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Fulltext Human health risk assessment of heavy metals in shellfish from Kudat, Sabah

Razinah Sharif, Chong, Elizabeth, Chan, Kok Meng

Malays J Nutr, 2016;22(2):301-305.
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Introduction: Shellfish is likely to be contaminated with heavy metals brought about by various environmental factors such as climate change, bioaccumulation of environmental contaminants and imbalanced natural ecosystem.

Methods: Shellfish were selected for heavy metal detection as they are mainly consumed by the locals in Kudat. Arsenic, Cadmium, Chromium, Nickel, and Plumbum (As, Cd, Cr, Ni, and Pb) content in clam (Meretrix spp.), scallop (Amusium pleuronectes) and conch (Strombus canabrium) were determined by the US EPA 200.3 acid digestion method and Inductively Coupled Plasma Mass Spectrophotometer (ICP-MS). Risk assessment was calculated to assess the total exposure of heavy metals among the population of Kudat.

Results: Among all the heavy metals, studied, As was found to have the highest concentration and this was found in scallop with the concentration level being 18.93±5.30 μg/g compared to clam and conch. Estimated daily intake of the heavy metals by the population ranged from 0.60-6.82 g/ day/ kg for As, 0.02-1.58μg/day/kg for Cd, 0.37-0.94μg/day/kg for Cr, 0.16-0.61 g/day/ kg for Ni and 0.10-0.25μg/day/kg for Pb based on previous calculation to exposure. The hazard quotient of As and Cd in scallop was greater than 1.0. No acceptable exposure level for these shellfish has been previously reported. The rate of consumption of these metals did not exceed the standards prescribed in the Food Act 1983 and Food Regulations 1985.

Conclusion: Based on this study, it is concluded that the exposure to heavy metals risk from the consumption of these shellfish among the population in Kudat, Sabah is at an acceptable level.
Fulltext Macronutrients content of red seaweed kappaphycus alvarezii and kappaphycus striatum

Chan, Kok Meng, Farah Diyana Ariffin, Aminah Abdullah, Shahrul Hisham Zainal Ariffin

Jurnal Sains Kesihatan Malaysia, 2017;15(2):19-27.
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Seaweed contains various nutrients that has the potential to be a source of nutritious food, but only a few studies done on
the red seaweeds in Malaysia. Therefore, this study was conducted to determine the macronutrients content, amino acid
profile and fatty acid component in Kappaphycus alvarezii and Kappaphycus striatum. The study found that the range
of moisture, fat, ash, protein, fiber and carbohydrates content for both red seaweeds were 6.9% - 7.3%, 0.5% - 2.6%,
29.4% - 30.9%, 2.5% - 5.7% , 5.3% - 5.5% and 50.1% - 53.3% respectively. A total of 16 amino acids were identified
in which the essential amino acid for K. alvarezii and K. striatum were 41.11% and 36.15% respectively. A total of 34
fatty acids were identified in which the content of saturated fatty acids (SFA) was the highest (42.7% - 72.8%), followed
by mono-unsaturated fatty acid (MUFA) (13.8% - 36.2%) and polyunsaturated fatty acids (PUFAs) was the lowest (13.5%
- 21.2%). In conclusion, this study suggest that K. alvarezii and K. striatum are potentially be used as raw materials or
food ingredients to improve the nutritional value of the human diet.
Fulltext Assessment of cytotoxicity potency of paclitaxel in combination with clinacanthus nutans extracts on human MDA-MB-231 breast cancer cells

Nor Fadilah Rajab, Chan Kok Meng, Nur Hasnieza Mohd Rosli, Fariza Juliana Nordin, Leong Lek Mun, Nur Syazwani Abdul Aziz

Jurnal Sains Kesihatan Malaysia, 2018;16(101):95-103.
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ABSTRACT
Clinacanthus nutans (C. nutans) leaf extracts have been widely used by cancer patients in Malaysia and local practice claims a cure to cancer. There were several studies done to determine the cytotoxicity potency of C. nutans extracts on various types of cells. However, there is still lacking on the knowledge regarding the combination effect of C. nutans with anticancer drugs. Thus, the study was carried out to determine the cytotoxicity potency of C. nutans extracts and paclitaxel (PTX) alone and, in combination on MDA-MB-231 cells. The cells were treated with 100% ethanol extract of C. nutans (CNE) and water extract of C. nutans (CNA), PTX and combination of both extracts and PTX for 72 hours and the cytotoxic activity was determined using SRB assay. Result showed that CNE had little cytotoxic activity, whereas CNA showed no cytotoxic activity on MDA-MB-231 cells. For combination treatment of C. nutans extracts and PTX, only CNE showed significant enhanced PTX-induced cytotoxicity (p < 0.05), meanwhile CNA inhibited PTX-induced cytotoxicity significantly (p < 0.05). As a conclusion, CNE was able to increase PTX potency to inhibit the viability of MDA-MB-231 cells.
Zinc Carnosine Inhibits Lipopolysaccharide-Induced Inflammatory Mediators by Suppressing NF-κb Activation in Raw 264.7 Macrophages, Independent of the MAPKs Signaling Pathway

