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Adipose tissue (AT) inflammation promotes insulin resistance (IR) and other obesity complications. AT inflammation and IR are associated with oxidative stress, adipocyte death, and the scavenging of dead adipocytes by proinflammatory CD11c+ AT macrophages (ATMΦ). We tested the hypothesis that supplementation of an obesitogenic (high-fat) diet with whole blueberry (BB) powder protects against AT inflammation and 18. Male C57BI/6j mice were maintained for 8 wk on 1 of 3 diets: low-fat (10% of energy) diet (LFD), high-fat (60% of energy) diet (HFD) or the HFD containing 4% (wt:wt) whole BB powder (1:1 Vaccinium ashei and V. corymbosum) (HFD+B). BB supplementation (2.7% of total energy) did not affect HFD-associated alterations in energy intake, metabolic rate, body weight, or adiposity. We observed an emerging pattern of gene expression in AT of HFD mice indicating a shift toward global upregulation of inflammatory genes (tumor necrosis factor-α, interleukin-6, monocyte chemoattractant protein 1, inducible nitric oxide synthase), increased M1-polarized ATMΦ (CD11c+), and increased oxidative stress (reduced glutathione peroxidase 31. This shift was attenuated or nonexistent in HFD+B-fed mice. Furthermore, mice fed the HFD+B were protected from IR and hyperglycemia coincident with reductions in adipocyte death. Salutary effects of BR on adipocyte physiology and ATMΦ gene expression may reflect the ability of BB anthocyanins to alter mitogen-activated protein kinase and nuclear factor-κB stress signaling pathways, which regulate cell fate and inflammatory genes. These results suggest that cytoprotective and antiinflammatory actions of dietary BB can provide metabolic benefits to combat obesity-associated pathology. [ABSTRACT FROM AUTHOR]

Hepatocyte apoptosis in addition to oxidative stress could be a key component in the pathogenesis of nonalcoholic steatohepatitis (NASH). However, the underlying mechanisms of hepatocellular apoptotic response associated with oxidative stress have not been investigated in high-fat diet (HFD)-induced NASH models. In this study, Sprague-Dawley rats were fed either a Lieber-DeCarli control diet (CD; 35% energy from fat) or a HFD (71% energy from fat) for 6 wk. Pathologic lesions, lipid peroxidation products, and apoptotic hepatocytes in the liver were examined. The expressions of hepatic tumor necrosis factor-α (TNFα) and protein concentrations of cleaved caspase-3, cytochrome p4502E1 (CYP2E1), phosphorylated c-Jun NH2-terminal kinase (JNK), Bax, Bcl-2, and Bcl-xl were measured. Results showed that the key histological features of NASH, including steatosis, inflammatory cell infiltration, and ballooning degeneration of hepatocytes, were induced by HFD feeding, with increased hepatic TNFα m RNA expression. H FD-fed rats had elevated lipid peroxidation products and CYP2E 1 protein in the liver. The apoptotic hepatocytes were significantly greater in livers of rats fed HFD than in those fed CD, and these were associated with a higher level of cleaved caspase-3. In addition, HFD feeding increased both hepatic phosphorylated JNK and pro-apoptotic Bax but did not affect anti-apoptotic Bcl-2 and Bcl-xl compared with CD feeding. These data indicate that the increased oxidative stress and its associated JNK activation as well as an imbalance of pro- and anti-apoptotic proteins in the Bcl-2 family all contribute to high hepatocyte apoptosis that may play an important role in the pathogenesis of NASH in this model. [ABSTRACT FROM AUTHOR]

Tumor necrosis factor (TNF)-related apoptosis-inducing ligand (TRAIL) is a member of the TNF superfamily that exhibits specific tumoricidal activity against a variety of tumors. It is expressed on different cells of the immune system and plays a role in natural killer cell–mediated tumor surveillance. In allogeneic hematopoietic-cell transplantation, the reactivity of the donor T cell against malignant cells is essential for the graft-versus-tumor (GVT) effect. Cytolytic activity of T cells is primarily mediated through the Fas–Fas ligand and perforin–granzyme pathways. However, T cells deficient for both Fas ligand and perforin can still exert GVT activity in vivo in mouse models. To uncover a potential role for TRAIL in donor T cell–mediated GVT activity, we compared donor T cells from TRAIL-deficient and wild-type mice in clinically relevant mouse bone-marrow transplantation models. We found that alloreactive T cells can express TRAIL, but the absence of TRAIL had no effect on their proliferative and cytokine response to alloantigens. TRAIL-deficient T cells showed significantly lower GVT activity than did TRAIL-expressing T cells, but no important differences in graft-versus-host disease, a major complication of allogeneic hematopoietic cell transplantation, were observed. These data suggest that strategies to enhance TRAIL-mediated GVT activity could decrease relapse rates of malignancies after hematopoietic cell transplantation without exacerbation of graft-versus-host disease. [ABSTRACT FROM AUTHOR]

Tumor necrosis factor-α (TNF-α) stimulates lipolysis in human adipocytes. However, the mechanisms regulating this process are largely unknown. We demonstrate that TNF-α increases lipolysis in differentiated human adipocytes by activation of mitogen-activated protein kinase (MEK), extracellular signal-related kinase (ERK), and elevation of intracellular cAMP. TNF-α activated ERK and increased lipolysis; these effects were inhibited by two specific MEK inhibitors, PD98059 and U0126. TNF-α treatment caused an electrophoretic shift of perilipin from 65 to 67 kDa, consistent with perilipin hyperphosphorylation by activated cAMP dependent protein kinase A (PKA). Coincubation with TNF-α and MEK inhibitors caused perilipin to migrate as a single 65-kDa band. Consistent with the hypothesis that TNF-α induces perilipin hyperphosphorylation by activating PKA, TNF-α increased intracellular cAMP ∼l.7-fold, and the increase was abrogated by PD98059. Furthermore, H89, a specific PKA inhibitor, blocked TNF-α-induced lipolysis and the electrophoretic shift of perilipin, suggesting a role for PKA in TNF-α-induced lipolysis. Finally, TNF-α decreased the expression of cyclic-nucleotide phosphodiesterase 3B (PDE3B) by ∼50%, delineating a mechanism by which TNF-α could increase intracellular cAMP. Cotreatment with PD98059 restored PDE3B expression. These studies suggest that in human adipocytes, TNF-α stimulates lipolysis through activation of MEK-ERK and subsequent increase in intracellular cAMP. [ABSTRACT FROM AUTHOR]

Investigates the effects of peroxisome proliferator-activated receptor(PPAR)-γ agonists and PPARα agonist on HIV replication and tumor necrosis factor (TNF)α production in peripheral blood mononuclear cells. Inhibition of cell replication; Absence of correlation of TNFα inhibition with the quantitative decrease in HIV replication.