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Fulltext Anti-Metastatic and Anti-Angiogenic Effects of Curcumin Analog DK1 on Human Osteosarcoma Cells In Vitro

Aziz MNM, Rahim NFC, Hussin Y, Yeap SK, Masarudin MJ, Mohamad NE, et al.

Pharmaceuticals (Basel), 2021 Jun 03;14(6).
PMID: 34204873 DOI: 10.3390/ph14060532

Osteosarcoma (OS) is a life-threatening malignant bone tumor associated with poor prognosis among children. The survival rate of the patient is still arguably low even with intensive treatment provided, plus with the inherent side effects from the chemotherapy, which gives more unfavorable outcomes. Hence, the search for potent anti-osteosarcoma agent with promising safety profile is still on going. Natural occurring substance like curcumin has gained a lot of attention due to its splendid safety profile as well as it pharmacological advantages such as anti-metastasis and anti-angiogenesis. However, natural curcumin was widely known for its poor cellular uptake, which undermines all potential that it possesses. This prompted the development of synthetically synthesized curcuminoid analog, known as (Z)-3-hydroxy-1-(2-hydroxyphenyl)-3-phenylprop-2- en-1-one (DK1). In this present study, in vitro scratch assay, transwell migration/invasion assay, HUVEC tube formation assay, and ex vivo rat aortic ring assays were performed in order to investigate the anti-metastatic and anti-angiogenic potential of DK1. For further comprehension of DK1 mechanism on human osteosarcoma cell lines, microarray gene expression analysis, quantitative polymerase chain reaction (qPCR), and proteome profiler were adopted, providing valuable forecast from the expression of important genes and proteins related to metastasis and angiogenesis. Based on the data gathered from the bioassays, DK1 was able to inhibit the metastasis and angiogenesis of human osteosarcoma cell lines by significantly reducing the cell motility, number of migrated and invaded cells as well as the tube formation and micro-vessels sprouting. Additionally, DK1 also has significantly regulated several cancer pathways involved in OS proliferation, metastasis, and angiogenesis such as PI3K/Akt and NF-κB in both U-2 OS and MG-63. Regulation of PI3K/Akt caused up-regulation of genes related to metastasis inhibition, namely, PTEN, FOXO, PLK3, and GADD45A. Meanwhile, NF-κB pathway was regulated by mitigating the expression of NF-κB activator such as IKBKB and IKBKE in MG-63, whilst up-regulating the expression of NF-κB inhibitors such as NFKBIA and NFKBIE in U-2 OS. Finally, DK1 also has successfully hindered the metastatic and angiogenic capability of OS cell lines by down-regulating the expression of pro-metastatic genes and proteins like MMP3, COL11A1, FGF1, Endoglin, uPA, and IGFBP2 in U-2 OS. Whilst for MG-63, the significantly down-regulated oncogenes were Serpin E1, AKT2, VEGF, uPA, PD-ECGF, and Endoglin. These results suggest that curcumin analog DK1 may serve as a potential new anti-osteosarcoma agent due to its anti-metastatic and anti-angiogenic attributes.
Fulltext Association of metabolic syndrome with risk of cardiovascular disease mortality and all-cause mortality among Malaysian adults: a retrospective cohort study

Chee Cheong K, Lim KH, Ghazali SM, Teh CH, Cheah YK, Baharudin A, et al.

BMJ Open, 2021 08 18;11(8):e047849.
PMID: 34408040 DOI: 10.1136/bmjopen-2020-047849

OBJECTIVES: This study is aimed at determining the association between metabolic syndrome and risk of cardiovascular disease (CVD) mortality and all-cause mortality among Malaysian adults.
DESIGN: Retrospective cohort study.
SETTING: The Malaysian Non-Communicable Disease Surveillance (MyNCDS-1) 2005/2006.
PARTICIPANTS: A total of 2525 adults (1013 men and 1512 women), aged 24-64 years, who participated in the MyNCDS-1 2005/2006.
METHODS: Participants' anthropometric indices, blood pressure, fasting lipid profile and fasting blood glucose levels were evaluated to determine the prevalence of metabolic syndrome by the Harmonized criteria. Participants' mortality status were followed up for 13 years from 2006 to 2018. Mortality data were obtained via record linkage with the Malaysian National Registration Department. The Cox proportional hazards regression model was applied to determine association between metabolic syndrome (MetS) and risk of CVD mortality and all-cause mortality with adjustment for selected sociodemographic and lifestyle behavioural factors.
RESULTS: The overall point prevalence of MetS was 30.6% (95% CI: 28.0 to 33.3). Total follow-up time was 31 668 person-years with 213 deaths (111 (11.3%) in MetS subjects and 102 (6.1%) in non-MetS subjects) from all-causes, and 50 deaths (33 (2.9%) in MetS group and 17 (1.2%) in non-MetS group) from CVD. Metabolic syndrome was associated with a significantly increased hazard of CVD mortality (adjusted HR: 2.18 (95% CI: 1.03 to 4.61), p=0.041) and all-cause mortality (adjusted HR: 1.47 (95% CI: 1.00 to 2.14), p=0.048). These associations remained significant after excluding mortalities in the first 2 years.
CONCLUSIONS: Our study shows that individuals with MetS have a higher hazard of death from all-causes and CVD compared with those without MetS. It is thus imperative to prescribe individuals with MetS, a lifestyle intervention along with pharmacological intervention to improve the individual components of MetS and reduce this risk.
Fulltext Validity of self-reported weight and height: a cross-sectional study among Malaysian adolescents

