Lauric acid epigenetically regulates lncRNA HOTAIR by remodeling chromatin H3K4 tri-methylation and modulates glucose transport in SH-SY5Y human neuroblastoma cells: Lipid switch in macrophage activation.

Lauric acid (LA) induces apoptosis in cancer and promotes the proliferation of normal cells by maintaining cellular redox homeostasis. Earlier, we postulated LA-mediated regulation of the NF-κB pathway by an epigenetic mechanism. However, the molecular mechanism and possible epigenetic events remained enigmatic. Herein, taking the lead from the alteration in cellular energetics in cancer cells upon LA exposure, we investigated whether LA exposure can epigenetically influence lncRNA HOTAIR, regulate glucose metabolism, and shift the cellular energetic state. Our results demonstrate LA induced modulation of lncRNA HOTAIR in a dose and time dependent manner. In addition, HOTAIR induces the expression of glucose transporter isoform 1 (GLUT1) and is regulated via NF-κB activation. Silencing HOTAIR by siRNA-mediated knockdown suppressed GLUT1 expression suggesting the key role of HOTAIR in LA-mediated metabolic reprogramming. Further, from our ChIP experiments, we observed that silencing HOTAIR subdues the recruitment of NF-κB on the GLUT1 (SLC2A1) promoter region. In addition, by performing western blot and immunocytochemistry studies, we found a dose dependent increase in Histone 3 Lysine 4 tri-methylation (H3K4me3) in the chromatin landscape. Taken together, our study demonstrates the epigenetic regulation in LA-treated SH-SY5Y cancer cells orchestrated by remodeling chromatin H3K4me3 and modulation of lncRNA HOTAIR that apparently governs the GLUT1 expression and regulates glucose uptake by exerting transcriptional control on NF-κB activation. Our work provides insights into the epigenetic regulation and metabolic reprogramming of LA through modulation of lncRNA HOTAIR, remodeling chromatin H3K4 tri-methylation, and shifting the energy metabolism in SH-SY5Y neuroblastoma cells.

Dual Roles of Coconut Oil and Its Major Component Lauric Acid on Redox Nexus: Focus on Cytoprotection and Cancer Cell Death.

It has been reported that coconut oil supplementation can reduce neuroinflammation. However, coconut oils are available as virgin coconut oil (VCO), crude coconut oil (ECO), and refined coconut oil (RCO). The impact of coconut oil extraction process (and its major fatty acid component lauric acid) at cellular antioxidant level, redox homeostasis and inflammation in neural cells is hitherto unexplained. Herein, we have shown the antioxidant levels and cellular effect of coconut oil extracted by various processes in human neuroblastoma cells (SH-SY5Y) cultured in vitro. Results indicate VCO and ECO treated cells displayed better mitochondrial health when compared to RCO. Similar trend was observed for the release of reactive oxygen species (ROS), key oxidative stress response genes (GCLC, HO-1, and Nqo1) and inflammatory genes (IL6, TNFα, and iNOS) in SH-SY5Y cells. Our results signified that both VCO and ECO offer better neural health primarily by maintaining the cellular redox balance. Further, RCO prepared by solvent extraction and chemical refining process lacks appreciable beneficial effect. Then, we extended our study to find out the reasons behind maintaining the cellular redox balance in neuroblastoma cells by VCO and ECO. Our GC-MS results showed that lauric acid (C14:0) (LA) content was the major difference in the fatty acid composition extracted by various processes. Therefore, we evaluated the efficacy of LA in SH-SY5Y cells. The LA showed dose-dependent effect. At IC50 concentration (11.8 µM), LA down regulated the oxidative stress response genes and inflammatory genes. The results clearly indicate that the LA inhibited the neuroinflammation and provided an efficient cellular antioxidant activity, which protects the cells. The efficiency was also evaluated in normal cell line such as fibroblasts (L929) to cross-validate that the results were not false positive. Different concentration of LA on L929 cells showed high compatibility. From our observation, we conclude that VCO and ECO offers better cellular protection owing to their powerful antioxidant system. Therefore, we advocate the inclusion of either VCO and/or ECO in the diet for a healthy lifestyle.

Cytotoxic cobalt (III) Schiff base complexes: in vitro anti-proliferative, oxidative stress and gene expression studies in human breast and lung cancer cells.

Increasing cancer drug chemo-resistance, especially in the treatment of breast and lung cancers, alarms the immediate need of newer and effective anticancer drugs. Until now, chemotherapeutics based on metal complexes are considered the most effective treatment modality. In the present study, we have evaluated the cytotoxic effect of two cobalt (III) Schiff base complexes based on the leads from complex combinatorial chemistry. Cobalt (III) Schiff base complexes (Complex 3 = Co(Ph-acacen)(HA)2](ClO4) and Complex 4 =  [Co(Ph-acacen)(DA)2](ClO4)] (Ph-acacen, 1-phenylbutane-1,3-dione; DA, dodecyl amine; HA, heptylamine) were evaluated against human breast cancer cell MCF-7 and lung cancer cell A549 using MTT cell viability assay, cellular morphological changes studied by Acridine Orange and Ethidium Bromide (AO/EB), Dual fluorescent staining, Hoechst staining 33248, Comet assay, Annexin V-Cy3 and 6 CFDA assay, JC-1 staining, Reactive oxygen species (ROS) assay, Immunofluorescence assay, and Real-time reverse transcription-polymerase chain reaction (RT-qPCR). Treatment of cobalt (III) Schiff base complexes (Complex 3 & 4) affected the viability of the cancer cells. The cell death induced by the complexes was predominantly apoptosis, but necrosis also occurred to a certain extent. Complex 4 produced better cytotoxic effect than complex 3, and MCF-7 cell was more responsive than A549. In that order, the complexes were more selective to cancer cell than normal cell, and more effective in overall performance than the standard drug cisplatin. Therefore, we conclude that cobalt (III) Schiff base complexes, especially complex 4, have the potential to be developed as effective drugs for treatment of cancers in general, and breast and lung cancers in particular.

Potential application of two cobalt (III) Schiff base complexes in cancer chemotherapy: Leads from a study using breast and lung cancer cells.

Cobalt (III) Schiff base complexes are of attraction in the context of their potential application in cancer therapy. The aim of this study has been to find the mechanism of action of cobalt (III) Schiff base complexes 1 and 2, the synthesis and characterization of which have already been reported, in inhibiting growth of human breast cancer cell MCF-7 and lung cancer cell A549. The already proclaimed anti-proliferative effect of the cobalt complexes was ascertained using MTT cytotoxicity assay. More assays such as Acridine orange & Ethidium bromide staining, AnnexinV-Cy3 staining, Hoechst staining, comet assay, and Reactive Oxygen Species (ROS) assay- all supported the cytotoxic property of the complexes. Moreover, the expression levels of mRNA of pro- and antiapoptotic genes also supported the effectiveness of cobalt complexes by modifying the ratio of Bax: Bcl-2. In addition, the cobalt complexes induced apoptosis in MCF- 7 and A549 cells through modulation of pro-apoptotic, anti-apoptotic, and ROS modulatory gene expressions. The present study validates the scientific evidence for antiproliferative efficacy of cobalt complexes against MCF-7 and A549 cells. Thus, this study takes cobalt complexes 1 and 2 to a step higher towards their use as anticancer agents.