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Fulltext Preliminary study on the occurrence of pten and PIK3CA gene mutations in endometrial cancer among Malaysian women

Subramaniam, K.S., Wong, M.S., Woo, Y.L., Mat Adenan, N.A., Mohamed, Z., Chung, I., et al.

JUMMEC, 2013;16(1):1-5.
MyJurnal

Genetic mutations in endometrial cancer (EC) have been extensively studied in the Western population but not much in Asian cohorts. This study has demonstrated that PTEN and PIK3CA mutations are commonly found in EC among Malaysian women. Following RNA extraction from 20 cancerous and 18 non-cancerous tissues, the presence of mutations in 9 exons of PTEN and 3 exons of PIK3CA genes were detected using real-time PCR, accompanied by High Resolution Melt (HRM) analysis. Sequencing confirmed specificity of each PCR product. The mutations for both genes were detected in the samples with varying frequencies. Notably, all samples expressed mutation of PTEN at exon 7 but none in exon 4. Further analysis demonstrated that strong concurrent mutations occurred between exons 7 of PTEN with exon 20 region 1 of PIK3CA gene (90%). Our data showed mutations are present in EC and not the non-cancerous tissues. Larger samples are being collected to validate this observation.
Mixed Oleic Acid-Erucic Acid Liposomes as a Carrier for Anticancer Drugs

Eh Suk VR, Chung I, Misran M

Curr Drug Deliv, 2020;17(4):292-302.
PMID: 32039684 DOI: 10.2174/1567201817666200210122933

BACKGROUND: Liposomes are mostly known to be prepared from phospholipids and lipids and have a remarkable capacity to encapsulate both lipophobic and lipophilic molecules. However, there is little research on developing fatty acid liposomes for chemotherapy.
OBJECTIVE: We have successfully prepared mixed fatty acid liposomes from two monounsaturated fatty acids, namely oleic acid and erucic acid, which stabilised by DOPEPEG2000. The Critical Vesicular Concentration (CVC) of liposomes was found to be within 0.09 to 0.21 mmol dm-3, with an average particle size of 400 nm.
METHODS: Encapsulation of various anticancer drugs such as folinic acid, methotrexate, doxorubicin, or irinotecan resulted in Encapsulation Efficiency (%EE) of up to 90%. Using a 3-(4, 5-dimethylthiazol-2- yl)-2,5-diphenyltetrazolium bromide (MTT) assay, the median Inhibitory Concentration (IC50) values of mixed oleic acid-erucic acid encapsulating hydrophilic drugs was remarkably reduced at the end of 24 hours of incubation with the human lung carcinoma cell line A549.
RESULTS: The results suggest that mixed oleic acid-erucic acid liposomes are a potential new approach to further develop as an alternative vehicle of various drugs for cancer treatment.
microRNA-548m suppresses cell migration and invasion by targeting aryl hydrocarbon receptor in breast cancer cells

Nor WMFSBW, Chung I, Said NABM

Oncol Res, 2020 Oct 27.
PMID: 33109304 DOI: 10.3727/096504020X16037933185170

Breast cancer is the most commonly diagnosed cancer among women and one of the leading causes of cancer mortality worldwide, in which the most severe form happens when it metastasizes to other regions of the body. Metastasis is responsible for most treatment failures in advanced breast cancer. Epithelial-mesenchymal transition (EMT) plays a significant role in promoting metastatic processes in breast cancer. MicroRNAs (miRNAs) are highly conserved endogenous short non-coding RNAs that play a role in regulating a broad range of biological processes, including cancer initiation and development, by functioning as tumor promoters or tumor suppressors. Expression of miR-548m has been found in various types of cancers, but the biological function and molecular mechanisms of miR-548m in cancers have not been fully studied. Here, we demonstrated the role of miR-548m in modulating EMT in the breast cancer cell lines MDA-MB-231 and MCF-7. Expression data for primary breast cancer obtained from NCBI GEO datasets showed that miR-548m expression was downregulated in breast cancer patients compared with healthy group. We hypothesize that miR-548m acts as a tumor suppressor in breast cancer. Overexpression of miR-548m in both cell lines increased E-cadherin expression and decreased the EMT-associated transcription factors SNAI1, SNAI2, ZEB1 and ZEB2, as well as MMP9 expression. Consequently, migration and invasion capabilities of both MDA-MB-231 and MCF-7 cells were significantly inhibited in miR-548m-overexpressing cells. Analysis of 1059 putative target genes of miR-548m revealed common pathways involving both tight junction and the mTOR signaling pathway, which has potential impacts on cell migration and invasion. Furthermore, this study identified aryl hydrocarbon receptor (AHR) as a direct target of miR-548m in breast cancer cells. Taken together, our findings suggest a novel function of miR-548m in reversing the EMT of breast cancer by reducing their migratory and invasive potentials, at least in part via targeting AHR expression.
Annonacin Exerts Antitumor Activity through Induction of Apoptosis and Extracellular Signal-regulated Kinase Inhibition

