Displaying publications 1 - 20 of 32 in total

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  1. Fulltext Evaluation of nutritional status among a group of young Chinese adults in Kuala Lumpur, Malaysia
    Karim N, Leong SW
    Asia Pac J Clin Nutr, 2000 Jun;9(2):82-6.
    PMID: 24394392
    A nutritional status study was carried out among a group of young Chinese adults, aged between 19 and 25, in Kuala Lumpur, Malaysia. Subjects comprised 108 young adults (55 women, 53 men) who were students at two institutes of higher learning. Physical characteristics were evaluated by anthropometric measurements while food intake was determined with a 3-day food record. Blood cholesterol and triglyceride were assessed using the Reflotron analyser. Birthweight was obtained from birth certificates or by proxy. The results showed that the mean body mass index (BMI) for men and women was 21.4 ± 3.3 and 20.0 ± 2.0, respectively, indicating normal weight. Further analysis of BMI classification demonstrated that 28% of men and 39% of women were underweight, 11% of men and 2% of women were overweight while 2% of men were obese. Mean waist-to-hip ratio showed that the subjects had a low risk of developing cardiovascular disease (0.72 ± 0.03 women; 0.81 ± 0.05 men). Mean energy intake was 8841 ± 1756 kJ per day for men and 6426 ± 1567 kJ per day for women. Closer analysis of energy intake of the subjects showed that 86% of men and 91% of women were consuming below the Malaysian recommendation for energy. Nutrients found to be deficient in at least one third of women were calcium, vitamin A, niacin and iron. Mean cholesterol intake in the diet was 278.7 ± 108.7 mg in men and 207.0 ± 82.5 mg in women and there was a significant difference between genders. Blood cholesterol and triglyceride levels were 3.88 ± 0.76 mmol/L and 1.08 ± 0.33 mmol/L, respectively in men, while these levels were lower in women, 3.87 ± 0.80 mmol/L for cholesterol and 0.99 ± 0.29 mmol/L for triglyceride. A general trend of higher mean blood cholesterol and triglyceride levels was shown in adults who were born with lower birthweights.
  2. Case series of testicular adrenal rest tumours in boys with congenital adrenal hyperplasia: A single centre experience
    Karen Leong SW, Wu LL
    Med J Malaysia, 2019 02;74(1):92-93.
    PMID: 30846672
    Testicular adrenal rest tumours (TART) are aberrant adrenal tissue within the testes (1). Although benign, they can lead to obstruction of the seminiferous tubules and infertility in patients with congenital adrenal hyperplasia (CAH). We report six boys who developed TART, a complication of CAH. Diagnosis was confirmed by ultrasound and testicular vein sampling of elevated 17-hydroxyprogesterone (17-OHP) levels. Glucocorticoids dosages were increased 1½-2 folds to suppress size of the aberrant adrenal tissues. Despite reductions in 17-OHP, the lesions remained unchanged. Three patients had testis-sparing surgery to excise the TART and to preserve normal testicular tissues.
  3. Learning to travel: reducing the health risks of study abroad opportunities
    Flaherty GT, Leong SW, Geoghegan R
    J Travel Med, 2018 01 01;25(1).
    PMID: 30239844 DOI: 10.1093/jtm/tay085
  4. Synthesis and in-vitro anti-cancer evaluations of multi-methoxylated asymmetrical diarylpentanoids as intrinsic apoptosis inducer against colorectal cancer
    Leong SW, Chia SL, Abas F, Yusoff K
    Bioorg Med Chem Lett, 2020 04 15;30(8):127065.
    PMID: 32127259 DOI: 10.1016/j.bmcl.2020.127065
    In the present study, a series of nine stable 3,4,5-methoxylphenyl-containing asymmetrical diarylpentanoids, derivatives of curcuminoids, have been synthesized, characterized and evaluated for their in-vitro anti-cancer potential against a panel of BRAF- and KRAS-mutated colorectal cancer cell lines including T84, LoVo and SW620, HT29, RKO and NCI-H508, respectively. Structure-activity relationship study on cytotoxicity of tested compounds suggested that the presence of meta-hydroxyl and adjacent dimethoxyl groups are crucial for enhanced cytotoxicity of diarylpentanoids. Among the evaluated analogs, 8 has been identified as the lead compound due to its highest chemotherapeutic index of 9.9 and nano molar scale cytotoxicity against SW620 and RKO. Colonies formation and cell cycle analyses on 8-treated RKO cells showed that 8 exhibits strong anti-proliferative activity by inducing G2/M-phase cell arrest. Subsequent flow cytometry based annexin-V and DCFHDA studies suggested that 8 could induce apoptosis through intracellular ROS-dependent pathway. Further Western blot studies confirmed that 8 has induced intrinsic apoptosis in RKO cells through the up-regulations of Bad and Bax pro-apoptotic proteins and down-regulations of Bcl-2 and Bcl-xL pro-survival proteins. In all, the present results suggest that 8 could be a potent lead which deserves further modification and investigation in the development of small molecule-based anti-colorectal cancer agents.