Kee CC, Lim KH, Sumarni MG, Teh CH, Chan YY, Nuur Hafizah MI, et al.

BMC Med Res Methodol, 2017 Jun 02;17(1):85.
PMID: 28577547 DOI: 10.1186/s12874-017-0362-0

BACKGROUND: Self-reported weight and height are commonly used in lieu of direct measurements of weight and height in large epidemiological surveys due to inevitable constraints such as budget and human resource. However, the validity of self-reported weight and height, particularly among adolescents, needs to be verified as misreporting could lead to misclassification of body mass index and therefore overestimation or underestimation of the burden of BMI-related diseases. The objective of this study was to determine the validity of self-reported weight and height among Malaysian secondary school children.

METHODS: Both self-reported and directly measured weight and height of a subgroup of 663 apparently healthy schoolchildren from the Malaysian Adolescent Health Risk Behaviour (MyAHRB) survey 2013/2014 were analysed. Respondents were required to report their current body weight and height via a self-administrative questionnaire before they were measured by investigators. The validity of self-reported against directly measured weight and height was examined using intraclass correlation coefficient (ICC), the Bland-Altman plot and weighted Kappa statistics.

RESULTS: There was very good intraclass correlation between self-reported and directly measured weight [r = 0.96, 95% confidence interval (CI): 0.93, 0.97] and height (r = 0.94, 95% CI: 0.90, 0.96). In addition the Bland-Altman plots indicated that the mean difference between self-reported and direct measurement was relatively small. The mean difference (self-reported minus direct measurements) was, for boys: weight, -2.1 kg; height, -1.6 cm; BMI, -0.44 kg/m2 and girls: weight, -1.2 kg; height, -0.9 cm; BMI, -0.3 kg/m2. However, 95% limits of agreement were wide which indicated substantial discrepancies between self-reported and direct measurements method at the individual level. Nonetheless, the weighted Kappa statistics demonstrated a substantial agreement between BMI status categorised based on self-reported weight and height and the direct measurements (kappa = 0.76, 95% CI: 0.67, 0.84).

CONCLUSION: Our results show that the self-reported weight and height were consistent with direct measurements and therefore can be used in assessing the nutritional status of Malaysian school children from the age of 13 to 17 years old in epidemiological studies and for surveillance purposes when direct measurements are not feasible, but not for assessing nutritional status at the individual level.
A synthetic hydroxypropenone inhibits nitric oxide, prostaglandin E2, and proinflammatory cytokine synthesis

Liew CY, Tham CL, Lam KW, Mohamad AS, Kim MK, Cheah YK, et al.

Immunopharmacol Immunotoxicol, 2010 Sep;32(3):495-506.
PMID: 20109039 DOI: 10.3109/08923970903575708