Ooi TC, Chan KM, Sharif R

Biol Trace Elem Res, 2016 Aug;172(2):458-464.
PMID: 26749414 DOI: 10.1007/s12011-015-0615-x

This study aimed to investigate the role of the mitogen-activated protein kinases (MAPKs) signaling pathway in the anti-inflammatory effects of zinc carnosine (ZnC) in lipopolysaccharide (LPS)-induced RAW 264.7 cells. Cells were pretreated with ZnC (0-100 μM) for 2 h prior to the addition of LPS (1 μg/ml). Following 24 h of treatment, ZnC was found not to be cytotoxic to RAW 264.7 cells up to the concentration of 100 μM. Our current findings showed that ZnC did not protect RAW 264.7 cells from LPS-induced "respiratory burst". Significant increment in intracellular glutathione (GSH) level and reduction in thiobarbituric acid reactive substances (TBARS) concentration can only be observed in cell pretreated with high doses of ZnC only (50 and 100 μM for GSH and 100 μM only for TBARS). On the other hand, pretreatment of cells with ZnC was able to inhibit LPS-induced inducible nitric oxide synthase and cyclooxygenase-2 expression significantly. Furthermore, results from immunoblotting showed that ZnC was able to suppress nuclear factor-kappaB (NF-κB) activation, and highest suppression can be observed at 100 μM of ZnC pretreatment. However, pretreatment of ZnC did not inhibit the early activation of MAPKs. In conclusion, pretreatment with ZnC was able to inhibit the expression of inflammatory mediators in LPS-induced RAW 264.7 cells, mainly via suppression of NF-κB activation, and is independent of the MAPKs signaling pathway.
Antioxidant, Anti-inflammatory, and Genomic Stability Enhancement Effects of Zinc l-carnosine: A Potential Cancer Chemopreventive Agent?

Ooi TC, Chan KM, Sharif R

Nutr Cancer, 2017 Feb-Mar;69(2):201-210.
PMID: 28094570 DOI: 10.1080/01635581.2017.1265132

Cancer is one of the major causes of death worldwide, and the incidence and mortality rates of cancer are expected to rise tremendously in the near future. Despite a better understanding of cancer biology and advancement in cancer management, current strategies in cancer treatment remain costly and ineffective. Hence, instead of putting more efforts to search for new cancer cures, attention has now been shifted to the development of cancer chemopreventive agents as a preventive measure for cancer formation. It is well known that neoplastic transformation of cells is multifactorial, and the occurrence of oxidative stress, chronic inflammation, and genomic instability events has been implicated in the carcinogenesis of cells. Zinc l-carnosine (ZnC), which is clinically used as gastric ulcer treatment in Japan, has been suggested to have the potential in preventing cancer development. Multiple studies have revealed that ZnC possesses potent antioxidant, anti-inflammatory, and genomic stability enhancement effects. Thus, this review provides some mechanistic insight into the antioxidant, anti-inflammatory, and genomic stability enhancement effects of ZnC in relevance to its chemopreventive potential.
Fulltext Anti-neuroinflammatory effects of hibiscus sabdariffa linn. (roselle) on lipopolysaccharides-induced microglia and neuroblastoma cells

Siti Masitah Musa, Munirah Ahmad Munawar, Leong, Lek Mun, Heng, Kai Yen, Farah Wahida Ibrahim, Chan, Kok Meng, et al.

