Methods: Several compounds were synthesized and their molecular identity was confirmed using nuclear magnetic resonance. Potential anticancer properties were determined using cytopathogenicity assays and growth inhibition assays using cervical cancer cells (HeLa). Cells were incubated with different concentrations of compounds belonging to Benzodioxane, Naphthalene diimide, Aminophenol derivatives and Porphyrins and effects were determined. HeLa cells cytopathogenicity was determined by measuring lactate dehydrogenase release using cytotoxicity detection assay. Growth inhibition assays were performed by incubating 50% semi-confluent HeLa cells with Benzodioxane, Naphthalene diimide, Aminophenol derivatives and Porphyrin compounds and HeLa cell proliferation was observed. Growth inhibition and host cell death were compared in the presence and absence of drugs.
Results: Cytopathogenicity assays showed that the selected compounds were cytotoxic against HeLa cells, killing up to 90% of cells. Growth inhibition assays exhibited 100% growth inhibition. These effects are likely via oxidative stress, production of reactive oxygen species, changes in cytosolic and intracellular calcium/adenine nucleotide homeostasis, inhibition of ribonucleotide reductase/cyclooxygenase and/or glutathione depletion.
Conclusions: Benzodioxane, Naphthalene diimide, Aminophenol derivatives and Porphyrins exhibited potent anticancer properties. These findings are promising and should pave the way in the rationale development of anticancer drugs. Using different cancer cell lines, future studies will determine their potential as anti-tumour agents as well as their precise molecular mode of action.
METHODS: Brain tumor tissues and corresponding blood specimens were obtained from 45 patients. The ND3 10398A>G alteration at target codon 114 was detected using the PCR-RFLP analysis and later was confirmed by DNA sequencing.
RESULTS: Twenty-six (57.8%) patients showed ND3 10398A>G mutation in their tumor specimens, in which 26.9% of these mutations were heterozygous mutations. ND3 10398A>G mutation was not significantly correlated with age, gender, and histological tumor grade, however was found more frequently in intra-axial than in extra-axial tumors (62.5% vs. 46.2%, p<0.01).
CONCLUSION: For the first time, we have been able to describe the occurrence of ND3 10398A>G mutations in a Malaysian brain tumor population. It can be concluded that mitochondrial ND3 10398A>G alteration is frequently present in brain tumors among Malaysian population and it shows an impact on the intra-axial tumors.
Methods: Human neuroblastoma cells SH-SY5Y (as a neuronal model) and human glioblastoma cells T98G (as an astrocytic model), were treated with 100-500 µM PA, oleic acid (OA) or lauric acid (LA) for 24 h or 48 h, and their cell viability was assessed by 3-(4,5-dimetylthiazol-2-yl)-2,5-diphenyltetrazolium bromide (MTT) assay. The effects of stable overexpression of γ-synuclein (γ-syn), a neuronal protein recently recognized as a novel regulator of lipid handling in adipocytes, and transient overexpression of Parkinson's disease (PD) α-synuclein [α-syn; wild-type (wt) and its pathogenic mutants A53T, A30P and E46K] in SH-SY5Y and T98G cells, were also evaluated. The effects of co-treatment of PA with paraquat (PQ), a Parkinsonian pesticide, and leptin, a hormone involved in the brain-adipose axis, were also assessed. Cell death mode and cell cycle were analyzed by Annexin V/PI flow cytometry. Reactive oxygen species (ROS) level was determined using 2',7'-dichlorofluorescien diacetate (DCFH-DA) assay and lipid peroxidation level was determined using thiobarbituric acid reactive substances (TBARS) assay.