HMP [3-(2-hydroxyphenyl)-1-(5-methyl-furan-2-y-l) propenone] was evaluated for its ability to inhibit the synthesis of major proinflammatory mediators and cytokines in interferon-gamma (IFN-gamma)- and lipopolysaccharide (LPS)-induced RAW 264.7 cells and phorbol myristate acetate (PMA)-differentiated/LPS-induced U937 cells. HMP suppressed the production of nitric oxide (NO) with significant inhibitory effects at doses as low as 0.78 microM (P < 0.05). Prostaglandin E2 (PGE2) secretion was also inhibited at doses of 12.5 microM and above (P < 0.01). The secretion of both TNF-alpha and IL-6 were only inhibited at the highest dose used (25 microM; P < 0.001). IL-1beta secretion was also inhibited from 12.5 microM onwards (P < 0.01). This inhibition was demonstrated to be caused by down-regulation of inducible enzymes, inducible nitric oxide synthase (iNOS), and cyclooxygenase-2 (COX-2), without direct effect upon iNOS or COX-2 enzyme activity. HMP only inhibited iNOS (P < 0.001) and IL-1beta (P < 0.05) gene expression at the highest tested concentration. HMP did not affect the secretion of chemokines IL-8 and monocyte chemotactic protein-1 (MCP-1) and the anti-inflammatory cytokine IL-10. The most striking effect of HMP was its NO inhibitory activity and therefore we conclude that HMP is a selective inhibitor of iNOS.
Fulltext Curcumin Analog DK1 Induces Apoptosis in Human Osteosarcoma Cells In Vitro through Mitochondria-Dependent Signaling Pathway

Aziz MNM, Hussin Y, Che Rahim NF, Nordin N, Mohamad NE, Yeap SK, et al.

Molecules, 2018 Jan 05;23(1).
PMID: 29303982 DOI: 10.3390/molecules23010075

Osteosarcoma is one of the primary malignant bone tumors that confer low survival rates for patients even with intensive regime treatments. Therefore, discovery of novel anti-osteosarcoma drugs derived from natural products that are not harmful to the normal cells remains crucial. Curcumin is one of the natural substances that have been extensively studied due to its anti-cancer properties and is pharmacologically safe considering its ubiquitous consumption for centuries. However, curcumin suffers from a poor circulating bioavailability, which has led to the development of a chemically synthesized curcuminoid analog, namely (Z)-3-hydroxy-1-(2-hydroxyphenyl)-3-phenylprop-2-en-1-one (DK1). In this study, the cytotoxic effects of the curcumin analog DK1 was investigated in both U-2OS and MG-63 osteosarcoma cell lines using 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide (MTT) assay and cell death was microscopically examined via acridine orange/propidium iodide (AO/PI) double staining. Flow cytometer analysis including Annexin V/Fluorescein isothiocyanate (FITC), cell cycle analysis and JC-1 were adapted to determine the mode of cell death. Subsequently in order to determine the mechanism of cell death, quantitative polymerase chain reaction (qPCR) and proteome profiling was carried out to measure the expression of several apoptotic-related genes and proteins. Results indicated that DK1 induced U-2 OS and MG-63 morphological changes and substantially reduced cell numbers through induction of apoptosis. Several apoptotic genes and proteins were steadily expressed after treatment with DK1; including caspase 3, caspase 9, and BAX, which indicated that apoptosis occurred through a mitochondria-dependent signaling pathway. In conclusion, DK1 could be considered as a potential candidate for an anti-osteosarcoma drug in the near future, contingent upon its ability to induce apoptosis in osteosarcoma cell lines.
Prevalence of COVID-19 among healthcare workers in the paediatric department: Estimates from a multicenter cross-sectional survey in Negeri Sembilan

David NCE, Juliana H, Chok M, Gan YZ, Tan YC, Nur Adlina MN, et al.

Med J Malaysia, 2023 Jan;78(1):80-86.
PMID: 36715196

INTRODUCTION: The COVID-19 pandemic has reached a phase where many have been infected at least once. Healthcare workers were not spared from being infected. This study aimed to determine the period prevalence of COVID-19 among the paediatric healthcare workers in Negeri Sembilan as the country transitioned into an endemic phase of the pandemic. Additionally, we investigate potential sociodemographic and occupational characteristics associated with SARS-CoV-2 infection among healthcare workers.
MATERIALS AND METHODS: A cross-sectional study was conducted among the healthcare workers in the paediatric department at three public specialist hospitals in Negeri Sembilan between 15 and 21 April 2022. Data were collected through a self-administered questionnaire.
RESULTS: Out of the 504 eligible healthcare workers, 493 participated in this study (response rate 97.8%). The overall prevalence of COVID-19 (11 March 2020-15 April 2022) among healthcare workers was 50.9%. The majority (80.1%) were infected during the Omicron wave two months before the survey. Household contacts accounted for 35.9% of infection sources. The proportion of non-doctors in the COVID-19-infected group was significantly higher compared to the non-infected group (74.1% vs 64.0%, p=0.016). The COVID-19-infected group had a higher proportion of schoolgoing children (44.6% vs 30.6%, p=0.001) and children who attended pre-school/sent to the babysitter (49.0% vs 24.4%, p<0.001). There were no significant differences between infection rates among the healthcare workers working in the tertiary hospital and the district hospitals. There were also no significant differences in the proportion of COVID-19- infected doctors and nurses when analysed by seniority.
CONCLUSION: Our study provided an estimate on the prevalence of COVID-19 among paediatric healthcare workers in Negeri Sembilan and the factors associated with infection, which captures the extent and magnitude of this pandemic on the state's paediatric department. Most infections resulted from household contact, with a higher proportion of infected healthcare workers having young children.
Humoral response to SARS-CoV-2 vaccines among healthcare workers in a tertiary hospital in Malaysia

Amrina MA, Shahidah M, Sofiah HR, Mirlia SCM, Thilakaveni R, Chong ZL, et al.