Jurnal Sains Kesihatan Malaysia, 2016;14(2):111-117.
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Hibiscus sabdariffa Linn. (roselle) is a polyphenol rich fruit. This study aimed to identify the neuroprotective effect of
roselle on LPS-induced cell proliferation and nitric oxide-induced free radical in microglia and neuroblastoma cells.
MTT assay was used to identify the appropriate concentration of roselle and LPS for microglia and neuroblastoma cells
proliferation study. Griess assay were used to determine the level of nitric oxide accumulated based on the reaction of
Griess to estimate the activity of iNOS in nitric oxide production. The results showed that roselle at the concentration of
50 μg/mL and 100 μg/mL and LPS at concentration of 1 μg/mL does not give cytotoxic effect towards microglia C8-B4 and
neuroblastoma LN18 cells. The roselle treatment at 50 μg/mL and 100 μg/mL showed a protective effect on LPS-induced
microglia C8-B4 cells. However, in neuroblastoma LN18 cells, no protective effect was seen on both 50 μg/mL and 100
μg/mL of roselle treatment following induction with 1 μg/mL of LPS. On the other hand, the production of nitric oxide
(NO) was reduced when LPS-induced microglia C8-B4 cells were treated with 50 μg/mL of roselle. Treatment of roselle
at concentration 100 μg/mL on LPS-induced neuroblastoma LN18 cells also reduced the production of nitric oxide. As a
conclusion, roselle had the ability to give neuroprotective effect by the inhibition of LPS induction activity on microglia
activation for normal and cancer cells at different concentrations
Zinc L-Carnosine Protects CCD-18co Cells from L-Buthionine Sulfoximine-Induced Oxidative Stress via the Induction of Metallothionein and Superoxide Dismutase 1 Expression

Ooi TC, Chan KM, Sharif R

Biol Trace Elem Res, 2020 Mar 08.
PMID: 32146577 DOI: 10.1007/s12011-020-02108-9

Zinc L-carnosine (ZnC) is the chelate form of zinc and L-carnosine and is one of the zinc supplements available in the market. This study aims to determine the protective effects of ZnC against L-buthionine sulfoximine (BSO)-induced oxidative stress in CCD-18co human normal colon fibroblast cell line. CCD-18co cells were pretreated with ZnC (0-100 μM) for 24 h before the induction of oxidative stress by BSO (1 mM) for another 24 h. Results from this present study demonstrated that ZnC up to the concentration of 100 μM was not cytotoxic to CCD-18co cells. Induction with BSO significantly increased the intracellular reactive oxygen species (ROS) levels and reduced the intracellular glutathione (GSH) levels in CCD-18co cells. Pretreatment with ZnC was able to attenuate the increment in intracellular ROS level in CCD-18co cells significantly in a concentration-dependent manner. However, ZnC did not have any effects on intracellular GSH levels and Nrf2 activation. Mechanistically, pretreatment with ZnC was able to upregulate the expression of metallothionein (MT) and superoxide dismutase 1 (SOD1) in CCD-18co cells. Results from dual-luciferase reporter gene assay reported that ZnC was able to increase the MRE-mediated relative luciferase activities in a concentration-dependent manner, suggesting that the induction of MT expression by ZnC was due to the activation of MTF-1 signaling pathway. Taken together, our current findings suggest that ZnC can protect CCD-18co cells from BSO-induced oxidative stress via the induction of MT and SOD1 expression.
Protective effects of zinc L-carnosine against hydrogen peroxide-induced DNA damage and micronucleus formation in CCD-18co human colon fibroblast cells

Ooi TC, Chan KM, Sharif R

Free Radic Res, 2020 May;54(5):330-340.
PMID: 32366187 DOI: 10.1080/10715762.2020.1763333

Zinc L-carnosine (ZnC) is a chelated compound of zinc and L-carnosine. The present study aims to determine the protective effects of ZnC against hydrogen peroxide (H2O2)-induced oxidative stress and genomic damage in CCD-18co human normal colon fibroblast cells. Generally, cells were pretreated with ZnC (0-100 µM) for 24 h before challenged with 20 µM of H2O2 for 1 h to induce oxidative damage. Results showed that pretreatment with ZnC was able to reduce the intracellular ROS level in CCD-18co cells after being challenged with H2O2. Moreover, pretreatment with ZnC demonstrated protection from H2O2-induced DNA strand breaks and micronucleus formation. Our current findings revealed that pretreatment with ZnC could induce the activation of MTF-1 signaling pathway and expression of metallothionein (MT) in a dose-dependent manner. However, ZnC did not have any effects on Nrf2 signaling pathway and the expression of glutathione, superoxide dismutase 1, and glutamate-cysteine ligase catalytic subunit (GCLC). Furthermore, pretreatment with ZnC did not induce the expression of OGG1 and PARP-1 in CCD-18co cells, suggesting that these two DNA repairing enzymes are not related to the genoprotective effects of ZnC. Since the expression of MT has been demonstrated to protect cells from oxidative DNA damage induced by various genotoxic agents, the genoprotective effects of ZnC might be due to the ability of ZnC to induce the expression of MT. In conclusion, ZnC pretreatment was able to protect CCD-18co cells from H2O2-induced genomic damage via the activation of the MTF-1 signalling pathway and the induction of MT expression.
Zinc L-carnosine suppresses inflammatory responses in lipopolysaccharide-induced RAW 264.7 murine macrophages cell line via activation of Nrf2/HO-1 signaling pathway

