DOI: 10.3233/JAD-230875
    BACKGROUND: Neuroinflammation and oxidative stress can aggravate the progression of Alzheimer's disease (AD). Centella asiatica has been traditionally consumed for memory and cognition. The triterpenes (asiaticoside, madecassoside, asiatic acid, madecassic acid) have been standardized in the ethanolic extract of Centella asiatica (SECA). The bioactivity of the triterpenes in different solvent polarities of SECA is still unknown.

    OBJECTIVE: In this study, the antioxidative and anti-neuroinflammatory effects of SECA and its fractions were explored on lipopolysaccharides (LPS)-induced microglial cells.

    METHODS: HPLC measured the four triterpenes in SECA and its fractions. SECA and its fractions were tested for cytotoxicity on microglial cells using MTT assay. NO, pro-inflammatory cytokines (TNF-α, IL-6, IL-1β), ROS, and MDA (lipid peroxidation) produced by LPS-induced microglial cells were measured by colorimetric assays and ELISA. Nrf2 and HO-1 protein expressions were measured using western blotting.

    RESULTS: The SECA and its fractions were non-toxic to BV2 microglial cells at tested concentrations. The levels of NO, TNF-α, IL-6, ROS, and lipid peroxidation in LPS-induced BV2 microglial cells were significantly reduced (p 

  12. Role of the IL8 rs4073 polymorphism in central nervous system toxicity in patients receiving multidrug-resistant tuberculosis treatment
    Badamasi IM, Muhammad M, Umar AA, Madugu UM, Gadanya MA, Aliyu IA, et al.
    J Bras Pneumol, 2024;50(1):e20230338.
    PMID: 38359298 DOI: 10.36416/1806-3756/e20230338
    OBJECTIVE: To determine the role of the IL8 rs4073 polymorphism in predicting the risk of central nervous system (CNS) toxicity in patients receiving standard pharmacological treatment for multidrug-resistant tuberculosis (MDR-TB).

    METHODS: A cohort of 85 consenting MDR-TB patients receiving treatment with second-line antituberculosis drugs had their blood samples amplified for the IL8 (rs4073) gene and genotyped. All patients were clinically screened for evidence of treatment toxicity and categorized accordingly. Crude and adjusted associations were assessed.

    RESULTS: The chief complaints fell into the following categories: CNS toxicity; gastrointestinal toxicity; skin toxicity; and eye and ear toxicities. Symptoms of gastrointestinal toxicity were reported by 59% of the patients, and symptoms of CNS toxicity were reported by 42.7%. With regard to the genotypes of IL8 (rs4073), the following were identified: AA, in 64 of the study participants; AT, in 7; and TT, in 11. A significant association was found between the dominant model of inheritance and CNS toxicity for the crude model (p = 0.024; OR = 3.57; 95% CI, 1.18-10.76) and the adjusted model (p = 0.031; OR = 3.92; 95% CI, 1.13-13.58). The AT+TT genotype of IL8 (rs4073) showed a 3.92 times increased risk of CNS toxicity when compared with the AA genotype.

    CONCLUSIONS: The AT+TT genotype has a tendency to be associated with an increased risk of adverse clinical features during MDR-TB treatment.