Med J Malaysia, 2023 Jan;78(1):20-24.
PMID: 36715186

INTRODUCTION: Healthcare workers (HCWs) were among the first to be fully vaccinated against SARS-CoV-2. However, the antibody responses to the vaccines and potential decline among Malaysian HCW are still unclear. The objective of this study is to follow-up anti-S antibody levels among HCW vaccinated with mRNA vaccine (BTN162b2) and inactivated vaccine (CoronaVac).
MATERIALS AND METHODS: Plasma samples were collected prevaccination, 2 weeks and 6 months post-vaccination and tested for total immunoglobulin levels using ELISA method.
RESULTS: A small percentage of HCW (2.2%, 15/677) had elevated anti-S antibody levels in their pre-vaccination plasma samples (median 20.4, IQR 5.8), indicating that they were exposed to SARS-CoV-2 infection prior to vaccination. The mRNA vaccine significantly increased anti-S levels of both previously infected and uninfected individuals to saturation levels (median 21.88, IQR.0.88) at 2 weeks postsecond dose of the vaccine. At 6 months post-vaccination, the antibody levels appeared to be maintained among the recipients of the mRNA vaccine. However, at this time point, anti-S antibody levels were lower in individuals given inactivated vaccine (median 20.39, IQR 7.31, n=28), and interestingly, their antibody levels were similar to anti-S levels in pre-vaccination exposed individuals. Antibody levels were not different between the sexes.
CONCLUSION: Anti-S levels differ in individuals given the different vaccines. While further study is required to determine the threshold level for protection against SARSCoV- 2, individuals with low antibody levels may be considered for boosters.
Fulltext Tear Samples for Protein Extraction: Comparative Analysis of Schirmer's Test Strip and Microcapillary Tube Methods

Tham ML, Mahmud A, Abdullah M, Md Saleh R, Mohammad Razali A, Cheah YK, et al.

Cureus, 2023 Dec;15(12):e50972.
PMID: 38259376 DOI: 10.7759/cureus.50972

INTRODUCTION: Tear sampling is an attractive option for collecting biological samples in ophthalmology clinics, as it offers a non-invasive alternative to other invasive techniques. However, there are many tear sampling methods still in consideration. This study explores the suitability of Schirmer's test strip and microcapillary tube as reliable and satisfactory methods for tear sampling.
METHODS: Tear samples were collected from eight healthy volunteers using the standard Schirmer's test strip method with or without anesthesia and microcapillary tubes. The total tear protein concentrations were analyzed via spectrophotometry and bicinchoninic acid (BCA) protein assay. The protein profile was determined by sodium dodecyl sulphate-polyacrylamide gel electrophoresis (SDS-PAGE). The optimal wetting length of Schirmer's strip and suitable buffer solutions were compared. Discomfort levels reported by participants and the ease of execution for ophthalmologists were also evaluated.
RESULTS: Tear samples exhibited typical protein profiles as shown by SDS-PAGE. The mean total protein obtained from an optimum wetting length of 20 mm using Schirmer's strip without anesthesia in phosphate-buffered saline (PBS) yielded substantial quantities of protein as measured by nanophotometer (220.20 ± 67.43 µg) and the BCA protein assay (210.34 ± 59.46 µg). This method collected a significantly higher quantity of protein compared to the microcapillary tube method (p=0.004) which was much more difficult to standardize. The clinician found it harder to utilize microcapillary tubes, while participants experienced higher insecurity and less discomfort with the microcapillary tube method. PBS used during the tear protein extraction process eluted higher tear protein concentration than ammonium bicarbonate, although the difference was not statistically significant. Using anaesthesia did not ease the sampling procedure substantially and protein quantity was maintained.
CONCLUSION: Good quality and quantity of protein from tear samples were extracted with the optimized procedure. Schirmer's strip test in the absence of local anesthesia provided a standard, convenient, and non-invasive method for tear collection.