Obesity is associated with an increasing prevalence of cardiovascular diseases and metabolic syndrome. It is of paramount importance to reduce obesity-associated cardiac dysfunction and impaired energy metabolism. In this study, the activation of the AMP-activated protein kinase (AMPK) pathway by punicalagin (PU), a major ellagitannin in pomegranate was investigated in the heart of a rat obesity model. In male SD rats, eight-week administration of 150 mg/kg pomegranate extract (PE) containing 40% punicalagin sufficiently prevented high-fat diet (HFD)-induced obesity associated accumulation of cardiac triglyceride and cholesterol as well as myocardial damage. Concomitantly, the AMPK pathway was activated, which may account for prevention of mitochondrial loss via upregulating mitochondrial biogenesis and amelioration of oxidative stress via enhancing phase II enzymes in the hearts of HFD rats. Together with the normalized expression of uncoupling proteins and mitochondrial dynamic regulators, PE significantly prevented HFD-induced cardiac ATP loss. Through in vitro cultures, we showed that punicalagin was the predominant component that activated AMPK by quickly decreasing the cellular ATP/ADP ratio specifically in cardiomyocytes. Our findings demonstrated that punicalagin, the major active component in PE, could modulate mitochondria and phase II enzymes through AMPK pathway to prevent HFD-induced cardiac metabolic disorders.
Hydroxytyrosol (HT) is a major polyphenolic compound found in olive oil with reported anti-cancer and anti-inflammatory activities. However, the neuroprotective effect of HT on type 2 diabetes remains unknown. In the present study, db/db mice and SH-SY-5Y neuroblastoma cells were used to evaluate the neuroprotective effects of HT. After 8 weeks of HT administration at doses of 10 and 50 mg/kg, expression levels of the mitochondrial respiratory chain complexes I/II/IV and the activity of complex I were significantly elevated in the brain of db/db mice. Likewise, targets of the antioxidative transcription factor nuclear factor erythroid 2 related factor 2 including p62 (sequestosome-1), haeme oxygenase 1 (HO-1), and superoxide dismutases 1 and 2 increased, and protein oxidation significantly decreased. HT treatment was also found to activate AMP-activated protein kinase (AMPK), sirtuin 1 and PPARg coactivator-1a, which constitute an energy-sensing protein network known to regulate mitochondrial function and oxidative stress responses. Meanwhile, neuronal survival indicated by neuron marker expression levels including activity-regulated cytoskeleton-associated protein, N-methyl-D-aspartate receptor and nerve growth factor was significantly improved by HT administration. Additionally, in a high glucose-induced neuronal cell damage model, HT effectively increased mitochondrial complex IV and HO-1 expression through activating AMPK pathway, followed by the prevention of high glucose-induced production of reactive oxygen species and declines of cell viability and V O2 capacity. Our observations suggest that HT improves mitochondrial function and reduces oxidative stress potentially through activation of the AMPK pathway in the brain of db/db mice. The escalating epidemic of the metabolic syndromes, including obesity and diabetes, represents one of the most pressing and costly medical challenges in public health of the twentyfirst century. A recent study has reported that 336 million people had diabetes in 2011, and this number is expected to rise to 552 million by 2030(1) . Diabetes is recognised by hyperglycaemia and glucose intolerance due to insulin deficiency, impaired insulin sensitivity or both. Type 2 diabetes mellitus (T2DM) is predominant and accounts for 90 % of patients with diabetes (2) . It is well established that diabetes has been associated with slowly progressing brain damage that impaired cognitive function (3 -5) . Although there is some evidence for a relationship between T2DM and brain damage, the mechanisms driving it remain unknown. Clinical studies have indicated that cognitive dysfunction is correlated with brain atrophy in patients with diabetes (3,6,7) . Kumar et al.(8) reported smaller total brain grey matter volumes in patients with diabetes, and the decrease is more pronounced in the cortical grey matter of the temporal lobe (9) . Despite the limited knowledge on the underlying mechanisms for cognitive dysfunction during the progression of T2DM, mitochondrial dysfunction and oxida...