  5. In vitro and in silico evaluations of diarylpentanoid series as α-glucosidase inhibitor
    Leong SW, Abas F, Lam KW, Yusoff K
    Bioorg Med Chem Lett, 2018 02 01;28(3):302-309.
    PMID: 29292226 DOI: 10.1016/j.bmcl.2017.12.048
    A series of thirty-four diarylpentanoids derivatives were synthesized and evaluated for their α-glucosidase inhibitory activity. Eleven compounds (19, 20, 21, 24, 27, 28, 29, 31, 32, 33 and 34) were found to significantly inhibit α-glucosidase in which compounds 28, 31 and 32 demonstrated the highest activity with IC50 values ranging from 14.1 to 15.1 µM. Structure-activity comparison shows that multiple hydroxy groups are essential for α-glucosidase inhibitory activity. Meanwhile, 3,4-dihydroxyphenyl and furanyl moieties were found to be crucial in improving α-glucosidase inhibition. Molecular docking analyses further confirmed the critical role of both 3,4-dihydroxyphenyl and furanyl moieties as they bound to α-glucosidase active site in different mode. Overall result suggests that diarylpentanoids with both five membered heterocyclic ring and polyhydroxyphenyl moiety could be a new lead design in the search of novel α-glucosidase inhibitor.
  6. Asymmetrical meta-methoxylated diarylpentanoids: Rational design, synthesis and anti-cancer evaluation in-vitro
    Leong SW, Chia SL, Abas F, Yusoff K
    Eur J Med Chem, 2018 Sep 05;157:716-728.
    PMID: 30138803 DOI: 10.1016/j.ejmech.2018.08.039
    In the present study, a series of forty-five asymmetrical meta-methoxylated diarylpentanoids have been synthesized, characterized and evaluated for their in-vitro anti-cancer potential. Among the forty-five analogs, three compounds (20, 33 and 42) have been identified as lead compounds due to their excellent inhibition against five human cancer cell lines including SW620, A549, EJ28, HT1080 and MCF-7. Structure-activity relationship study on cytotoxicity of tested compounds suggested that the presence of meta-oxygenated phenyl ring played a critical role in enhancing their cytotoxic effects. Compounds 33 and 42 in particular, exhibited strongest cytotoxicity against tested cell lines with the IC50 values ranging from 1.1 to 4.3 μM. Subsequent colony formation assay on SW620 cell line showed that both compounds 33 and 42 possessed strong anti-proliferative activity. In addition, flow cytometry based experiments revealed that these compounds could trigger intracellular ROS production thus inducing G2/M-phase cell arrest and apoptosis. All these results suggested that poly meta-oxygenated diarylpentnoid is a promising scaffold which deserved further modification and investigation in the development of natural product-based anti-cancer drug.
  7. Integration of molecular dynamics simulation and hotspot residues grafting for de novo scFv design against Salmonella Typhi TolC protein
    Leong SW, Lim TS, Ismail A, Choong YS
    J. Mol. Recognit., 2018 05;31(5):e2695.
    PMID: 29230887 DOI: 10.1002/jmr.2695
    With the development of de novo binders for protein targets from non-related scaffolds, many possibilities for therapeutics and diagnostics have been created. In this study, we described the use of de novo design approach to create single-chain fragment variable (scFv) for Salmonella enterica subspecies enterica serovar Typhi TolC protein. Typhoid fever is a global health concern in developing and underdeveloped countries. Rapid typhoid diagnostics will improve disease management and therapy. In this work, molecular dynamics simulation was first performed on a homology model of TolC protein in POPE membrane bilayer to obtain the central structure that was subsequently used as the target for scFv design. Potential hotspot residues capable of anchoring the binders to the target were identified by docking "disembodied" amino acid residues against TolC surface. Next, scFv scaffolds were selected from Protein Data Bank to harbor the computed hotspot residues. The hotspot residues were then incorporated into the scFv scaffold complementarity determining regions. The designs recapitulated binding energy, shape complementarity, and interface surface area of natural protein-antibody interfaces. This approach has yielded 5 designs with high binding affinity against TolC that may be beneficial for the future development of antigen-based detection agents for typhoid diagnostics.