Yap CV, Subramaniam KS, Khor SW, Chung I

Pharmacognosy Res, 2017 Oct-Dec;9(4):378-383.
PMID: 29263632 DOI: 10.4103/pr.pr_19_17

Background: Endometrial cancer (EC) is the most common gynecologic malignancy in developed countries. Annonacin, a natural pure compound extracted from the seeds of Annona muricata, is a potential alternative therapeutic agent to treat EC.

Objective: To study the antitumor activity of annonacin and its mechanism of action in EC cells (ECCs).

Materials and Methods: Viability of ECCs treated with annonacin for 72 h was determined using methyl thiazolyl tetrazolium assay. The induction of cell cycle arrest and apoptotic cell death was evaluated using propidium iodide and annexin V-PE/7-AAD assay, respectively. DNA strand breaks were visualized using transferase dUTP nick end labeling assay, and the effects of annonacin on survival signaling were determined using western blotting.

Results: Annonacin exhibited antiproliferative effects on EC cell lines (ECC-1 and HEC-1A) and primary cells (EC6-ept and EC14-ept) with EC50values ranging from 4.62 to 4.92 μg/ml. EC cells were shown arrested at G2/M phase after treated with 4 μg/ml of annonacin for 72 h. This led to a significant increase in apoptotic cell death (65.7%) in these cells when compared to vehicle-treated cells (P < 0.005). We further showed that annonacin-mediated apoptotic cell death was associated with an increase in caspase-3 cleavage and DNA fragmentation. Cell apoptosis was accompanied with downregulation of extracellular signal-regulated kinase survival protein expression and induction of G2/M cell cycle arrest.

Conclusion: Annonacin may be a potential novel therapeutic agent for EC patients.

SUMMARY: We aimed to study the antitumor activity of annonacin and its mechanism of action in endometrial cancer cells. Annonacin exerted antiproliferation effects on both endometrial cancer cell lines and primary cells via induction of apoptosis and inhibition of extracellular signal-regulated kinase. Our data represented that annonacin could be an alternative therapeutic treatment to combat endometrial cancer. Abbreviations Used: 7-AAD: 7-Amino-Actinomycin, ATP: Adenosine diphosphate, BSA: Bovine serum albumin, DNA: Deoxyribonucleic acid, EC: Endometrial cancer, ECC-1: Endometrial cancer cell-1, EC50: Half maximal effective concentration, Ept: Epithelial, FBS: Fetal bovine serum, HEC-1A: Human endometrial carcinoma-1A, MTT: Methyl thiazolyl tetrazolium, NaCl: Sodium chloride, NADH: Nicotinamide adenine dinucleotide, RPMI 1640: Roswell Park Memorial Institute Medium, SDS: Sodium dodecyl sulfate.
Fulltext Soluble factors from stellate cells induce pancreatic cancer cell proliferation via Nrf2-activated metabolic reprogramming and ROS detoxification

Wu YS, Looi CY, Subramaniam KS, Masamune A, Chung I

Oncotarget, 2016 Jun 14;7(24):36719-36732.
PMID: 27167341 DOI: 10.18632/oncotarget.9165

