plastochromanol-8 and Inflammation

Tocotrienols (T3s) are a subclass of unsaturated vitamin E that have been extensively studied for their anti-proliferative, anti-oxidative and anti-inflammatory properties in numerous cancer studies. Recently, T3s have received increasing attention due to their previously unrecognized property to attenuate obesity and its associated metabolic complications. In this review, we comprehensively evaluated the recent published scientific literature about the influence of T3s on obesity, with a particular emphasis on the signaling pathways involved. T3s have been demonstrated in animal models or human subjects to reduce fat mass, body weight, plasma concentrations of free fatty acid, triglycerides and cholesterol, as well as to improve glucose and insulin tolerance. Their mechanisms of action in adipose tissue mainly include (1) modulation of fat cell adipogenesis and differentiation; (2) modulation of energy sensing; (3) induction of apoptosis in preadipocytes and (4) modulation of inflammation. Studies have also been conducted to investigate the effects of T3s on other targets, e.g., the immune system, liver, muscle, pancreas and bone. Since δT3 and γT3 are regarded as the most active isomers among T3s, their clinical relevance to reduce obesity should be investigated in human trials.

Topics: Adipogenesis; Adipose Tissue; Animals; Anti-Obesity Agents; Apoptosis; Biological Availability; Chromans; Energy Metabolism; Humans; Immunomodulation; Inflammation; Liver; Obesity; Signal Transduction; Vitamin E

The Nod-like receptor 3 (NLRP3) inflammasome is an intracellular sensor that sets off the innate immune system in response to microbial-derived and endogenous metabolic danger signals. We previously reported that γ-tocotrienol (γT3) attenuated adipose tissue inflammation and insulin resistance in diet-induced obesity, but the underlying mechanism remained elusive. Here, we investigated the effects of γT3 on NLRP3 inflammasome activation and attendant consequences on type 2 diabetes. γT3 repressed inflammasome activation, caspase-1 cleavage, and interleukin (IL) 1β secretion in murine macrophages, implicating the inhibition of NLRP3 inflammasome in the anti-inflammatory and antipyroptotic properties of γT3. Furthermore, supplementation of leptin-receptor KO mice with γT3 attenuated immune cell infiltration into adipose tissue, decreased circulating IL-18 levels, preserved pancreatic β-cells, and improved insulin sensitivity. Mechanistically, γT3 regulated the NLRP3 inflammasome via a two-pronged mechanism: 1) the induction of A20/TNF-α interacting protein 3 leading to the inhibition of the TNF receptor-associated factor 6/nuclear factor κB pathway and 2) the activation of AMP-activated protein kinase/autophagy axis leading to the attenuation of caspase-1 cleavage. Collectively, we demonstrated, for the first time, that γT3 inhibits the NLRP3 inflammasome thereby delaying the progression of type 2 diabetes. This study also provides an insight into the novel therapeutic values of γT3 for treating NLRP3 inflammasome-associated chronic diseases.

Topics: Adipose Tissue; AMP-Activated Protein Kinases; Animals; Carrier Proteins; Caspase 1; Chromans; Diabetes Mellitus, Type 2; Inflammasomes; Inflammation; Insulin Resistance; Interleukin-1beta; Lipopolysaccharides; Macrophages, Peritoneal; Male; Mice; Mice, Inbred NOD; Mice, Knockout; NF-kappa B; NLR Family, Pyrin Domain-Containing 3 Protein; Obesity; Signal Transduction; Tumor Necrosis Factor-alpha; Vitamin E

