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The mTOR signalling pathway in cancer and the potential mTOR inhibitory activities of natural phytochemicals

Tan HK, Moad AI, Tan ML

Asian Pac J Cancer Prev, 2014;15(16):6463-75.
PMID: 25169472

The mammalian target of rapamycin (mTOR) kinase plays an important role in regulating cell growth and cell cycle progression in response to cellular signals. It is a key regulator of cell proliferation and many upstream activators and downstream effectors of mTOR are known to be deregulated in various types of cancers. Since the mTOR signalling pathway is commonly activated in human cancers, many researchers are actively developing inhibitors that target key components in the pathway and some of these drugs are already on the market. Numerous preclinical investigations have also suggested that some herbs and natural phytochemicals, such as curcumin, resveratrol, timosaponin III, gallic acid, diosgenin, pomegranate, epigallocatechin gallate (EGCC), genistein and 3,3'-diindolylmethane inhibit the mTOR pathway either directly or indirectly. Some of these natural compounds are also in the clinical trial stage. In this review, the potential anti-cancer and chemopreventive activities and the current status of clinical trials of these phytochemicals are discussed.
14-Deoxy-11,12-didehydroandrographolide induces DDIT3-dependent endoplasmic reticulum stress-mediated autophagy in T-47D breast carcinoma cells

Tan HK, Muhammad TST, Tan ML

Toxicol Appl Pharmacol, 2016 06 01;300:55-69.
PMID: 27049118 DOI: 10.1016/j.taap.2016.03.017

14-Deoxy-11,12-didehydroandrographolide (14-DDA), a major diterpenoid isolated from Andrographis paniculata (Burm.f.) Nees, is known to be cytotoxic and elicits a non-apoptotic cell death in T-47D breast carcinoma cells. In this study, the mechanistic toxicology properties of 14-DDA in T-47D cells were further investigated. 14-DDA is found to induce the formation of endoplasmic reticulum (ER) vacuoles and autophagosomes, with concurrent upregulation of LC3-II in the breast carcinoma cells. It stimulated an increase in cytosolic calcium concentration and caused a collapse in mitochondrial membrane potential in these cells. In addition, both DDIT3 and GADD45A, molecules implicated in ER stress pathway, were significantly upregulated. DDIT3 knockdown suppressed the formation of both ER vacuoles and autophagosomes, indicating that 14-DDA-induced ER stress and autophagy is dependent on this transcription factor. Collectively, it is possible that GADD45A/p38 MAPK/DDIT3 pathway is involved in the 14-DDA-induced ER-stress-mediated autophagy in T-47D cells.
Fulltext The significance of tubular and glomerular proteinuria in critically ill patients with severe acute kidney injury

Lim CT, Tan HK, Lau YK

Pak J Med Sci, 2014 Nov-Dec;30(6):1186-90.
PMID: 25674105 DOI: 10.12669/pjms.306.5684

Critically ill patients with acute kidney injury (AKI) frequently need acute renal replacement therapy (aRRT). We evaluated an inexpensive, rapid quantitative and qualitative analysis of proteinuria on the course of AKI patients requiring aRRT in intensive care.
Trans fatty acid content in Malaysian supermarket foods: a field-to-laboratory approach in assessing food risk

Karupaiah T, Tan HK, Ong WW, Tan CH, Sundram K

Food Addit Contam Part A Chem Anal Control Expo Risk Assess, 2014;31(8):1375-84.
PMID: 24872121 DOI: 10.1080/19440049.2014.929183

The extent of industrial trans fatty acids (TFA) in the food supply is unknown in Malaysia, whilst TFA disclosure on food labels is not mandatory by Malaysian food standards. Supermarket foods such as dairy products, fats and oils, meat products, snack foods, soups, and confectionery are commonly cited to be major contributors of TFA in the diet. A consumer survey (n = 622) was used to develop a food listing of these 'high risk' foods. TFA content of high-risk foods were analysed by gas chromatography. Food samples (n = 158) were analysed and their total TFA content were compared with Malaysian Food Standards. A wide variation in TFA content within food categories was indicated. Of the foods containing TFA, many food labels did not cite TFA content or the use of partially hydrogenated vegetable oils (PHVO) as an ingredient. Hypothesised estimates of TFA intake from these supermarket foods in a sample day's menu providing 2000 kcal projected a minimum intake of 0.5 g and a maximum intake of 5.2 g TFA. This study found there was no voluntary disclosure of TFA content on food labels or identifying PHVO as an ingredient. It appears that health education targeting consumers to minimise TFA consumption is required supported by mandatory PHVO disclosure on the food label.
Variants and pitfalls in MR imaging of knee injuries