  8. Fulltext In-Vitro and In-Silico Evaluations of Heterocyclic-Containing Diarylpentanoids as Bcl-2 Inhibitors Against LoVo Colorectal Cancer Cells
    Leong SW, Chia SL, Abas F, Yusoff K
    Molecules, 2020 Aug 26;25(17).
    PMID: 32858795 DOI: 10.3390/molecules25173877
    In the present study, we investigated the in-vitro anti-cancer potential of six diarylpentanoids against a panel of BRAF- and KRAS-mutated colorectal cancer cell lines including T84, SW620, LoVo, HT29, NCI-H508, RKO, and LS411N cells. Structure-activity relationship study suggested that the insertions of tetrahydro-4H-thiopyran-4-one and brominated phenyl moieties are essential for better cytotoxicity. Among the evaluated analogs, 2e has been identified as the lead compound due to its low IC50 values of approximately 1 µM across all cancer cell lines and high chemotherapeutic index of 7.1. Anti-proliferative studies on LoVo cells showed that 2e could inhibit cell proliferation and colony formations by inducing G2/M cell cycle arrest. Subsequent cell apoptosis assay confirmed that 2e is a Bcl-2 inhibitor that could induce intrinsic cell apoptosis by creating a cellular redox imbalance through its direct inhibition on the Bcl-2 protein. Further molecular docking studies revealed that the bromophenyl moieties of 2e could interact with the Bcl-2 surface pocket through hydrophobic interaction, while the tetrahydro-4H-thiopyran-4-one fragment could form additional Pi-sulfur and Pi-alkyl interactions in the same binding site. In all, the present results suggest that 2e could be a potent lead that deserves further modification and investigation in the development of a new Bcl-2 inhibitor.
  9. Fulltext Assembly and stability of Salmonella enterica ser. Typhi TolC protein in POPE and DMPE
    Leong SW, Lim TS, Tye GJ, Ismail A, Aziah I, Choong YS
    J Biol Phys, 2014 Sep;40(4):387-400.
    PMID: 25011632 DOI: 10.1007/s10867-014-9357-9
    In this work we assessed the suitability of two different lipid membranes for the simulation of a TolC protein from Salmonella enterica serovar Typhi. The TolC protein family is found in many pathogenic Gram-negative bacteria including Vibrio cholera and Pseudomonas aeruginosa and acts as an outer membrane channel for expulsion of drug and toxin from the cell. In S. typhi, the causative agent for typhoid fever, the TolC outer membrane protein is an antigen for the pathogen. The lipid environment is an important modulator of membrane protein structure and function. We evaluated the conformation of the TolC protein in the presence of DMPE and POPE bilayers using molecular dynamics simulation. The S. typhi TolC protein exhibited similar conformational dynamics to TolC and its homologues. Conformational flexibility of the protein is seen in the C-terminal, extracellular loops, and α-helical region. Despite differences in the two lipids, significant similarities in the motion of the protein in POPE and DMPE were observed, including the rotational motion of the C-terminal residues and the partially open extracellular loops. However, analysis of the trajectories demonstrated effects of hydrophobic matching of the TolC protein in the membrane, particularly in the lengthening of the lipids and subtle movements of the protein's β-barrel towards the lower leaflet in DMPE. The study exhibited the use of molecular dynamics simulation in revealing the differential effect of membrane proteins and lipids on each other. In this study, POPE is potentially a more suitable model for future simulation of the S. typhi TolC protein.
  10. 2-Benzoyl-6-benzylidenecyclohexanone analogs as potent dual inhibitors of acetylcholinesterase and butyrylcholinesterase
    Leong SW, Abas F, Lam KW, Shaari K, Lajis NH
    Bioorg Med Chem, 2016 08 15;24(16):3742-51.