  13. Fulltext Effect of Edible Bird's Nest Extract on Lipopolysaccharide-Induced Impairment of Learning and Memory in Wistar Rats
    Careena S, Sani D, Tan SN, Lim CW, Hassan S, Norhafizah M, et al.
    Evid Based Complement Alternat Med, 2018;2018:9318789.
    PMID: 30186358 DOI: 10.1155/2018/9318789
    Cognitive disability is a common feature associated with a variety of neurological conditions including Alzheimer's Disease (AD), Parkinson's Disease (PD), brain injury, and stroke. Emerging evidence has demonstrated that neuroinflammation plays an important role in the development of cognitive impairment. Current available therapies are relatively ineffective in treating or preventing cognitive disabilities, thus representing an important, unfulfilled medical need. Hence, developing potential treatment is one of the major areas of research interest. Edible bird's nests (EBN) are nests formed by swiftlet's saliva containing sialic acid, which is believed to improve brain function. This present study was embarked upon to evaluate the learning and memory enhancing potential effect of EBN by using Morris water maze test in a Wistar rat model of LPS-induced neuroinflammation. LPS elicited cognitive impairment in the rats by significantly increasing the escape latency while decreasing the number of entries in the probe trial, which are coupled with increased production of proinflammatory cytokines (TNF-α, IL-1β, and IL-6) and oxidative markers (ROS and TBARS) in the hippocampus. Treatment with EBN (125 mg/kg, 250 mg/kg, and 500 mg/kg; p.o.) effectively reversed the effect of LPS on escape latency and probe trial and, in addition, inhibited the LPS-induced upregulation of proinflammatory cytokines and oxidative markers. These findings are suggestive that there is existence of neuroprotective effect contained inside the edible bird's nest.
  14. Fulltext Lignosus rhinocerotis Cooke Ryvarden ameliorates airway inflammation, mucus hypersecretion and airway hyperresponsiveness in a murine model of asthma
    Johnathan M, Muhamad SA, Gan SH, Stanslas J, Mohd Fuad WE, Hussain FA, et al.
    PLoS One, 2021;16(3):e0249091.
    PMID: 33784348 DOI: 10.1371/journal.pone.0249091
    Lignosus rhinocerotis Cooke. (L. rhinocerotis) is a medicinal mushroom traditionally used in the treatment of asthma and several other diseases by the indigenous communities in Malaysia. In this study, the effects of L. rhinocerotis on allergic airway inflammation and hyperresponsiveness were investigated. L. rhinocerotis extract (LRE) was prepared by hot water extraction using soxhlet. Airway hyperresponsiveness (AHR) study was performed in house dust mite (HDM)-induced asthma in Balb/c mice while airway inflammation study was performed in ovalbumin (OVA)-induced asthma in Sprague-Dawley rats. Treatment with different doses of LRE (125, 250 and 500 mg/kg) significantly inhibited AHR in HDM-induced mice. Treatment with LRE also significantly decreased the elevated IgE in serum, Th2 cytokines in bronchoalveolar lavage fluid and ameliorated OVA-induced histological changes in rats by attenuating leukocyte infiltration, mucus hypersecretion and goblet cell hyperplasia in the lungs. LRE also significantly reduced the number of eosinophils and neutrophils in BALF. Interestingly, a significant reduction of the FOXP3+ regulatory T lymphocytes was observed following OVA induction, but the cells were significantly elevated with LRE treatment. Subsequent analyses on gene expression revealed regulation of several important genes i.e. IL17A, ADAM33, CCL5, IL4, CCR3, CCR8, PMCH, CCL22, IFNG, CCL17, CCR4, PRG2, FCER1A, CLCA1, CHIA and Cma1 which were up-regulated following OVA induction but down-regulated following treatment with LRE. In conclusion, LRE alleviates allergy airway inflammation and hyperresponsiveness, thus suggesting its therapeutic potential as a new armamentarium against allergic asthma.
  15. Challenges and Strategies for Improving Access to Cancer Drugs in Malaysia: Summary of Opinions Expressed at the 2nd MACR International Scientific Conference 2022
    Tan SC, Poh WT, Yong ACH, Chua EW, Ooi J, Mahmud R, et al.
    Cancer Manag Res, 2023;15:851-862.
    PMID: 37636030 DOI: 10.2147/CMAR.S420890
    Considerable progress has been made in cancer drug development in recent decades. However, for people in low- and middle-income countries, including Malaysia, many of these drugs are not readily available. During the 2nd Malaysian Association for Cancer Research (MACR) International Scientific Conference, a forum discussion was held to address these challenges and explore strategies to improve access to cancer medicines in the country. This paper presents the results of the said forum discussion. A few challenges to cancer drug access were highlighted, including lengthy approval and regulatory practices, cost of medicines, and manufacturing barriers. Besides, a few strategies for mitigating some of these challenges were proposed, such as mechanisms for cost reduction, uptake of biosimilars and generics, local manufacturing, public-private partnerships, strengthening the role of insurance companies, funding and regulation, and advocacy for fair pricing, by drawing examples from cancer medicines access initiatives in Malaysia and initiatives for different disease groups. Overall, this paper provides a comprehensive overview of the challenges and strategies for improving access to cancer medicines in Malaysia and provides valuable insights for policymakers, healthcare providers, the pharmaceutical industry, cancer patients, cancer support groups, and other stakeholders working on this important issue.
  16. Bioassay-guided identification of an anti-inflammatory prenylated acylphloroglucinol from Melicope ptelefolia and molecular insights into its interaction with 5-lipoxygenase
    Shaari K, Suppaiah V, Wai LK, Stanslas J, Tejo BA, Israf DA, et al.
    Bioorg Med Chem, 2011 Nov 1;19(21):6340-7.
    PMID: 21958738 DOI: 10.1016/j.bmc.2011.09.001
    A bioassay-guided investigation of Melicope ptelefolia Champ ex Benth (Rutaceae) resulted in the identification of an acyphloroglucinol, 2,4,6-trihydroxy-3-geranylacetophenone or tHGA, as the active principle inhibiting soybean 15-LOX. The anti-inflammatory action was also demonstrated on human leukocytes, where the compound showed prominent inhibitory activity against human PBML 5-LOX, with an IC(50) value of 0.42 μM, very close to the effect produced by the commonly used standard, NDGA. The compound concentration-dependently inhibited 5-LOX product synthesis, specifically inhibiting cysteinyl leukotriene LTC(4) with an IC(50) value of 1.80 μM, and showed no cell toxicity effects. The anti-inflammatory action does not seem to proceed via redox or metal chelating mechanism since the compound tested negative for these bioactivities. Further tests on cyclooxygenases indicated that the compound acts via a dual LOX/COX inhibitory mechanism, with greater selectivity for 5-LOX and COX-2 (IC(50) value of 0.40 μM). The molecular features that govern the 5-LOX inhibitory activity was thus explored using in silico docking experiments. The residues Ile 553 and Hie 252 were the most important residues in the interaction, each contributing significant energy values of -13.45 (electrostatic) and -5.40 kcal/mol (electrostatic and Van der Waals), respectively. The hydroxyl group of the phloroglucinol core of the compound forms a 2.56Å hydrogen bond with the side chain of the carboxylate group of Ile 553. Both Ile 553 and Hie 252 are crucial amino acid residues which chelate with the metal ion in the active site. Distorting the geometry of these ligands could be the reason for the inhibition activity shown by tHGA. The molecular simulation studies supported the bioassay results and served as a good model for understanding the way tHGA binds in the active site of human 5-LOX enzyme.
  17. Fulltext Screening of brain-derived neurotrophic factor (BDNF) single nucleotide polymorphisms and plasma BDNF levels among Malaysian major depressive disorder patients
    Aldoghachi AF, Tor YS, Redzun SZ, Lokman KAB, Razaq NAA, Shahbudin AF, et al.
    PLoS One, 2019;14(1):e0211241.
    PMID: 30677092 DOI: 10.1371/journal.pone.0211241
    BACKGROUND: Brain-derived neurotrophic factor (BDNF) is a neurotrophin found in abundance in brain regions such as the hippocampus, cortex, cerebellum and basal forebrain. It has been associated with the risk of susceptibility to major depressive disorder (MDD). This study aimed to determine the association of three BDNF variants (rs6265, rs1048218 and rs1048220) with Malaysian MDD patients.