We have previously demonstrated that gamma tocotrienol (γT3) potently inhibits adipocyte hyperplasia in human adipose-derived stem cells (hASCs). In this study, our objective was to investigate the γT3 effects on early-onset obesity, inflammation and insulin resistance in vivo.. Young C57BL/6J mice were fed a high-fat (HF) diet supplemented with 0.05% γT3 for 4 weeks. The concentrations of γT3 in plasma and adipose tissue were measured using high-performance liquid chromatography. Effects of γT3 on body weight gain, adipose volume, plasma levels of fasting glucose, insulin (enzyme-linked immunosorbent assay (ELISA)), proinflammatory cytokines (mouse cytokine array), insulin signaling (western blotting) and gene expression (quantitative real-time PCR, qPCR) in the liver and adipose tissue were examined. Influences of γT3 on [3H]-2-deoxyglucose uptake and lipopolysaccharide (LPS)-mediated NFκB signaling (western blotting) were assessed in hASCs. Effects of γT3 on macrophage M1/M2 activation were investigated using qPCR in mouse bone marrow-derived macrophages.. After a 4-week treatment, γT3 accumulated in adipose tissue and reduced HF diet-induced weight gain in epididymal fat, mesenteric fat and the liver. Compared with HF diet-fed mice, HF+γT3-fed mice were associated with (1) decreased plasma levels of fasting glucose, insulin and proinflammatory cytokines, (2) improved glucose tolerance and (3) enhanced insulin signaling in adipose tissue. There were substantial decreases in macrophage specific markers, and monocyte chemoattractant protein-1, indicating that γT3 reduced the recruitment of adipose tissue macrophages (ATMs). In addition, γT3 treatment in human adipocytes resulted in (1) activation of insulin-stimulated glucose uptake and (2) a significant suppression of MAP kinase and NFκB activation. In parallel, γT3 treatment led to a reduction of LPS-mediated M1 macrophage polarization.. Our results demonstrated that γT3 ameliorates HF diet-mediated obesity and insulin resistance by inhibiting systemic and adipose inflammation, as well as ATM recruitment.

Topics: Adipose Tissue; Animals; Anti-Obesity Agents; Blotting, Western; Chromans; Diet, High-Fat; Disease Models, Animal; Enzyme-Linked Immunosorbent Assay; Inflammation; Insulin Resistance; Macrophage Activation; Macrophages; Male; Mice; Mice, Inbred C57BL; Obesity; Real-Time Polymerase Chain Reaction; Vitamin E

Pancreatic cancers generally respond poorly to chemotherapy, prompting a need to identify agents that could sensitize tumors to treatment. In this study, we investigated the response of human pancreatic cells to γ-tocotrienol (γ-T3), a novel, unsaturated form of vitamin E found in palm oil and rice bran oil, to determine whether it could potentiate the effects of gemcitabine, a standard of care in clinical treatment of pancreatic cancer. γ-T3 inhibited the in vitro proliferation of pancreatic cancer cell lines with variable p53 status and potentiated gemcitabine-induced apoptosis. These effects correlated with an inhibition of NF-κB activation by γ-T3 and a suppression of key cellular regulators including cyclin D1, c-Myc, cyclooxygenase-2 (COX-2), Bcl-2, cellular inhibitor of apoptosis protein, survivin, vascular endothelial growth factor (VEGF), ICAM-1, and CXCR4. In an orthotopic nude mouse model of human pancreatic cancer, p.o. administration of γ-T3 inhibited tumor growth and enhanced the antitumor properties of gemcitabine. Immunohistochemical analysis indicated a correlation between tumor growth inhibition and reduced expression of Ki-67, COX-2, matrix metalloproteinase-9 (MMP-9), NF-κB p65, and VEGF in the tissue. Combination treatment also downregulated NF-κB activity along with the NF-κB-regulated gene products, such as cyclin D1, c-Myc, VEGF, MMP-9, and CXCR4. Consistent with an enhancement of tumor apoptosis, caspase activation was observed in tumor tissues. Overall, our findings suggest that γ-T3 can inhibit the growth of human pancreatic tumors and sensitize them to gemcitabine by suppressing NF-κB-mediated inflammatory pathways linked to tumorigenesis.

Topics: Animals; Antimetabolites, Antineoplastic; Apoptosis; Blotting, Western; Cell Proliferation; Chromans; Cyclooxygenase 2; Deoxycytidine; Drug Resistance, Neoplasm; Gemcitabine; Humans; Inflammation; Inflammation Mediators; Male; Matrix Metalloproteinase 9; Mice; Mice, Nude; NF-kappa B; Pancreatic Neoplasms; Reverse Transcriptase Polymerase Chain Reaction; Ribonucleotide Reductases; RNA, Messenger; Tumor Cells, Cultured; Vitamin E; Xenograft Model Antitumor Assays