Ooi TC, Chan KM, Sharif R

Immunopharmacol Immunotoxicol, 2017 Oct;39(5):259-267.
PMID: 28697633 DOI: 10.1080/08923973.2017.1344987

CONTEXT: Zinc L-carnosine (ZnC) is a chelate of Zn and L-carnosine and is used clinically in the treatment of peptic ulcer.
OBJECTIVE: In this study, we aim to investigate the involvement of heme oxygenase-1 (HO-1) in the anti-inflammatory effects of ZnC in lipopolysaccharide (LPS)-induced RAW 264.7 murine macrophages.
MATERIALS AND METHODS: We used immunoblotting analysis to evaluate the involvement of HO-1 in the anti-inflammatory effects of ZnC and the signaling pathway involved was measured using Dual luciferase reporter assay.
RESULTS: Results from immunoblotting analysis demonstrated that pretreatment of cells with ZnC enhanced the expression of HO-1 in RAW 264.7 cells. Pretreatment of cells with HO-1 inhibitor (tin protoporphyrin IX dichloride) significantly attenuated the inhibitory effects of ZnC on nitric oxide (NO) production, inducible nitric oxide synthase (iNOS) expression and NF-κB activation in LPS-induced RAW 264.7 cells, suggesting that HO-1 play an important role in the suppression of inflammatory responses induced by ZnC. Furthermore, results from co-immunoprecipitation of Nrf2 and Keap1 and dual luciferase reporter assay showed that pretreatment of ZnC was able to activate the Nrf2 signaling pathway. Treatment of cells with p38 inhibitor (SB203580), c-Jun N-terminal kinase inhibitor (SP600125), and MEK 1/2 inhibitor (U0126) did not significantly suppress the induction of HO-1 by ZnC. Moreover, our present findings suggest that the effects of ZnC on NO production, HO-1 expression, and Nrf2 activation were attributed to its Zn subcomponent, but not l-carnosine.
CONCLUSION: Pretreatment with ZnC was able to activate Nrf2/HO-1 signaling pathway, thus suppressing the expression of inflammatory mediators, such as NO and iNOS in LPS-induced RAW 264.7 cells.
Fulltext Assessment of cytotoxicity and genotoxicity of stem bark extracts from Canarium odontophyllum Miq. (dabai) against HCT 116 human colorectal cancer cell line

Basri DF, Alamin ZA, Chan KM

BMC Complement Altern Med, 2016;16:36.
PMID: 26822971 DOI: 10.1186/s12906-016-1015-2

Canarium odontophyllum Miq. is a plant species widely known as 'dabai' and can be vastly found in Sarawak. The aim of this study was to assess the cytotoxic and genotoxic effect of extracts from stem bark of C. odontophyllum against HCT 116 human colorectal cancer cell line.
Fulltext Cellular Basis of Organotin(IV) Derivatives as Anticancer Metallodrugs: A Review

Syed Annuar SN, Kamaludin NF, Awang N, Chan KM

Front Chem, 2021;9:657599.
PMID: 34368075 DOI: 10.3389/fchem.2021.657599

Organotin(IV) compounds have wide applications in industrial and agricultural fields owing to their ability to act as poly(vinyl chloride) stabilizers and catalytic agents as well as their medicinal properties. Moreover, organotin(IV) compounds may have applications as antitumor, anti-inflammatory, antifungal, or antimicrobial agents based on the observation of synergistic effects following the binding of their respective ligands, resulting in the enhancement of their biological activities. In this review, we describe the antiproliferative activities of organotin(IV) compounds in various human cancer cell lines based on different types of ligands. We also discuss the molecular mechanisms through which organotin(IV) compounds induce cell death via apoptosis through the mitochondrial intrinsic pathway. Finally, we present the mechanisms of cell cycle arrest induced by organotin(IV) compounds. Our report provides a basis for studies of the antitumor activities of organotin(IV) compounds and highlights the potential applications of these compounds as anticancer metallodrugs with low toxicity and few side effects.
Fulltext Inhibitory effects of compounds from Phyllanthus amarus on nitric oxide production, lymphocyte proliferation, and cytokine release from phagocytes

