PURPOSE: We adopted a combinatorial approach with the joint application of γ-tocotrienol and jerantinine A at lower concentrations in order to minimize toxicity towards non-cancerous cells while improving the potency on brain cancer cells.
METHODS: The antiproliferative potency of individual γ-tocotrienol and jerantinine A as well as combined in low-concentration was firstly evaluated on U87MG cancer and MRC5 normal cells. Morphological changes, DNA damage patterns, cell cycle arrests and the effects of individual and combined low-concentration compounds on microtubules were then investigated. Finally, the potential roles of caspase enzymes and apoptosis-related proteins in mediating the apoptotic mechanisms were investigated using apoptosis antibody array, ELISA and Western blotting analysis.
RESULTS: Combinatorial study between γ-tocotrienol at a concentration range (0-24µg/ml) and fixed IC20 concentration of jerantinine A (0.16µg/ml) induced a potent antiproliferative effect on U87MG cells and led to a reduction on the new half maximal inhibitory concentration of γ-tocotrienol (i.e.tIC50=1.29µg/ml) as compared to that of individual γ-tocotrienol (i.e. IC50=3.17µg/ml). A reduction on undesirable toxicity to MRC5 normal cells was also observed. G0/G1 cell cycle arrest was evident on U87MG cells receiving IC50 of individual γ-tocotrienol and combined low-concentration compounds (1.29µg/ml γ-tocotrienol + 0.16µg/ml jerantinine A), whereas, a profound G2/M arrest was evident on cells treated with IC50 of individual jerantinine A. Additionally, individual jerantinine A and combined compounds (except individual γ-tocotrienol) caused a disruption of microtubule networks triggering Fas- and p53-induced apoptosis mediated via the death receptor and mitochondrial pathways.
CONCLUSIONS: These findings demonstrated that the combined use of lower concentrations of γ-tocotrienol and jerantinine A induced potent cytotoxic effects on U87MG cancer cells resulting in a reduction on the required individual concentrations and thereby minimizing toxicity of jerantinine A towards non-cancerous MRC5 cells as well as probably overcoming the high-dose limiting application of γ-tocotrienol. The multi-targeted mechanisms of action of the combination approach have shown a therapeutic potential against brain cancer in vitro and therefore, further in vivo investigations using a suitable animal model should be the way forward.
METHODS: We used a combination of proliferation and apoptosis assays to assess the effect of JB on AML cell lines and patient samples, with BH3 profiling being performed to identify early effects of the drug (4 h). Phosphokinase arrays were adopted to identify potential driver proteins in the cellular response to JB, the results of which were confirmed and extended using western blotting and inhibitor assays and measuring levels of reactive oxygen species.
RESULTS: AML cell growth was significantly impaired following JB exposure in a dose-dependent manner; potent colony inhibition of primary patient cells was also observed. An apoptotic mode of death was demonstrated using Annexin V and upregulation of apoptotic biomarkers (active caspase 3 and cleaved PARP). Using BH3 profiling, JB was shown to prime cells to apoptosis at an early time point (4 h) and phospho-kinase arrays demonstrated this to be associated with a strong upregulation and activation of both total and phosphorylated c-Jun (S63). The mechanism of c-Jun activation was probed and significant induction of reactive oxygen species (ROS) was demonstrated which resulted in an increase in the DNA damage response marker γH2AX. This was further verified by the loss of JB-induced C-Jun activation and maintenance of cell viability when using the ROS scavenger N-acetyl-L-cysteine (NAC).
CONCLUSIONS: This work provides the first evidence of cytotoxicity of JB against AML cells and identifies ROS-induced c-Jun activation as the major mechanism of action.
METHODS: This study used data from the 2015 National Health and Morbidity Survey (NHMS), a nationwide cross-sectional survey that implemented a two-stage stratified random sampling design. Respondents aged 18 years and above (n = 17,261) were included in the analysis. The short version of International Physical Activity Questionnaire (IPAQ) was administered to assess the respondents' PA levels. The respondents' height and weight were objectively measured and body mass index (BMI) was calculated. The respondents were categorized according to BMI as either normal-weight (18.5-24.9 kg/m2) or overweight/obese (≥ 25 kg/m2). Descriptive and complex sample logistic regression analyses were employed as appropriate.
RESULTS: Overall, approximately 1 in 2 respondents (51.2%) were overweight/obese, even though the majority (69.0%) reporting at least a moderate level of PA (total PA ≥ 10 MET-hours/week). In both normal-weight and overweight/obese groups, a significantly higher prevalence of high PA (total PA ≥ 50 MET-hours/week) was observed among men than women (p
METHODS: The National Health and Morbidity Survey (NHMS) 2017 (n = 8230) was used for analyses. It was a nationwide survey conducted in Malaysia. The dependent variables were measured by three risk behaviors (cigarette smoking, alcohol drinking and use of illicit drugs). Probit regressions were utilized to examine the effect of mental health on the probability of smoking, drinking and using illicit drugs. Demographic and lifestyle factors were used as the control variables. Truancy was identified as a mediating variable.
RESULTS: Anxiety, depression and suicidal ideation affected cigarette smoking, alcohol drinking and use of illicit drugs through mediation of truancy. After controlling for demographic and lifestyle factors, students with anxiety, depression and suicidal ideation were more likely to smoke, drink and use illicit drugs compared with their peers without any mental health disorders. Furthermore, the likelihood of consuming cigarettes, alcohol and illicit drugs was found to be higher among students who played truant than those who did not.
CONCLUSION: Mental health plays an important role in determining participation in risk behaviors among ethnic minority students in Malaysia. Public health administrators and schools have to be aware that students who suffer from mental health disorders are likely to indulge in risk behaviors.