Both hydrostatic and osmotic pressures are altered in the tumour microenvironment. Glioblastoma (GBM) is a brain tumour with high invasiveness and poor prognosis. We hypothesized that physical and osmotic forces regulate glioblastoma (GBM) invasiveness. the osmotic pressure of GBM cell culture medium was adjusted using sodium chloride or water. Alternatively, cells were subjected to increased hydrostatic force. The proteolytic profile and epithelial-mesenchymal transition (EMT) were investigated using zymography and real-time qPCR. The EMT markers assessed were Snail-1, Snail-2, N-cadherin, Twist and vimentin. Invasion was investigated in vitro using extracellular matrixcoated Transwell inserts. In response to osmotic and mechanical pressure, GBM cell lines U87 and U251 and patient-derived neural oncospheres upregulated the expression of urokinase-type plasminogen activator (upA) and/or matrix metalloproteinases (MMps) as well as some of the eMt markers tested. the adherent cell lines invaded more when placed in media of increased osmolality. therefore, GBM respond to osmotic or mechanical pressure by increasing matrix degrading enzyme production, and adopting a phenotype reminiscent of eMt. Better understanding the molecular and cellular mechanisms by which increased pressure promotes GBM invasiveness may help to develop innovative therapeutic approaches. Physical solid and fluid forces play a key role when solid tumours grow, progress and also respond to therapy 1. Compressive stresses affect cancer cells by promoting invasiveness and metastasis 2. Tumours are generally hypoperfused, and interstitial fluid pressure is increased compared to normal tissue 1,3,4 with both increased hydrostatic pressure 4 and oncotic pressure 5,6. Increased interstitial fluid pressure results from abnormal blood and lymphatic vessels, fibrosis and contraction of the matrix by stromal cells 7. In addition to these stresses common to most solid tumours, brain tumours experience pressure when the tumour grows within a space limited by the skull 8. Glioblastoma is the most common primary brain cancer. The average survival time is approximately one year after diagnosis. A major feature of GBM that contributes to its poor prognosis is its high invasiveness. The urokinase-type plasminogen activator (uPA) derives its name from its ability to activate plasminogen into plasmin. While tissue-type plasminogen activator (tPA) plays a role in the fibrinolytic process, uPA is involved in cell migration and tissue remodelling, thereby playing a major role in cancer development and spreading. This role is especially crucial in glioblastoma 9-11. Equally important and complementary to the uPA system, MMPs play a key role in the control of the tumour microenvironment and ECM, thereby modulating tumor growth, angiogenesis, invasion and metastasis. Recently reports showed that the MMPs play pivotal roles in the invasiveness of GBM by degrading surrounding tissue, activating signal transduction, releasing ECM-bound growth factors, activating
Macrophages are abundant in the tumor microenvironment where they adopt a pro-tumor phenotype following alternative polarization induced by paracrine factors from cancer and stromal cells. In contrast, classically activated macrophages have tumoricidal activities, such that the polarization of tumor-associated macrophages has become a novel therapeutic target. Toll-like receptor 4 engagement promotes classical activation of macrophages, and recent literature suggests TLR4 agonism to prevent metastasis and promote survival in experimental metastasis models. A growing number of studies indicate that TLR4 can respond to opioids, including the opioid receptor-inactive morphine metabolite morphine-3-glucuronide (M3G). We measured the activation of TLR4 in a reporter cell line exogenously expressing TLR4 and TLR4 co-receptors, and confirmed that M3G weakly but significantly activates TLR4. We hypothesized that M3G would promote the expression of classical activation signature genes in macrophages in vitro. We exposed mouse and human macrophage cell lines to M3G or the TLR4 activator lipopolysaccharide (LPS), alone or in combination with interferon gamma (IFN-γ). The classical macrophage activation markers tested were iNOS, CD86, IL-6, or TNF-α in RAW 264.7 cells and IL-6, IL-12, IL-23, TNF-α, CXCL10, and CXCL11 in THP1 cells. Our results show that despite exhibiting TLR4-activation ability, M3G does not elicit the expression of classical activation markers in LPS-responsive macrophages.
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