Pancreatic stellate cells (PSC), a prominent stromal cell, contribute to the progression of pancreatic ductal adenocarcinoma (PDAC). We aim to investigate the mechanisms by which PSC promote cell proliferation in PDAC cell lines, BxPC-3 and AsPC-1. PSC-conditioned media (PSC-CM) induced proliferation of these cells in a dose- and time-dependent manner. Nrf2 protein was upregulated and subsequently, its transcriptional activity was increased with greater DNA binding activity and transcription of target genes. Downregulation of Nrf2 led to suppression of PSC-CM activity in BxPC-3, but not in AsPC-1 cells. However, overexpression of Nrf2 alone resulted in increased cell proliferation in both cell lines, and treatment with PSC-CM further enhanced this effect. Activation of Nrf2 pathway resulted in upregulation of metabolic genes involved in pentose phosphate pathway, glutaminolysis and glutathione biosynthesis. Downregulation and inhibition of glucose-6-phosphate-dehydrogenase with siRNA and chemical approaches reduced PSC-mediated cell proliferation. Among the cytokines present in PSC-CM, stromal-derived factor-1 alpha (SDF-1α) and interleukin-6 (IL-6) activated Nrf2 pathway to induce cell proliferation in both cells, as shown with neutralization antibodies, recombinant proteins and signaling inhibitors. Taken together, SDF-1α and IL-6 secreted from PSC induced PDAC cell proliferation via Nrf2-activated metabolic reprogramming and ROS detoxification.
Fulltext King cobra (Ophiophagus hannah) venom L-amino acid oxidase induces apoptosis in PC-3 cells and suppresses PC-3 solid tumor growth in a tumor xenograft mouse model

Lee ML, Fung SY, Chung I, Pailoor J, Cheah SH, Tan NH

Int J Med Sci, 2014;11(6):593-601.
PMID: 24782648 DOI: 10.7150/ijms.8096

King cobra (Ophiophagus hannah) venom L-amino acid oxidase (OH-LAAO), a heat stable enzyme, has been shown to exhibit very potent anti-proliferative activity against human breast and lung tumorigenic cells but not in their non-tumorigenic counterparts. We further examine its in vitro and in vivo anti-tumor activity in a human prostate adenocarcinoma (PC-3) model. OH-LAAO demonstrated potent cytotoxicity against PC-3 cells with IC50 of 0.05 µg/mL after 72 h incubation in vitro. It induced apoptosis as evidenced with an increase in caspase-3/7 cleavages and an increase in annexin V-stained cells. To examine its in vivo anti-tumor activity, we treated PC-3 tumor xenograft implanted subcutaneously in immunodeficient NU/NU (nude) mice with 1 µg/g OH-LAAO given intraperitoneally (i.p.). After 8 weeks of treatment, OH-LAAO treated PC-3 tumors were markedly inhibited, when compared to the control group (P <0.05). TUNEL staining analysis on the tumor sections showed a significantly increase of apoptotic cells in the LAAO-treated animals. Histological examinations of the vital organs in these two groups showed no significant differences with normal tissues, indicating no obvious tissue damage. The treatment also did not cause any significant changes on the body weight of the mice during the duration of the study. These observations suggest that OH-LAAO cytotoxic effects may be specific to tumor xenografts and less to normal organs. Given its potent anti-tumor activities shown in vitro as well as in vivo, the king cobra venom LAAO can potentially be developed to treat prostate cancer and other solid tumors.
Fulltext Antiproliferative activity of king cobra (Ophiophagus hannah) venom L-amino acid oxidase

Li Lee M, Chung I, Yee Fung S, Kanthimathi MS, Hong Tan N

Basic Clin Pharmacol Toxicol, 2014 Apr;114(4):336-43.
PMID: 24118879 DOI: 10.1111/bcpt.12155

King cobra (Ophiophagus hannah) venom L-amino acid oxidase (LAAO), a heat-stable enzyme, is an extremely potent antiproliferative agent against cancer cells when compared with LAAO isolated from other snake venoms. King cobra venom LAAO was shown to exhibit very strong antiproliferative activities against MCF-7 (human breast adenocarcinoma) and A549 (human lung adenocarcinoma) cells, with an IC50 value of 0.04±0.00 and 0.05±0.00 μg/mL, respectively, after 72-hr treatment. In comparison, its cytotoxicity was about 3-4 times lower when tested against human non-tumourigenic breast (184B5) and lung (NL 20) cells, suggesting selective antitumour activity. Furthermore, its potency in MCF-7 and A549 cell lines was greater than the effects of doxorubicin, a clinically established cancer chemotherapeutic agent, which showed an IC50 value of 0.18±0.03 and 0.63±0.21 μg/mL, respectively, against the two cell lines. The selective cytotoxic action of the LAAO was confirmed by phycoerythrin (PE) annexin V/7-amino-actinomycin (AAD) apoptotic assay, in which a significant increase in apoptotic cells was observed in LAAO-treated tumour cells than in their non-tumourigenic counterparts. The ability of LAAO to induce apoptosis in tumour cells was further demonstrated using caspase-3/7 and DNA fragmentation assays. We also determined that this enzyme may target oxidative stress in its killing of tumour cells, as its cytotoxicity was significantly reduced in the presence of catalase (a H2O2 scavenger). In view of its heat stability and selective and potent cytotoxic action on cancer cells, king cobra venom LAAO can be potentially developed for treating solid tumours.
Fulltext Antioxidant and pro-oxidant effects of oil palm (Elaeis guineensis) leaves extract in experimental diabetic nephropathy: a duration-dependent outcome