Yuandani, Jantan I, Ilangkovan M, Husain K, Chan KM

Drug Des Devel Ther, 2016;10:1935-45.
PMID: 27354767 DOI: 10.2147/DDDT.S105651

Standardized extract of Phyllanthus amarus has previously been shown to have a strong inhibitory effect on phagocytic activity of human neutrophils. The current study was carried out to evaluate the effects of constituents of the extract of P. amarus on nitric oxide (NO) production as well as lymphocyte proliferation and cytokine release from phagocytes. Three compounds, ethyl 8-hydroxy-8-methyl-tridecanoate, 7β,19α dihydroxy-urs-12-ene, and 1,7,8-trihydroxy-2-naphtaldehyde, together with seven known compounds were isolated from the whole plant of P. amarus. The isolated compounds and reference standards, ie, gallic acid, ellagic acid, corilagin, and geraniin, which were quantitatively analyzed in the extracts, were evaluated for their effects on immune cells. Among the compounds tested, the lignans, especially phyltetralin and phyllanthin, showed strong inhibition on lymphocyte proliferation with half maximal inhibitory concentration (IC50) values of 1.07 μM and 1.82 μM, respectively. Ethyl 8-hydroxy-8-methyl-tridecanoate and 1,7,8-trihydroxy-2-naphtaldehyde exhibited strong inhibition on nitric oxide production with IC50 values of 0.91 μM and 1.07 μM, respectively. Of all the compounds, corilagin was the strongest inhibitor of tumor necrosis factor-α release with an IC50 value of 7.39 μM, whereas geraniin depicted the strongest inhibitory activity on interleukin-1β release with an IC50 value of 16.41 μM. The compounds constituting the extract of P. amarus were able to inhibit the innate immune response of phagocytes at different steps.
Fulltext Cytoprotective effects of (E)-N-(2-(3, 5-dimethoxystyryl) phenyl) furan-2-carboxamide (BK3C231) against 4-nitroquinoline 1-oxide-induced damage in CCD-18Co human colon fibroblast cells

Tan HH, Thomas NF, Inayat-Hussain SH, Chan KM

PLoS One, 2020;15(5):e0223344.
PMID: 32365104 DOI: 10.1371/journal.pone.0223344

Stilbenes are a group of chemicals characterized with the presence of 1,2-diphenylethylene. Previously, our group has demonstrated that synthesized (E)-N-(2-(3, 5-dimethoxystyryl) phenyl) furan-2-carboxamide (BK3C231) possesses potential chemopreventive activity specifically inducing NAD(P)H:quinone oxidoreductase 1 (NQO1) protein expression and activity. In this study, the cytoprotective effects of BK3C231 on cellular DNA and mitochondria were investigated in normal human colon fibroblast, CCD-18Co cells. The cells were pretreated with BK3C231 prior to exposure to the carcinogen 4-nitroquinoline 1-oxide (4NQO). BK3C231 was able to inhibit 4NQO-induced cytotoxicity. Cells treated with 4NQO alone caused high level of DNA and mitochondrial damages. However, pretreatment with BK3C231 protected against these damages by reducing DNA strand breaks and micronucleus formation as well as decreasing losses of mitochondrial membrane potential (ΔΨm) and cardiolipin. Interestingly, our study has demonstrated that nitrosative stress instead of oxidative stress was involved in 4NQO-induced DNA and mitochondrial damages. Inhibition of 4NQO-induced nitrosative stress by BK3C231 was observed through a decrease in nitric oxide (NO) level and an increase in glutathione (GSH) level. These new findings elucidate the cytoprotective potential of BK3C231 in human colon fibroblast CCD-18Co cell model which warrants further investigation into its chemopreventive role.
Fulltext (E)-N-(2-(3, 5-Dimethoxystyryl) phenyl) furan-2-carboxamide (BK3C231) induces cytoprotection in CCD18-Co human colon fibroblast cells through Nrf2/ARE pathway activation