    PMID: 27328658 DOI: 10.1016/j.bmc.2016.06.016
    In the present study, a series of 2-benzoyl-6-benzylidenecyclohexanone analogs have been synthesized and evaluated for their anti-cholinesterase activity. Among the forty-one analogs, four compounds (38, 39, 40 and 41) have been identified as lead compounds due to their highest inhibition on both AChE and BChE activities. Compounds 39 and 40 in particular exhibited highest inhibition on both AChE and BChE with IC50 values of 1.6μM and 0.6μM, respectively. Further structure-activity relationship study suggested that presence of a long-chain heterocyclic in one of the rings played a critical role in the dual enzymes' inhibition. The Lineweaver-Burk plots and docking results suggest that both compounds could simultaneously bind to the PAS and CAS regions of the enzyme. ADMET analysis further confirmed the therapeutic potential of both compounds based upon their high BBB-penetrating. Thus, 2-benzoyl-6-benzylidenecyclohexanone containing long-chain heterocyclic amine analogs represent a new class of cholinesterase inhibitor, which deserve further investigation for their development into therapeutic agents for cognitive diseases such as Alzheimer.
  11. Improved Fab presentation on phage surface with the use of molecular chaperone coplasmid system
    Loh Q, Leong SW, Tye GJ, Choong YS, Lim TS
    Anal Biochem, 2015 May 15;477:56-61.
    PMID: 25769419 DOI: 10.1016/j.ab.2015.02.026
    The low presentation efficiency of Fab (fragment antigen binding) fragments during phage display is largely due to the complexity of disulphide bond formation. This can result in the presentation of Fab fragments devoid of a light chain during phage display. Here we propose the use of a coplasmid system encoding several molecular chaperones (DsbA, DsbC, FkpA, and SurA) to improve Fab packaging. A comparison was done using the Fab fragment from IgG and IgD. We found that the use of the coplasmid during phage packaging was able to improve the presentation efficiency of the Fab fragment on phage surfaces. A modified version of panning using the coplasmid system was evaluated and was successful at enriching Fab binders. Therefore, the coplasmid system would be an attractive alternative for improved Fab presentation for phage display.
  12. Travellers with type 1 diabetes: questionnaire development and descriptive analysis of knowledge and practices
    Flaherty GT, Leong SW, Finn Y, Sulaiman LH, Noone C
    J Travel Med, 2020 Sep 26;27(6).
    PMID: 32634210 DOI: 10.1093/jtm/taaa110
    BACKGROUND: Little is known about the awareness of travellers with diabetes about the health effects of international travel. This study aimed to design and validate a questionnaire to examine the travel health knowledge, attitudes and practices of people living with type 1 diabetes.

    METHODS: A set of 74 items based on a conceptual framework analysis underwent revision and its content validity was established. Items were grouped into three domains. A development study was conducted to establish evidence regarding their factorial structure. A construct validation study was then conducted in which the retained items were tested in an independent sample using confirmatory factor analysis (CFA).

    RESULTS: Four factors emerged from our development study and were labelled as pre-travel preparation-insect bites, pre-travel preparation-consultation, insulin and glycaemic control and travel risk behaviour. A CFA confirmed the factorial structure identified in the development study in an independent sample. Each factor loading had a significant (P 

  13. Fulltext Cephalomannine inhibits hypoxia-induced cellular function via the suppression of APEX1/HIF-1α interaction in lung cancer
    Ullah A, Leong SW, Wang J, Wu Q, Ghauri MA, Sarwar A, et al.
    Cell Death Dis, 2021 05 14;12(5):490.
    PMID: 33990544 DOI: 10.1038/s41419-021-03771-z
    Lung cancer (LC) is one of the leading causes of cancer-related death. As one of the key features of tumor microenvironment, hypoxia conditions are associated with poor prognosis in LC patients. Upregulation of hypoxic-induced factor-1α (HIF-1α) leads to the activation of various factors that contribute to the increased drug resistance, proliferation, and migration of tumor cells. Apurinic/apyrimidinic endonuclease-1 (APEX1) is a multi-functional protein that regulates several transcription factors, including HIF-1α, that contribute to tumor growth, oxidative stress responses, and DNA damage. In this study, we explored the mechanisms underlying cell responses to hypoxia and modulation of APEX1, which regulate HIF-1α and downstream pathways. We found that hypoxia-induced APEX1/HIF-1α pathways regulate several key cellular functions, including reactive oxygen species (ROS) production, carbonic anhydrase 9 (CA9)-mediated intracellular pH, migration, and angiogenesis. Cephalomannine (CPM), a natural compound, exerted inhibitory effects in hypoxic LC cells via the inhibition of APEX1/HIF-1α interaction in vitro and in vivo. CPM can significantly inhibit cell viability, ROS production, intracellular pH, and migration in hypoxic LC cells as well as angiogenesis of HUVECs under hypoxia through the inhibition of APEX1/HIF-1α interaction. Taken together, CPM could be considered as a promising compound for LC treatment.