Tan HK, Bakri MM, Peh WC

Semin Musculoskelet Radiol, 2014 Feb;18(1):45-53.
PMID: 24515881 DOI: 10.1055/s-0034-1365834

MR imaging is an established tool for the detection and diagnosis of various injuries and internal derangements of the knee, enabling excellent anatomical visualization and producing good soft tissue contrast and characterization. However, numerous normal variants and potential pitfalls may lead to diagnostic errors. Understanding the basic MR imaging principles, applying the correct technique, knowing the normal anatomy and variants, recognizing artifacts, and assuring good clinical and radiographic correlation helps avoid these potential pitfalls.
Prevalence of refractive error in malay primary school children in suburban area of Kota Bharu, Kelantan, Malaysia

Hashim SE, Tan HK, Wan-Hazabbah WH, Ibrahim M

Ann Acad Med Singap, 2008 Nov;37(11):940-6.
PMID: 19082201

INTRODUCTION: Refractive error remains one of the primary causes of visual impairment in children worldwide, and the prevalence of refractive error varies widely. The objective of this study was to determine the prevalence of refractive error and study the possible associated factors inducing refractive error among primary school children of Malay ethnicity in the suburban area of Kota Bharu, Kelantan, Malaysia.
MATERIALS AND METHODS: A school-based cross-sectional study was performed from January to July 2006 by random selection on Standard 1 to Standard 6 students of 10 primary schools in the Kota Bharu district. Visual acuity assessment was measured using logMAR ETDRS chart. Positive predictive value of uncorrected visual acuity equal or worse than 20/40, was used as a cut-off point for further evaluation by automated refraction and retinoscopic refraction.
RESULTS: A total of 840 students were enumerated but only 705 were examined. The prevalence of uncorrected visual impairment was seen in 54 (7.7%) children. The main cause of the uncorrected visual impairment was refractive error which contributed to 90.7% of the total, and with 7.0% prevalence for the studied population. Myopia is the most common type of refractive error among children aged 6 to 12 years with prevalence of 5.4%, followed by hyperopia at 1.0% and astigmatism at 0.6%. A significant positive correlation was noted between myopia development with increasing age (P <0.005), more hours spent on reading books (P <0.005) and background history of siblings with glasses (P <0.005) and whose parents are of higher educational level (P <0.005). Malays in suburban Kelantan (5.4%) have the lowest prevalence of myopia compared with Malays in the metropolitan cities of Kuala Lumpur (9.2%) and Singapore (22.1%).
CONCLUSION: The ethnicity-specific prevalence rate of myopia was the lowest among Malays in Kota Bharu, followed by Kuala Lumpur, and is the highest among Singaporean Malays. Better socio-economic factors could have contributed to higher myopia rates in the cities, since the genetic background of these ethnic Malays are similar.
Fulltext Cytotoxic data of 14-deoxy-11, 12-didehydroandrographolide (14-DDA), double transfection and DDIT3 silencing data in T-47D breast carcinoma cells

Tan HK, Tengku Muhammad TS, Tan ML

Data Brief, 2016 Jun;7:1506-10.
PMID: 27182548 DOI: 10.1016/j.dib.2016.04.046

The data presented in this article are related to the research article entitled "14-deoxy-11,12-didehydroandrographolide induces DDIT3-dependent endoplasmic reticulum stress-mediated autophagy in T-47D breast carcinoma cells", which the mechanistic toxicology properties of 14-deoxy-11,12-didehydroandrographolide (14-DDA) were investigated (Tan et al., 2016 [1]). This article describes the derivation of cytotoxic parameters of 14-DDA, cell viability data after double transfection and DDIT3 silencing in T-47D cells.
Identification of genes involved in the regulation of 14-deoxy-11,12-didehydroandrographolide-induced toxicity in T-47D mammary cells

Tan ML, Tan HK, Oon CE, Kuroyanagi M, Muhammad TS

Food Chem Toxicol, 2012 Feb;50(2):431-44.
PMID: 22101062 DOI: 10.1016/j.fct.2011.11.001

14-Deoxy-11,12-didehydroandrographolide is one of the principle compounds of the medicinal plant, Andrographis paniculata Nees. This study explored the mechanisms of 14-deoxy-11,12-didehydroandrographolide-induced toxicity and non-apoptotic cell death in T-47D breast carcinoma cells. Gene expression analysis revealed that 14-deoxy-11,12-didehydroandrographolide exerted its cytotoxic effects by regulating genes that inhibit the cell cycle or promote cell cycle arrest. This compound regulated genes that are known to reduce/inhibit cell proliferation, induce growth arrest and suppress cell growth. The growth suppression activities of this compound were demonstrated by a downregulation of several genes normally found to be over-expressed in cancers. Microscopic analysis revealed positive monodansylcadaverine (MDC) staining at 8h, indicating possible autophagosomes. TEM analysis revealed that the treated cells were highly vacuolated, thereby suggesting that 14-deoxy-11,12-didehydroandrographolide may cause autophagic morphology in these cells. This morphology may be correlated with the concurrent expression of genes known to affect lysosomal activity, ion transport, protein degradation and vesicle transport. Interestingly, some apoptotic-like bodies were found, and these bodies contained multiple large vacuoles, suggesting that this compound is capable of eliciting a combination of apoptotic and autophagic-like morphological characteristics.
Determination of CYP3A4 Inducing Properties of Compounds Using a Laboratory-Developed Cell-Based Assay