Tan HH, Thomas NF, Inayat-Hussain SH, Chan KM

Sci Rep, 2021 02 26;11(1):4773.
PMID: 33637843 DOI: 10.1038/s41598-021-83163-7

Cytoprotection involving the nuclear factor erythroid 2-related factor 2 (Nrf2)/antioxidant response element (ARE) signaling pathway is an important preventive strategy for normal cells against carcinogenesis. In our previous study, the chemopreventive potential of (E)-N-(2-(3, 5-Dimethoxystyryl) phenyl) furan-2-carboxamide (BK3C231) has been elucidated through its cytoprotective effects against DNA and mitochondrial damages in the human colon fibroblast CCD-18Co cell model. Therefore this study aimed to investigate the molecular mechanisms underlying BK3C231-induced cytoprotection and the involvement of the Nrf2/ARE pathway. The cells were pretreated with BK3C231 before exposure to carcinogen 4-nitroquinoline N-oxide (4NQO). BK3C231 increased the protein expression and activity of cytoprotective enzymes namely NAD(P)H:quinone oxidoreductase 1 (NQO1), glutathione S-transferase (GST) and heme oxygenase-1 (HO-1), as well as restoring the expression of glutamate-cysteine ligase catalytic subunit (GCLC) back to the basal level. Furthermore, dissociation of Nrf2 from its inhibitory protein, Keap1, and ARE promoter activity were upregulated in cells pretreated with BK3C231. Taken together, our findings suggest that BK3C231 exerts cytoprotection by activating the Nrf2 signaling pathway which leads to ARE-mediated upregulation of cytoprotective proteins. This study provides new mechanistic insights into BK3C231 chemopreventive activities and highlights the importance of stilbene derivatives upon development as a potential chemopreventive agent.
Lineage-related cytotoxicity and clonogenic profile of 1,4-benzoquinone-exposed hematopoietic stem and progenitor cells

Chow PW, Abdul Hamid Z, Chan KM, Inayat-Hussain SH, Rajab NF

Toxicol Appl Pharmacol, 2015 Apr 1;284(1):8-15.
PMID: 25645895 DOI: 10.1016/j.taap.2015.01.016

Hematopoietic stem cells (HSCs) and hematopoietic progenitor cells (HPCs) are sensitive targets for benzene-induced hematotoxicity and leukemogenesis. The impact of benzene exposure on the complex microenvironment of HSCs and HPCs remains elusive. This study aims to investigate the mechanism linking benzene exposure to targeting HSCs and HPCs using phenotypic and clonogenic analyses. Mouse bone marrow (BM) cells were exposed ex vivo to the benzene metabolite, 1,4-benzoquinone (1,4-BQ), for 24h. Expression of cellular surface antigens for HSC (Sca-1), myeloid (Gr-1, CD11b), and lymphoid (CD45, CD3e) populations were confirmed by flow cytometry. The clonogenicity of cells was studied using the colony-forming unit (CFU) assay for multilineage (CFU-GM and CFU-GEMM) and single-lineage (CFU-E, BFU-E, CFU-G, and CFU-M) progenitors. 1,4-BQ demonstrated concentration-dependent cytotoxicity in mouse BM cells. The percentage of apoptotic cells increased (p < 0.05) following 1,4-BQ exposure. Exposure to 1,4-BQ showed no significant effect on CD3e(+) cells but reduced the total counts of Sca-1(+), CD11b(+), Gr-1(+), and CD45(+) cells at 7 and 12 μM (p < 0.05). Furthermore, the CFU assay showed reduced (p < 0.05) clonogenicity in 1,4-BQ-treated cells. 1,4-BQ induced CFU-dependent cytotoxicity by significantly inhibiting colony growth for CFU-E, BFU-E, CFU-G, and CFU-M starting at a low concentration of exposure (5μM); whereas for the CFU-GM and CFU-GEMM, the inhibition of colony growth was remarkable only at 7 and 12μM of 1,4-BQ, respectively. Taken together, 1,4-BQ caused lineage-related cytotoxicity in mouse HPCs, demonstrating greater toxicity in single-lineage progenitors than in those of multi-lineage.
Fulltext Diorganotin(IV) derivatives of N-methyl p-fluorobenzo-hydroxamic acid: preparation, spectral characterization, X-ray diffraction studies and antitumor activity

Naqeebullah, Farina Y, Chan KM, Mun LK, Rajab NF, Ooi TC

Molecules, 2013 Jul 22;18(7):8696-711.
PMID: 23881054 DOI: 10.3390/molecules18078696