  14. Fulltext Lung transplantation for interstitial lung disease: evolution over three decades
    Leong SW, Bos S, Lordan JL, Nair A, Fisher AJ, Meachery G
    BMJ Open Respir Res, 2023 Feb;10(1).
    PMID: 36854571 DOI: 10.1136/bmjresp-2022-001387
    BACKGROUND: Interstitial lung disease (ILD) has emerged as the most common indication for lung transplantation globally. However, post-transplant survival varies depending on the underlying disease phenotype and comorbidities. This study aimed to describe the demographics, disease classification, outcomes and factors associated with post-transplant survival in a large single-centre cohort.

    METHODS: Data were retrospectively assessed for 284 recipients who underwent lung transplantation for ILD in our centre between 1987 and 2020. Patient characteristics and outcomes were stratified by three eras: 1987-2000, 2001-2010 and 2011-2020.

    RESULTS: Median patients' age at time of transplantation was significantly higher in the most recent decade (56 (51-61) years, p<0.0001). Recipients aged over 50 years had worse overall survival compared with younger patients (adjusted HR, aHR 2.36, 95% CI 1.55 to 3.72, p=0.0001). Better survival was seen with bilateral versus single lung transplantation in patients younger than 50 years (log-rank p=0.0195). However, this survival benefit was no longer present in patients aged over 50 years. Reduced survival was observed in fibrotic non-specific interstitial pneumonia compared with idiopathic pulmonary fibrosis, which remained the most common indication throughout (aHR 2.61, 95% CI 1.40 to 4.60, p=0.0015).

    CONCLUSION: In patients transplanted for end-stage ILD, older age and fibrotic non-specific interstitial pneumonia were associated with poorer post-transplant survival. The benefit of bilateral over single lung transplantation diminished with increasing age, suggesting that single lung transplantation might still be a feasible option in older candidates.

  15. Discovery of a novel dual functional phenylpyrazole-styryl hybrid that induces apoptotic and autophagic cell death in bladder cancer cells
    Leong SW, Wang J, Okuda KS, Su Q, Zhang Y, Abas F, et al.
    Eur J Med Chem, 2023 Apr 20;254:115335.
    PMID: 37098306 DOI: 10.1016/j.ejmech.2023.115335
    Unpleasant side effects and resistance development remained the Achilles heel of chemotherapy. Since low tumor-selectivity and monotonous effect of chemotherapy are closely related to such bottleneck, targeting tumor-selective multi-functional anticancer agents may be an ideal strategy in the search of new safer drugs. Herein, we report the discovery of compound 21, a nitro-substituted 1,5-diphenyl-3-styryl-1H-pyrazole that possesses dual functional characteristics. The 2D- and 3D-culture-based studies revealed that 21 not only could induce ROS-independent apoptotic and EGFR/AKT/mTOR-mediated autophagic cell deaths in EJ28 cells simultaneously but also has the ability in inducing cell death at both proliferating and quiescent zones of EJ28 spheroids. The molecular modelling analysis showed that 21 possesses EGFR targeting capability as it forms stable interactions in the EGFR active site. Together with its good safety profile in the zebrafish-based model, the present study showed that 21 is promising and may lead to the discovery of tumor-selective multi-functional anti-cancer agents.
  16. Fulltext Persistent Newcastle disease virus infection in bladder cancer cells is associated with putative pro-survival and anti-viral transcriptomic changes
    Chan LC, Kalyanasundram J, Leong SW, Masarudin MJ, Veerakumarasivam A, Yusoff K, et al.
    BMC Cancer, 2021 May 27;21(1):625.