Seah TC, Tay YL, Tan HK, Muhammad TS, Wahab HA, Tan ML

Int J Toxicol, 2015 08 12;34(5):454-68.
PMID: 26268769 DOI: 10.1177/1091581815599335

A cell-based assay to measure cytochrome P450 3A4 (CYP3A4) induction was developed to screen for potential CYP3A4 inducers. This 96-well format assay utilizes HepG2 cells transfected with a gene construct of CYP3A4 proximal promoter linked to green fluorescence protein (GFP) gene, and the expression of the GFP is then measured quantitatively. Bergamottin at 5 to 25 µmol/L produced low induction relative to the positive control. Both curcumin and lycopene were not found to affect the expression of GFP, suggesting no induction properties toward CYP3A4. Interestingly, resveratrol produced significant induction from 25 µmol/L onward, which was similar to omeprazole and may warrant further studies. In conclusion, the present study demonstrated that this cell-based assay can be used as a tool to evaluate the potential CYP3A4 induction properties of compounds. However, molecular docking data have not provided satisfactory pointers to differentiate between CYP3A4 inducers from noninducers or from inhibitors, more comprehensive molecular screening may be indicated.
Fulltext Use of a Novel Anti-Infective Noble Metal Alloy-Coated Titanium Orthopedic Nail in Patients with Open Fractures: A Case Series from Malaysia

Karupiah T, Yong AP, Ong ZW, Tan HK, Tang WC, Salam HB

Antibiotics (Basel), 2022 Dec 07;11(12).
PMID: 36551422 DOI: 10.3390/antibiotics11121763

Fracture-related infection is a serious complication in orthopedic surgery with severe consequences for the patient. We evaluated whether a novel noble metal nail-coating technology can prevent bacterial adhesion and biofilm formation without interfering with bony union. In this retrospective, single-center case series, we described the incidence of fracture-related infections and bony union achievement in patients who had Gustilo type IIIa or IIIb femoral or tibial fractures treated with noble metal alloy-coated titanium nails. Patients were treated between January 2017 and January 2019 at the Sultanah Aminah Hospital, Johor Bahru, Malaysia. Information on fracture-related infections and bone healing assessments was collected from patient records. Additionally, three independent experts retrospectively reviewed patient X-ray images from follow-up visits to further evaluate bony union achievement. Thirty-five patients were included. Infection developed in 3/35 (8.6%) patients; all cases were resolved by antibiotic therapy. Radiographs were available for 32 patients; these confirmed the presence of bone healing in 30/32 (93.8%) patients. However, according to patient records, bony union was achieved in all patients. No safety issues were recorded. This case series suggests that a noble metal alloy-coated titanium nail can prevent infection and facilitate bony union achievement in patients undergoing surgery for severe open fractures.
Fulltext A Study on the Central Corneal Thickness of Primary Angle Closure and Primary Angle Closure Glaucoma and Its Effect on Visual Field Progression

Tan HK, Ahmad Tajuddin LS, Lee MY, Ismail S, Wan-Hitam WH

Asia Pac J Ophthalmol (Phila), 2015;4(3):161-5.
PMID: 26065503 DOI: 10.1097/APO.0000000000000058

PURPOSE: To determine the mean central corneal thickness (CCT) and the relationship between the CCT and visual field progression in primary angle closure (PAC) and primary angle closure glaucoma (PACG).
DESIGN: A combined cross-sectional and prospective study on PAC and PACG.
METHODS: A total of 35 eyes were included in the study for each group of normal control, PAC, and PACG patients from eye clinics in Kota Bharu, state of Kelantan, Malaysia, from January 2007 to November 2009. The PAC and PACG patients were divided into thin and thick CCT groups. They were followed up for 12 to 18 months for visual field progression assessment with their mean Advanced Glaucoma Intervention Study (AGIS) score.
RESULTS: The CCT was 516.8 ± 26.0 µm for PAC and 509.7 ± 27.4 µm for PACG. Both were significantly thinner compared with the control group with CCT of 540 ± 27.8 µm (P < 0.001). There was a statistically significant increase in the mean AGIS score after 12.9 ± 1.7 months of follow-up in the thin CCT group for PACG (P = 0.002). However, no significant increase in the mean AGIS score was found for the thick CCT group in PACG and for both thin and thick CCT in PAC.
CONCLUSIONS: The PAC and PACG had statistically significant thinner CCT compared with the controls. Thin CCT was associated with visual field progression based on the mean AGIS score in PACG.
A review of the burden of disease due to otitis media in the Asia-Pacific

Mahadevan M, Navarro-Locsin G, Tan HK, Yamanaka N, Sonsuwan N, Wang PC, et al.