Three diorganotin(IV) complexes of the general formula R2Sn[RcC(O)N(RN)O] (Rc = aryl, RN = Alkyl) have been synthesized by refluxing in toluene the corresponding diorganotin(IV) oxides with the free ligand N-methyl p-fluorobenzohydroxamic acid, using a Dean and Stark water separator. The ligand was derived from the reaction of the corresponding p-fluorobenzoyl chloride and N-methylhydroxylamine hydrochloride in the presence of sodium hydrogen carbonate. The isolated free ligand and its respective diorganotin compounds have been characterized by elemental analysis, IR and 1H-, 13C-, 119Sn-NMR spectroscopies. The crystal structures of the diorganotin complexes have been confirmed by single crystal X-ray diffraction methods. The investigations carried out on the diorganotin(IV) complexes of N-methyl p-fluorobenzohydroxamic acid confirmed a 1:2 stoichiometry. The complex formation took place through the O,O-coordination via the carbonyl oxygen and subsequent deprotonated hydroxyl group to the tin atom. The crystal structures of three diorganotin complexes were determined and were found to adopt six coordination geometries at the tin centre with coordination to two ligand moieties.
Fulltext Goniothalamin induces coronary artery smooth muscle cells apoptosis: the p53-dependent caspase-2 activation pathway

Chan KM, Rajab NF, Siegel D, Din LB, Ross D, Inayat-Hussain SH

Toxicol. Sci., 2010 Aug;116(2):533-48.
PMID: 20498002 DOI: 10.1093/toxsci/kfq151

Goniothalamin (GN), a styryl-lactone isolated from Goniothalamus andersonii, has been demonstrated to possess antirestenostic properties by inducing apoptosis on coronary artery smooth muscle cells (CASMCs). In this study, the molecular mechanisms of GN-induced CASMCs apoptosis were further elucidated. Apoptosis assessment based on the externalization of phosphatidylserine demonstrated that GN induces CASMCs apoptosis in a concentration-dependent manner. The GN-induced DNA damage occurred with concomitant elevation of p53 as early as 2 h, demonstrating an upstream signal for apoptosis. However, the p53 elevation in GN-treated CASMCs was independent of NAD(P)H: quinone oxidoreductase 1 and Mdm-2 expression. An increase in hydrogen peroxide and reduction in free thiols confirmed the role for oxidative stress in GN treatment. Pretreatment with the pan-caspase inhibitor benzyloxycarbonyl-Val-Ala-Asp-fluoromethyl ketone (z-VAD-FMK) that significantly abrogated GN-induced CASMCs apoptosis suggested the involvement of caspase(s). The role of apical caspase-2, -8, and -9 was then investigated, and sequential activation of caspase-2 and -9 but not caspase-8 leading to downstream caspase-3 cleavage was observed in GN-treated CASMCs. Reduction of ATP level and decrease in oxygen consumption further confirmed the role of mitochondria in GN-induced apoptosis in CASMCs. The mitochondrial release of cytochrome c was seen without mitochondrial membrane potential loss and was independent of cardiolipin. These data provide insight into the mechanisms of GN-induced apoptosis, which may have important implications in the development of drug-eluting stents.
Fulltext Dendritic cells pulsed with generated tumor cell lysate from Phyllanthus amarus Schum. & Thonn. induces anti-tumor immune response

Mohamed SIA, Jantan I, Nafiah MA, Seyed MA, Chan KM

BMC Complement Altern Med, 2018 Aug 06;18(1):232.
PMID: 30081891 DOI: 10.1186/s12906-018-2296-4

BACKGROUND: Dendritic cells (DCs) are unique antigen presenting cells (APC) which play a pivotal role in immunotherapy and induction of an effective immune response against tumors. In the present study, 80% ethanol extract of Phyllanthus amarus was used to generate tumor lysate (TLY) derived from HCT 116 and MCF-7 cancer cell lines via induction of apoptosis. Monocyte-derived DCs were generated ex vivo from the adherent population of peripheral blood mononuclear cells (PBMCs). The generated TLY were used to impulse DCs to investigate its effect on their cellular immune functions including antigen presentation capacity, phagocytic activity, chemotaxis capacity, T-cell proliferation and cytokines release.
METHODS: The effect of P. amarus-generated TLY on DCs maturation was evaluated by determination of MHC class I, II and CD 11c expression as well as the co-stimulatory molecules CD 83 and 86 by using flow cytometry. The phagocytic capacity of TLY-pulsed DCs was investigated through FITC-dextran uptake by using flow cytometry. The effect on the cytokines release including IL-12, IL-6 and IL-10 was elucidated by using ELISA. The migration capacity and T cell proliferation activity of pulsed DCs were measured. The relative gene expression levels of cytokines were determined by using qRT-PCR. The major constituents of P. amarus extract were qualitatively and quantitatively analyzed by using validated reversed-phase high performance liquid chromatography (HPLC) methods.
RESULTS: P. amarus-generated TLY significantly up-regulated the expression levels of MHC class I, CD 11 c, CD 83 and 86 in pulsed DCs. The release of interleukin IL-12 and IL-6 was enhanced by TLY-DCs at a ratio of 1 DC: 3 tumor apoptotic bodies (APO), however, the release of IL-10 was suppressed. The migration ability as well as allogeneic T-cell proliferation activities of loaded DCs were significantly enhanced, but their phagocytic capacity was highly attenuated. The gene expression profiles for IL-12 and IL-6 of DCs showed increase in their mRNA gene expression in TLY pulsed DCs versus unloaded and LPS-treated only DCs.
CONCLUSION: The effect of P. amarus-generated TLY on the immune effector mechanisms of DCs verified its potential to induce an in vitro anti-tumor immune response against the recognized tumor antigen.
Fulltext In vitro toxicological assessment of gadolinium (III) chloride in V79-4 fibroblasts