Varatharajan R, Sattar MZ, Chung I, Abdulla MA, Kassim NM, Abdullah NA

BMC Complement Altern Med, 2013;13:242.
PMID: 24074026 DOI: 10.1186/1472-6882-13-242

Catechins-rich oil palm (Elaeis guineensis) leaves extract (OPLE) is known to have antioxidant activity. Several polyphenolic compounds reported as antioxidants such as quercetin, catechins and gallic acid have been highlighted to have pro-oxidant activity at high doses. Therefore, the present study was conducted to investigate the antioxidant and pro-oxidant effects of chronically administering high dose of OPLE (1000 mg kg⁻¹) in an animal model of diabetic nephropathy (DN).
Fulltext Cancer-associated fibroblasts promote proliferation of endometrial cancer cells

Subramaniam KS, Tham ST, Mohamed Z, Woo YL, Mat Adenan NA, Chung I

PLoS One, 2013;8(7):e68923.
PMID: 23922669 DOI: 10.1371/journal.pone.0068923

Endometrial cancer is the most commonly diagnosed gynecologic malignancy worldwide; yet the tumor microenvironment, especially the fibroblast cells surrounding the cancer cells, is poorly understood. We established four primary cultures of fibroblasts from human endometrial cancer tissues (cancer-associated fibroblasts, CAFs) using antibody-conjugated magnetic bead isolation. These relatively homogenous fibroblast cultures expressed fibroblast markers (CD90, vimentin and alpha-smooth muscle actin) and hormonal (estrogen and progesterone) receptors. Conditioned media collected from CAFs induced a dose-dependent proliferation of both primary cultures and cell lines of endometrial cancer in vitro (175%) when compared to non-treated cells, in contrast to those from normal endometrial fibroblast cell line (51%) (P<0.0001). These effects were not observed in fibroblast culture derived from benign endometrial hyperplasia tissues, indicating the specificity of CAFs in affecting endometrial cancer cell proliferation. To determine the mechanism underlying the differential fibroblast effects, we compared the activation of PI3K/Akt and MAPK/Erk pathways in endometrial cancer cells following treatment with normal fibroblasts- and CAFs-conditioned media. Western blot analysis showed that the expression of both phosphorylated forms of Akt and Erk were significantly down-regulated in normal fibroblasts-treated cells, but were up-regulated/maintained in CAFs-treated cells. Treatment with specific inhibitors LY294002 and U0126 reversed the CAFs-mediated cell proliferation (P<0.0001), suggesting for a role of these pathways in modulating endometrial cancer cell proliferation. Rapamycin, which targets a downstream molecule in PI3K pathway (mTOR), also suppressed CAFs-induced cell proliferation by inducing apoptosis. Cytokine profiling analysis revealed that CAFs secrete higher levels of macrophage chemoattractant protein (MCP)-1, interleukin (IL)-6, IL-8, RANTES and vascular endothelial growth factor (VEGF) than normal fibroblasts. Our data suggests that in contrast to normal fibroblasts, CAFs may exhibit a pro-tumorigenic effect in the progression of endometrial cancer, and PI3K/Akt and MAPK/Erk signaling may represent critical regulators in how endometrial cancer cells respond to their microenvironment.
Cancer-associated fibroblasts promote endometrial cancer growth via activation of interleukin-6/STAT-3/c-Myc pathway

Subramaniam KS, Omar IS, Kwong SC, Mohamed Z, Woo YL, Mat Adenan NA, et al.