    METHODS: The correlation of these variants to the plasma BDNF level among Malaysian MDD patients was assessed. A total of 300 cases and 300 matched controls recruited from four public hospitals within the Klang Valley of Selangor State, Malaysia and matched for age, sex and ethnicity were screened for BDNF rs6265, rs1048218 and rs1048220 using high resolution melting (HRM).

    FINDINGS: BDNF rs1048218 and BDNF rs1048220 were monomorphic and were excluded from further analysis. The distribution of the alleles and genotypes for BDNF rs6265 was in Hardy-Weinberg equilibrium for the controls (p = 0.13) but was in Hardy Weinberg disequilibrium for the cases (p = 0.011). Findings from this study indicated that having BDNF rs6265 in the Malaysian population increase the odds of developing MDD by 2.05 folds (95% CI = 1.48-3.65). Plasma from 206 cases and 206 controls were randomly selected to measure the BDNF level using enzyme-linked immunosorbent assay (ELISA). A significant decrease in the plasma BDNF level of the cases as compared to controls (p<0.0001) was observed. However, there was no evidence of the effect of the rs6265 genotypes on the BDNF level indicating a possible role of other factors in modulating the BDNF level that warrants further investigation.

    CONCLUSION: The study indicated that having the BDNF rs6265 allele (A) increase the risk of developing MDD in the Malaysian population suggesting a possible role of BDNF in the etiology of the disorder.

  18. Fulltext Predictors of recurrence of major depressive disorder
    Lye MS, Tey YY, Tor YS, Shahabudin AF, Ibrahim N, Ling KH, et al.
    PLoS One, 2020;15(3):e0230363.
    PMID: 32191745 DOI: 10.1371/journal.pone.0230363
    A total of 201 patients with major depressive disorder from four hospitals in Malaysia were followed up for 5 years to determine the prognostic factors of recurrent major depressive disorder that could potentially contribute to improving the management of MDD patients. For each individual patient, at the time of recruitment as part of a case-control study, information was collected on recent threatening life events, personality and social and occupational functioning, while blood samples were collected to genotype single nucleotide polymorphisms of vitamin D receptor (VDR), zinc transporter-3 (ZnT3), dopamine transporter-1 (DAT1), brain-derived neurotropic factor (BDNF), serotonin receptor 1A (HT1A) and 2A (HT2A) genes. Kaplan-Meier and Cox-regression were used to estimate hazard functions for recurrence of major depressive disorder. Individuals with severe MDD in previous major depressive episodes had five and a half times higher hazard of developing recurrence compared to mild and moderate MDD (HR = 5.565, 95% CI = 1.631-18.994, p = 0.006). Individuals who scored higher on social avoidance had three and a half times higher hazard of recurrence of MDD (HR = 3.525, 95% CI = 1.349-9.209; p = 0.010). There was significant interaction between ApaI +64978C>A single nucleotide polymorphism and severity. The hazard ratio increased by 6.4 times from mild and moderate to severe MDD for A/A genotype while that for C/A genotype increased by 11.3 times. Social avoidance and severity of depression at first episode were prognostic of recurrence. Screening for personality factors at first encounter with MDD patients needs to be considered as part of the clinical practice. For those at risk of recurrence in relation to social avoidance, the psychological intervention prescribed should be customized to focus on this modifiable factor. Prompt and appropriate management of severe MDD is recommended to reduce risk of recurrence.
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