Siew EL, Farris AF, Rashid N, Chan KM, Rajab NF

Genes Environ, 2020;42:22.
PMID: 32537035 DOI: 10.1186/s41021-020-00161-3

Background: Rare earth minerals of the lanthanide series are widely used in the field of medical and clinical application. Gadolinium (Gd), the most preferred rare earth mineral is frequently used as magnets, superconductors and magnetic resonance imaging (MRI) contrast agent. Increasing production of gadolinium waste, known potent toxicity of this element and lack of information on its Material Safety Data Sheet (MSDS) prompts health risk assessment on gadolinium. In this study, cytotoxicity and genotoxicity of Gadolinium (III) chloride (GdCl3) were investigated using MTT assay, Alkaline Comet assay and Micronucleus assay, respectively.
Results: Our results demonstrated that the viability of GdCl3 treated V79-4 cells was significantly (p 0.05) DNA damage both in the presence and absence of metabolic activation. However, it induced significant (p
Fulltext Immunomodulatory potential of Clinacanthus nutans extracts in the co-culture of triple-negative breast cancer cells, MDA-MB-231, and THP-1 macrophages

Nordin FJ, Pearanpan L, Chan KM, Kumolosasi E, Yong YK, Shaari K, et al.

PLoS One, 2021;16(8):e0256012.
PMID: 34379689 DOI: 10.1371/journal.pone.0256012

Triple-negative breast cancer is the main type of breast carcinoma that causes mortality among women because of the limited treatment options and high recurrence. Chronic inflammation has been linked with the tumor microenvironment (TME) in breast cancer progression. Clinacanthus nutans (CN) has gained much attention because of its anticancer properties, but its mechanism remains unclear. We aimed to study the qualitative phytochemical content and elucidate the cytotoxicity effects of CN on human triple-negative breast cancer (TNBC), MDA-MB-231 and human macrophage-like cells such as THP-1 by using sulforhodamine B (SRB) assay. As highly metastatic cells, MDA-MB-231 cells can migrate to the distal position, the effect of CN on migration were also elucidated using the scratch assay. The CN effects on ameliorating chronic inflammation in TME were studied following the co-culture of MDA-MB-231/THP-1 macrophages. The cytokine expression levels of IL-6, IL-1β and tumor necrosis factor-alpha (TNF-α) were determined using ELISA assays. The results showed that both ethanolic and aqueous CN extracts contained alkaloid, phenol and tannin, flavonoid, terpenoid, glycoside and steroid. However, saponin was only found in the aqueous extract of CN. CN was not cytotoxic to both MDA-MB-231 and THP-1 cells. The ability of MDA-MB-231 to migrate was also not halted by CN treatment. However, CN ethanol extract decreased IL-6 at 25 μg/mL (p = 0.02) and 100 μg/mL (p = 0.03) but CN aqueous extract increased IL-6 expression at 50 μg/mL (p = 0.08) and 100 μg/mL (p = 0.02). IL-1β showed decreased expression after treated with CN ethanol and CN aqueous both at 25 μg/mL (p = 0.03). TNF-α were significantly decreased after CN ethanol treatment at concentration 25- (p = 0.001), 50- (p = 0.000) and 100 μg/mL (p = 0.000). CN aqueous extract slightly inhibited TNF-α at all 25-50- and 100 μg/mL (p = 0.001, p = 0.000, p = 0.000, respectively). Overall, CN acts by ameliorating the pro-inflammatory condition in the TME and may be a potential strategy for its anticancer mechanism on highly metastatic breast cancer condition. The major pathways that link both cancer and inflammation were NF-κB and STATs thus further study on the upstream and downstream pathways is needed to fully understand the mechanism of CN extracts in cooling the inflamed TME in breast cancer.

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