Am J Cancer Res, 2016;6(2):200-13.
PMID: 27186396

Cancer-associated fibroblasts (CAFs) secrete various pro-tumorigenic cytokines, yet the role of these cytokines in the progression of endometrial cancer remains unclear. We found that CAFs isolated from human endometrial cancer (EC) tissues secreted high levels of interleukin-6 (IL-6), which promotes EC cell proliferation in vitro. Neutralizing IL-6 in CAF-conditioned media reduced (47% inhibition) while IL-6 recombinant protein increased cell proliferation (~2.4 fold) of both EC cell lines and primary cultures. IL-6 receptors (IL-6R and gp130) were expressed only in EC epithelial cells but not in CAF, indicating a one-way paracrine signaling. In the presence of CAF-conditioned media, Janus kinase/signal transducers and activators of transcription (JAK/STAT3) pathway was activated in EC cells. Treatment with JAK and STAT3 specific inhibitors, AD412 and STATTIC, respectively, significantly abrogated CAF-mediated cell proliferation, indicating the role of IL-6 activation in EC cell proliferation. We further showed that one of STAT-3 target genes, c-Myc, was highly induced in EC cells after exposure to CAF-conditioned medium at both mRNA (>105-fold vs. control) and protein level (>2-fold vs. control). EC cell proliferation was dependent on c-Myc expression, as RNAi-mediated c-Myc down-regulation led to a significant 46% reduction in cell viability when compared with scrambled control. Interestingly, CAF-conditioned media failed to promote proliferation in EC cells with reduced c-Myc expression, suggesting that CAF-mediated cell proliferation was also dependent on c-Myc expression. Subcutaneous tumor xenograft model showed that EC cells grew at least 1.4 times larger when co-injected with CAF, when compared to those injected with EC cells alone. Mice injected with EC cells with down-regulated c-Myc expression, however, showed at least 2.5 times smaller tumor compared to those in control group. Notably, there was no increase of tumor size when co-injected with CAFs. Further immunohistochemical staining on human tissues showed positive expression of IL-6 receptors, phosphorylated-STAT3 and c-Myc in human EC tissues with less signals in benign endometrium. Taken together, our data suggests that IL-6 secreted by CAF induces c-Myc expression to promote EC proliferation in vitro and in vivo. IL-6 pathway can be a potential target to disrupt tumor-stroma interaction in endometrial cancer progression.
Fatty acid binding protein 7 mediates linoleic acid-induced cell death in triple negative breast cancer cells by modulating 13-HODE

Kwong SC, Abd Jamil AH, Rhodes A, Taib NA, Chung I

Biochimie, 2020 Dec;179:23-31.
PMID: 32931863 DOI: 10.1016/j.biochi.2020.09.005

Different fatty acids have distinct effects on the survival of breast cancer cells, which could be mediated by fatty acid binding proteins (FABPs), a family of lipid chaperones. Due to the diverse structures of the members of FABP family, each FABP demonstrates distinct binding affinities to different fatty acids. Of note, FABP7 is predominantly expressed in triple negative breast cancer (TNBC), the most aggressive subtype of breast cancer. Yet, the role of FABP7 in modulating the effects of fatty acids on TNBC survival was unclear. In contrast to the high expression of FABP7 in human TNBC tumours, FABP7 protein was undetectable in TNBC cell lines. Hence, a FABP7 overexpression model was used for this study, in which the transduced TNBC cell lines (MDA-MB-231 and Hs578T) were treated with various mono- and polyunsaturated fatty acids. Oleic acid (OA), docosahexaenoic acid (DHA) and arachidonic acid (AA) inhibited TNBC cell growth at high concentrations, with no differences resulted from FABP7 overexpression. Interestingly, overexpression of FABP7 augmented linoleic acid-induced cell death in MDA-MB-231 cells. The increased cell death may be explained by a decrease in 13-HODE, a pro-tumorigenic oxidation product of linoleic acid. The phenotype was, however, attenuated with a rescue treatment using 25 nM 13-HODE. The decrease in 13-HODE was potentially due to fatty acid partitioning modulated by FABP7, as demonstrated by a 3-fold increase in fatty acid oxidation. Our findings suggest that linoleic acid could be a potential therapeutic strategy for FABP7-overexpressing TNBC patients.
Fulltext Virtual Group Exercises and Psychological Status among Community-Dwelling Older Adults during the COVID-19 Pandemic-A Feasibility Study

Ibrahim A, Chong MC, Khoo S, Wong LP, Chung I, Tan MP

Geriatrics (Basel), 2021 Mar 22;6(1).
PMID: 33810155 DOI: 10.3390/geriatrics6010031