Int J Pediatr Otorhinolaryngol, 2012 May;76(5):623-35.
PMID: 22404948 DOI: 10.1016/j.ijporl.2012.02.031

The burden of disease due to otitis media (OM) in Asia Pacific countries was reviewed to increase awareness and raise understanding within the region.
Cryptotanshinone attenuates in vitro oxLDL-induced pre-lesional atherosclerotic events

Ang KP, Tan HK, Selvaraja M, Kadir AA, Somchit MN, Akim AM, et al.

Planta Med, 2011 Nov;77(16):1782-7.
PMID: 21614753 DOI: 10.1055/s-0030-1271119

Development of early stage atherosclerosis involves the activation of endothelial cells by oxidized low-density lipoprotein (oxLDL) with subsequent increases in endothelial permeability and expression of adhesion molecules favoring the adherence of monocytes to the endothelium. Cryptotanshinone (CTS), a major compound derived from the Chinese herb Salvia miltiorrhiza, is known for its protective effects against cardiovascular diseases. The aim of this study was to determine whether CTS could prevent the oxLDL-induced early atherosclerotic events. OxLDL (100 µg/mL) was used to increase endothelial permeability and induce monocyte-endothelial cell adhesion in human umbilical vein endothelial cells (HUVECs). Endothelial nitric oxide (NO) concentrations, a permeability-regulating molecule, and expressions of intercellular adhesion molecule-1 (ICAM-1) and vascular cell adhesion molecule-1 (VCAM-1) were measured. Results show that a) endothelial hyperpermeability was suppressed by 94 % (p
The changing pattern of primary glomerulonephritis in Singapore and other countries over the past 3 decades

Woo KT, Chan CM, Mooi CY, -L-Choong H, Tan HK, Foo M, et al.

Clin. Nephrol., 2010 Nov;74(5):372-83.
PMID: 20979946

This review of 2,586 renal biopsies over the past 3 decades in Singapore documents the changing pattern of glomerulonephritis (GN) from that of a third world country to that of a developed nation. In the 1st decade, mesangial proliferative glomerulonephritis was the most common form of primary GN, just as it was in the surrounding Asian countries. In the 2nd decade, the prevalence of mesangial proliferative GN decreased with a rise in membranous, GN which is also seen in China and Thailand. In the 3rd decade, there was a dramatic increase in focal sclerosing glomerulosclerosis. This increase reflects aging and obesity in keeping with more developed countries like Australia, India, Thailand and the United States of America. IgA nephritis remains the most common GN. Apart from the geographical influence, other socioeconomic factors play a significant role in the evolution of the renal biopsy pattern. Mesangial proliferative GN remains prevalent in many Asian countries, but in Singapore the prevalence is decreasing just as it is in Japan, Korea and Malaysia. Worldwide, the prevalence of focal sclerosing glomerulosclerosis continues to increase in many countries.
Changes in primary glomerulonephritis in Singapore over four decades 

Woo KT, Chan CM, Lim C, Choo J, Chin YM, Teng WL, et al.

Clin. Nephrol., 2019 Mar;91(3):155-161.
PMID: 30663975 DOI: 10.5414/CN109577

This review of 3,289 native kidney biopsies over the past four decades in Singapore documents the changing pattern of biopsy-proven glomerulonephritis (GN)from that of a third world country to that of a developed nation. In the 1st decade, mesangial proliferative GN was the most common form of primary GN, similar to the Asian region. In the 2nd decade, the percentage of mesangial proliferative GN decreased, but membranous GN became more common, as was seen in China and Thailand. In the 3rd decade, focal segmental glomerulosclerosis (FSGS) and membranous nephropathy continued to rise, but it was only recently, in the 4th decade, that FSGS prevalence increased dramatically, although membranous nephropathy continues to increase in some Asian countries. In the last decade in Singapore, Malaysia, and Japan, prevalence of IgA nephritis has decreased but remains the most common GN. The percentage of FSGS continues to increase in many countries like in Italy, United States of America, United Kingdom, China, and Malaysia. We surmise that socioeconomic factors play significant roles in the evolution of the renal biopsy pattern. .

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