Results: MTT assay revealed dose- and time-dependent PA cytotoxicity on SH-SY5Y and T98G cells, but not OA and LA. The cytotoxicity was significantly lower in SH-SY5Y-γ-syn cells, while transient overexpression of wt α-syn or its PD mutants (A30P and E46K, but not A53T) modestly (but still significantly) rescued the cytotoxicity of PA in SH-SY5Y and T98G cells. Co-treatment of increasing concentrations of PQ exacerbated PA's neurotoxicity. Pre-treatment of leptin, an anti-apoptotic adipokine, did not successfully rescue SH-SY5Y cells from PA-induced cytotoxicity-suggesting a mechanism of PA-induced leptin resistance. Annexin V/PI flow cytometry analysis revealed PA-induced increase in percentages of cells in annexin V-positive/PI-negative quadrant (early apoptosis) and subG0-G1 fraction, accompanied by a decrease in G2-M phase cells. The PA-induced ROS production and lipid peroxidation was at greater extent in T98G as compared to that in SH-SY5Y.
Discussion: In conclusion, PA induces apoptosis by increasing oxidative stress in neurons and astrocytes. Taken together, the results suggest that HFD may cause neuronal and astrocytic damage, which indirectly proposes that CNS pathologies involving neuroinflammation and reactive gliosis could be prevented via the diet regimen.
AIM OF THE STUDY: This review is an attempt to assess the anti-inflammatory activity of Polyalthia species by giving critical appraisal and establishing evidences of their traditional uses. Moreover this review will highlight the lead compounds for future drug development that can serve as a potential anti-inflammatory drug with comparative efficacy and minimum side effects.
MATERIALS AND METHODS: An extensive literature review, focusing the anti-inflammatory potential of Polyalthia species was conducted using the following databases: PubMed, ScienceDirect, SpringerLink, Ovid, Scopus and ProQuest, as well as the locally available books, journals and relevant documents. The reference lists of retrieved papers were also searched for additional studies.
RESULTS: The Polyalthia species have shown significant anti-inflammatory activity through various mechanism of action. The most significant anti-inflammatory mechanism includes the inhibition of nuclear factor kappa B (NF-κB), prostaglandins (PGs), pro-inflammatory cytokines, inducible nitric oxide synthase (iNOS) and reactive oxygen species (ROS). The data suggests that hydroxycleroda-3,13-dien-15,16-olide and 16-oxocleroda-3,13-dien-15-oic acid, quercetin, rutin, spinasterol, α-spinasterol, goniothalamin and (-)-5-hydroxygoniothalamin are the most potent anti-inflammatory compounds from Polyalthia species with comparable IC50 with positive controls.
CONCLUSIONS: Numerous pharmacological studies have supported the use of Polyalthia species against pain, rheumatic fever, haemorrhages and inflammation in traditional medicine. Flavonoids, diterpenoids, sterols and styrylpyrones from genus Polyalthia are the most significant class of compounds with potent anti-inflammatory activity. Secondary metabolites from these classes should be brought into further research to fill the gaps of knowledge in pharmacokinetics, pharmacodynamics, bioavailability, and toxicity in order to convert the pre-clinical results into clinical data for further investigation.
RESULTS: The host counter-attack was evidenced based on fungal hyphae and Ganoderma DNA observed at 3 d.p.i which became significantly reduced at 7 and 11 d.p.i. DEGs revealed upregulation of multifaceted defense related genes such as PR-protein (EgPR-1), protease inhibitor (EgBGIA), PRR protein (EgLYK3) chitinase (EgCht) and expansin (EgEXPB18) at 3 d.p.i and 7 d.p.i which dropped at 11 d.p.i. Later stage involved highly expressed transcription factors EgERF113 and EgMYC2 as potential regulators of necrotrophic defense at 11 d.p.i. The reactive oxygen species (ROS) elicitor: peroxidase (EgPER) and NADPH oxidase (EgRBOH) were upregulated and maintained throughout the treatment period. Growth and nutrient distribution were probably compromised through suppression of auxin signalling and iron uptake genes.
CONCLUSIONS: Based on the analysis of oil palm gene expression, it was deduced that the biotrophic phase of Ganoderma had possibly occurred at the early phase (3 until 7 d.p.i) before being challenged by the fungus via switching its lifestyle into the necrotrophic phase at later stage (11 d.p.i) and finally succumbed the host. Together, the findings suggest the dynamic defense process in oil palm and potential candidates that can serve as phase-specific biomarkers at the early stages of oil palm-G. boninense interaction.