Social isolation, magnified by the restriction of movement order during the COVID-19 pandemic, may lead to negative psychosocial health impacts among community-dwelling older adults. We, therefore, aimed to evaluate recruitment rates, data collection, and group exercises conducted through virtual technology among individuals aged 60 years and over in Malaysia. Participants were recruited from the Promoting Independence in Seniors with Arthritis (PISA) pilot cohort through social media messaging. A four-week course of virtual group exercise was offered. Anxiety and depression were assessed with the Hospital Anxiety and Depression Scale (HADS) during the last attended follow-up of the cohort study (pre-pandemic), pre-intervention, and post-intervention. Exercise adherence was recorded using diaries with daily entries and attendance to the virtual group exercise sessions were also captured electronically daily. The outcomes of interest were changes in anxiety and depression scores from baseline to pre-intervention (pandemic-related) and post-intervention (virtual exercise related). Forty-three individuals were recruited. A significant increase in anxiety scores from baseline to pre-intervention was observed. Comparisons using repeated-measures analysis of variance between those who attendance ≥14 and <14 group exercise sessions revealed no between-within subject differences in depression scores. There was a 23% dropout rate in the post intervention survey and 60.5% of diaries were returned. Virtual group exercises could be conducted among older adults residing in a middle-income country, though recruitment would have been limited to those with internet access.
Metabolic role of fatty acid binding protein 7 in mediating triple-negative breast cancer cell death via PPAR-α signaling

Kwong SC, Jamil AHA, Rhodes A, Taib NA, Chung I

J Lipid Res, 2019 11;60(11):1807-1817.
PMID: 31484694 DOI: 10.1194/jlr.M092379

Triple-negative breast cancer (TNBC) is the most aggressive subtype of breast cancer, partly due to the lack of targeted therapy available. Cancer cells heavily reprogram their metabolism and acquire metabolic plasticity to satisfy the high-energy demand due to uncontrolled proliferation. Accumulating evidence shows that deregulated lipid metabolism affects cancer cell survival, and therefore we sought to understand the function of fatty acid binding protein 7 (FABP7), which is expressed predominantly in TNBC tissues. As FABP7 was not detected in the TNBC cell lines tested, Hs578T and MDA-MB-231 cells were transduced with lentiviral particles containing either FABP7 open reading frame or red fluorescent protein. During serum starvation, when lipids were significantly reduced, FABP7 decreased the viability of Hs578T, but not of MDA-MB-231, cells. FABP7-overexpressing Hs578T (Hs-FABP7) cells failed to efficiently utilize other available bioenergetic substrates such as glucose to sustain ATP production, which led to S/G2 phase arrest and cell death. We further showed that this metabolic phenotype was mediated by PPAR-α signaling, despite the lack of fatty acids in culture media, as Hs-FABP7 cells attempted to survive. This study provides imperative evidence of metabolic vulnerabilities driven by FABP7 via PPAR-α signaling.
Fulltext Correction to: Impact of migraine on workplace productivity and monetary loss: a study of employees in banking sector in Malaysia

Wong LP, Alias H, Bhoo-Pathy N, Chung I, Chong YC, Kalra S, et al.

J Headache Pain, 2020 Aug 18;21(1):104.
PMID: 32811428 DOI: 10.1186/s10194-020-01172-9

An amendment to this paper has been published and can be accessed via the original article.
Fulltext Therapeutic roles of natural remedies in combating hereditary ataxia: A systematic review

Phang MWL, Lew SY, Chung I, Lim WK, Lim LW, Wong KH

Chin Med, 2021 Jan 28;16(1):15.
PMID: 33509239 DOI: 10.1186/s13020-020-00414-x

BACKGROUND: Hereditary ataxia (HA) represents a group of genetically heterogeneous neurodegenerative diseases caused by dysfunction of the cerebellum or disruption of the connection between the cerebellum and other areas of the central nervous system. Phenotypic manifestation of HA includes unsteadiness of stance and gait, dysarthria, nystagmus, dysmetria and complaints of clumsiness. There are no specific treatments for HA. Management strategies provide supportive treatment to reduce symptoms.
OBJECTIVES: This systematic review aimed to identify, evaluate and summarise the published literature on the therapeutic roles of natural remedies in the treatment of HA to provide evidence for clinical practice.
METHODS: A systematic literature search was conducted using the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA). Web of Science, PubMed and Science Direct Scopus were thoroughly searched for relevant published articles from June 2007 to July 2020.
RESULTS: Ten pre-clinical and two clinical studies were eligible for inclusion in this systematic review. We identified the therapeutic roles of medicinal plants Brassica napus, Gardenia jasminoides, Gastrodia elata, Ginkgo biloba, Glycyrrhiza inflata, Paeonia lactiflora, Pueraria lobata and Rehmannia glutinosa; herbal formulations Shaoyao Gancao Tang and Zhengan Xifeng Tang; and medicinal mushroom Hericium erinaceus in the treatment of HA. In this review, we evaluated the mode of actions contributing to their therapeutic effects, including activation of the ubiquitin-proteasome system, activation of antioxidant pathways, maintenance of intracellular calcium homeostasis and regulation of chaperones. We also briefly highlighted the integral cellular signalling pathways responsible for orchestrating the mode of actions.
CONCLUSION: We reviewed the therapeutic roles of natural remedies in improving or halting the progression of HA, which warrant further study for applications into clinical practice.
Synthesis and anticancer activity of novel water soluble benzimidazole carbamates