    PMID: 34044804 DOI: 10.1186/s12885-021-08345-y
    BACKGROUND: Newcastle disease virus (NDV) is an oncolytic virus with excellent selectivity against cancer cells, both in vitro and in vivo. Unfortunately, prolonged in vitro NDV infection results in the development of persistent infection in the cancer cells which are then able to resist NDV-mediated oncolysis. However, the mechanism of persistency of infection remains poorly understood.

    METHODS: In this study, we established persistently NDV-infected EJ28 bladder cancer cells, designated as EJ28P. Global transcriptomic analysis was subsequently carried out by microarray analysis. Differentially expressed genes (DEGs) between EJ28 and EJ28P cells identified by the edgeR program were further analysed by Gene Set Enrichment Analysis (GSEA) and Ingenuity Pathway Analysis (IPA) analyses. In addition, the microarray data were validated by RT-qPCR.

    RESULTS: Persistently NDV-infected EJ28 bladder cancer cells were successfully established and confirmed by flow cytometry. Microarray analysis identified a total of 368 genes as differentially expressed in EJ28P cells when compared to the non-infected EJ28 cells. GSEA revealed that the Wnt/β-catenin and KRAS signalling pathways were upregulated while the TGF-β signalling pathway was downregulated. Findings from this study suggest that the upregulation of genes that are associated with cell growth, pro-survival, and anti-apoptosis may explain the survivability of EJ28P cells and the development of persistent infection of NDV.

    CONCLUSIONS: This study provides insights into the transcriptomic changes that occur and the specific signalling pathways that are potentially involved in the development and maintenance of NDV persistency of infection in bladder cancer cells. These findings warrant further investigation and is crucial towards the development of effective NDV oncolytic therapy against cancer.

  17. Fulltext Analgesic Effect of 5-(3,4-Dihydroxyphenyl)-3-hydroxy-1-(2-hydroxyphenyl)penta-2,4-dien-1-one in Experimental Animal Models of Nociception
    Kamarudin N, Hisamuddin N, Ong HM, Ahmad Azmi AF, Leong SW, Abas F, et al.
    Molecules, 2018 Aug 21;23(9).
    PMID: 30134576 DOI: 10.3390/molecules23092099
    Curcuminoids derived from turmeric rhizome have been reported to exhibit antinociceptive, antioxidant and anti-inflammatory activities. We evaluated the peripheral and central antinociceptive activities of 5-(3,4-dihydroxyphenyl)-3-hydroxy-1-(2-hydroxyphenyl)penta-2,4-dien-1-one (DHHPD), a novel synthetic curcuminoid analogue at 0.1, 0.3, 1 and 3 mg/kg (intraperitoneal), through chemical and thermal models of nociception. The effects of DHHPD on the vanilloid and glutamatergic systems were evaluated through the capsaicin- and glutamate-induced paw licking tests. Results showed that DHHPD significantly (p < 0.05) attenuated the writhing response produced by the 0.8% acetic acid injection. In addition, 1 and 3 mg/kg of DHHPD significantly (p < 0.05) reduced the licking time spent by each mouse in both phases of the 2.5% formalin test and increased the response latency of mice on the hot-plate. However, the effect produced in the latter was not reversed by naloxone, a non-selective opioid receptor antagonist. Despite this, DHHPD decreased the licking latency of mice in the capsaicin- and glutamate-induced paw licking tests in a dose response manner. In conclusion, DHHPD showed excellent peripheral and central antinociceptive activities possibly by attenuation of the synthesis and/or release of pro-inflammatory mediators in addition to modulation of the vanilloid and glutamatergic systems without an apparent effect on the opioidergic system.
  18. Metallointercalator [Ru(dppz)2(PIP)]2+ Renders BRCA Wild-Type Triple-Negative Breast Cancer Cells Hypersensitive to PARP Inhibition
    Yusoh NA, Leong SW, Chia SL, Harun SN, Rahman MBA, Vallis KA, et al.
    ACS Chem. Biol., 2020 02 21;15(2):378-387.