Cheong JE, Zaffagni M, Chung I, Xu Y, Wang Y, Jernigan FE, et al.

Eur J Med Chem, 2018 Jan 20;144:372-385.
PMID: 29288939 DOI: 10.1016/j.ejmech.2017.11.037

Metastases account for more than 90% of all cancer deaths and respond poorly to most therapies. There remains an urgent need for new therapeutic modalities for the treatment of advanced metastatic cancers. The benzimidazole methylcarbamate drugs, commonly used as anti-helmitics, have been suggested to have anticancer activity, but progress has been stalled by their poor water solubility and poor suitability for systemic delivery to disseminated cancers. We synthesized and characterized the anticancer activity of novel benzimidazoles containing an oxetane or an amine group to enhance solubility. Among them, the novel oxetanyl substituted compound 18 demonstrated significant cytotoxicity toward a variety of cancer cell types including prostate, lung, and ovarian cancers with strong activity toward highly aggressive cancer lines (IC50: 0.9-3.8 μM). Compound 18 achieved aqueous solubility of 361 μM. In a mouse xenograft model of a highly metastatic human prostate cancer, compound 18 (30 mg/kg) significantly inhibited the growth of established tumors (T/C: 0.36) without noticeable toxicity.
Paracrine IL-6 signaling mediates the effects of pancreatic stellate cells on epithelial-mesenchymal transition via Stat3/Nrf2 pathway in pancreatic cancer cells

Wu YS, Chung I, Wong WF, Masamune A, Sim MS, Looi CY

Biochim Biophys Acta Gen Subj, 2017 Feb;1861(2):296-306.
PMID: 27750041 DOI: 10.1016/j.bbagen.2016.10.006

BACKGROUND: We previously showed that pancreatic stellate cells (PSC) secreted interleukin (IL)-6 and promoted pancreatic ductal adenocarcinoma (PDAC) cell proliferation via nuclear factor erythroid 2 (Nrf2)-mediated metabolic reprogramming. Epithelial-mesenchymal transition (EMT) is a key process for the metastatic cascade. To study the mechanism of PDAC progression to metastasis, we investigated the role of PSC-secreted IL-6 in activating EMT and the involvement of Nrf2 in this process.
METHODS: Gene expression of IL-6 and IL-6Rα in PSC and PDAC cells was measured with qRT-PCR. The role of PSC-secreted IL-6, JAK/Stat3 signaling, and Nrf2 mediation on EMT-related genes expression was also examined with qRT-PCR. EMT phenotypes were assessed with morphological change, wound healing, migration, and invasion.
RESULTS: PSC expressed higher mRNA levels of IL-6 but lower IL-6Rα compared to PDAC cells. Neutralizing IL-6 in PSC secretion reduced mesenchymal-like morphology, migration and invasion capacity, and mesenchymal-like gene expression of N-cadherin, vimentin, fibronectin, collagen I, Sip1, Snail, Slug, and Twist2. Inhibition of JAK/Stat3 signaling induced by IL-6 repressed EMT and Nrf2 gene expression. Induction of Nrf2 activity by tert-butylhydroquinone (tBHQ) increased both EMT phenotypes and gene expression (N-cadherin, fibronectin, Twist2, Snail, and Slug) repressed by IL-6 neutralizing antibody. Simultaneous inhibition of Nrf2 expression with siRNA and Stat3 signaling further repressed EMT gene expression, indicating that Stat3/Nrf2 pathway mediates EMT induced by IL-6.
CONCLUSIONS: IL-6 from PSC promotes EMT in PDAC cells via Stat3/Nrf2 pathway.
GENERAL SIGNIFICANCE: Targeting Stat3/Nrf2 pathway activated by PSC-secreted IL-6 may provide a novel therapeutic option to improve the prognosis of PDAC.
Corrigendum to "Aberrant upregulation of CDK1 contributes to medroxyprogesterone acetate (MPA) resistance in cancer-associated fibroblasts of the endometrium" [Biochem. Biophys. Res. Commun. 628 (2022) 133-140]

Omar IS, Mat Adenan NA, Godoy A, Teo IH, Gunasagran Y, Chung I

Biochem Biophys Res Commun, 2023 Jan 15;640:202.
PMID: 36593136 DOI: 10.1016/j.bbrc.2022.12.065
Fulltext Impact of migraine on workplace productivity and monetary loss: a study of employees in banking sector in Malaysia

Wong LP, Alias H, Bhoo-Pathy N, Chung I, Chong YC, Kalra S, et al.

J Headache Pain, 2020 Jun 08;21(1):68.
PMID: 32513174 DOI: 10.1186/s10194-020-01144-z

BACKGROUND/OBJECTIVE: Productivity and monetary loss due to migraine in the workplace may be substantial. This study aimed to determine the impact of migraine on productivity and monetary lost among employees in the banking sectors, in a multiethnic middle income country.
METHODS: A cross-sectional online survey was conducted among employees in two multinational banks in Malaysia between April and July 2019. Screening for migraine was conducted using the self-administered ID-Migraine™ questionnaire. Migraine-related disability (MIDAS) and headache frequency were recorded. Impact of migraine on work productivity and activities were evaluated using the Work Productivity and Activity Impairment (WPAI) questionnaire.
RESULTS: Of the 1268 employees who submitted complete responses, 47.2% (n = 598) were screened positive for migraine. Strikingly, the mean percent productivity loss at work (presenteeism) was almost 20-fold higher than the mean percent work time missed due to migraine (absenteeism) (39.1% versus 1.9%). The mean percent productivity loss in regular activity (activity impairment) and overall work productivity loss (work impairment) was 38.4% and 39.9%, respectively. It was also found that the costs related to presenteeism (MYR 5392.6) (US$1296) was 3.5-fold higher than absenteeism (MYR1,548.3) (US$370). Highest monetary loss related to presenteeism was reported in migraineurs with frequency of headache of above 3 days (MYR 25,691.2) (US$6176), whereas highest monetary loss related to absenteeism was reported in migraineurs with MIDAS grade IV (MYR 12,369.1) (US$2973). Only 30% of migraineurs of MIDAS grade IV reported taking prescribed medication. Notably, a vast majority (96%) of migraineurs who had three or lower episodes of migraine per month did not seek treatment.
CONCLUSION: The significant impact of migraine on work productivity and regular activity, appears to lead to substantial monetary loss attributed to not only absenteeism, but more importantly to presenteeism. This study also highlights the unmet needs in migraine management among employees in the banking sector.
Cholesterol-linoleic acid liposomes induced extracellular vesicles secretion from immortalized adipose-derived mesenchymal stem cells for in vitro cell migration

Chen JW, Liew FF, Tan HW, Misran M, Chung I

Artif Cells Nanomed Biotechnol, 2023 Dec;51(1):346-360.
PMID: 37524112 DOI: 10.1080/21691401.2023.2237534

Extracellular vesicles (EVs) are small vesicles that are naturally released by cells and play a crucial role in cell-to-cell communication, tissue repair and regeneration. As naturally secreted EVs are limited, liposomes with different physicochemical properties, such as 1,2-dioleoyl-3-trimethylammonium propane (DOTAP) and linoleic acid (LA) with modifications have been formulated to improve EVs secretion for in vitro wound healing. Various analyses, including dynamic light scattering (DLS) and transmission electron microscopy (TEM) were performed to monitor the successful preparation of different types of liposomes. The results showed that cholesterol-LA liposomes significantly improved the secretion of EVs from immortalized adipose-derived mesenchymal stem cells (AD-MSCs) by 1.5-fold. Based on the cell migration effects obtained from scratch assay, both LA liposomal-induced EVs and cholesterol-LA liposomal-induced EVs significantly enhanced the migration of human keratinocytes (HaCaT) cell line. These findings suggested that LA and cholesterol-LA liposomes that enhance EVs secretion are potentially useful and can be extended for various tissue regeneration applications.

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