    PMID: 31898884 DOI: 10.1021/acschembio.9b00843
    There is a need to improve and extend the use of clinically approved poly(ADP-ribose) polymerase (PARP) inhibitors (PARPi), including for BRCA wild-type triple-negative breast cancer (TNBC). The demonstration that ruthenium(II) polypyridyl complex (RPC) metallointercalators can rapidly stall DNA replication fork progression provides the rationale for their combination alongside DNA damage response (DDR) inhibitors to achieve synergism in cancer cells. The aim of the present study was to evaluate use of the multi-intercalator [Ru(dppz)2(PIP)]2+ (dppz = dipyrido[3,2-a:2',3'-c]phenazine, PIP = (2-(phenyl)imidazo[4,5-f][1,10]phenanthroline, Ru-PIP) alongside the PARPi olaparib and NU1025. Cell proliferation and clonogenic survival assays indicated a synergistic relationship between Ru-PIP and olaparib in MDA-MB-231 TNBC and MCF7 human breast cancer cells. Strikingly, low dose Ru-PIP renders both cell lines hypersensitive to olaparib, with a >300-fold increase in olaparib potency in TNBC, the largest nongenetic PARPi enhancement effect described to date. A negligible impact on the viability of normal human fibroblasts was observed for any combination tested. Increased levels of DNA double-strand break (DSB) damage and olaparib abrogation of Ru-PIP-activated pChk1 signaling are consistent with PARPi-facilitated collapse of Ru-PIP-associated stalled replication forks. This results in enhanced G2/M cell-cycle arrest, apoptosis, and decreased cell motility for the combination treatment compared to single-agent conditions. This work establishes that an RPC metallointercalator can be combined with PARPi for potent synergy in BRCA-proficient breast cancer cells, including TNBC.
  19. Fulltext Antinociceptive activities of a novel diarylpentanoid analogue, 2-benzoyl-6-(3-bromo-4-hydroxybenzylidene)cyclohexen-1-ol, and its possible mechanisms of action in mice
    Ong HM, Azmi AFA, Leong SW, Abas F, Perimal EK, Farouk AAO, et al.
    Sci Rep, 2021 12 16;11(1):24121.
    PMID: 34916536 DOI: 10.1038/s41598-021-02961-1
    A novel synthetic compound from the 2-benzoyl-6-benzylidenecyclohexanone analogue, namely 2-benzoyl-6-(3-bromo-4-hydroxybenzylidene)cyclohexen-1-ol (BBHC), showed pronounced nitric oxide inhibition in IFN-γ/LPS-induced RAW 264.7 cells. Based on this previous finding, our present study aimed to investigate the antinociceptive effects of BBHC via chemical and thermal stimuli in vivo. The investigation of the antinociceptive activity of BBHC (0.1, 0.3, 1.0 and 3.0 mg/kg, i.p.) was initiated with 3 preliminary screening tests, then BBHC was subjected to investigate its possible involvement with excitatory neurotransmitters and opioid receptors. The potential acute toxicity of BBHC administration was also studied. Administration of BBHC significantly inhibited acetic acid-induced abdominal constrictions, formalin-induced paw licking activity and developed notable increment in the latency time. BBHC's ability to suppress capsaicin- and glutamate-induced paw licking activities, as well as to antagonise the effect of naloxone, had indicated the possible involvement of its antinociception with TRPV1, glutamate and opioid receptors, respectively. The antinociceptive activities of BBHC was not related to any sedative action and no evidence of acute toxic effect was detected. The present study showed that BBHC possessed significant peripheral and central antinociceptive activities via chemical- and thermal-induced nociceptive murine models without any locomotor alteration and acute toxicity.
  20. Flavonoid diversity and roles in the lipopolysaccharide-mediated inflammatory response of monocytes and macrophages
    Rullah K, Shamsudin NF, Koeberle A, Tham CL, Fasihi Mohd Aluwi MF, Leong SW, et al.
    Future Med Chem, 2024 Jan;16(1):75-99.
    PMID: 38205612 DOI: 10.4155/fmc-2023-0174
    Targeting lipopolysaccharide (LPS)/toll-like receptor 4 signaling in mononuclear phagocytes has been explored for the treatment of inflammation and inflammation-related disorders. However, only a few key targets have been translated into clinical applications. Flavonoids, a class of ubiquitous plant secondary metabolites, possess a privileged scaffold which serves as a valuable template for designing pharmacologically active compounds directed against diseases with inflammatory components. This perspective provides a general overview of the diversity of flavonoids and their multifaceted mechanisms that interfere with LPS-induced signaling in monocytes and macrophages. Focus is placed on flavonoids targeting MD-2, IκB kinases, c-Jun N-terminal kinases, extracellular signal-regulated kinase, p38 MAPK and PI3K/Akt or modulating LPS-related gene expression.
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