bims-stacyt 2018-08-12 papers

Mol Cells. 2018 Jul 30.

Roles of Endoplasmic Reticulum Stress in Immune Responses.

The endoplasmic reticulum (ER) is a critical organelle for protein synthesis, folding and modification, and lipid synthesis and calcium storage. Dysregulation of ER functions leads to the accumulation of misfolded- or unfolded-protein in the ER lumen, and this triggers the unfolded protein response (UPR), which restores ER homeostasis. The UPR is characterized by three distinct downstream signaling pathways that promote cell survival or apoptosis depending on the stressor, the intensity and duration of ER stress, and the cell type. Mammalian cells express the UPR transducers IRE1, PERK, and ATF6, which control transcriptional and translational responses to ER stress. Direct links between ER stress and immune responses are also evident, but the mechanisms by which UPR signaling cascades are coordinated with immunity remain unclear. This review discusses recent investigations of the roles of ER stress in immune responses that lead to differentiation, maturation, and cytokine expression in immune cells. Further understanding of how ER stress contributes to the pathogenesis of immune disorders will facilitate the development of novel therapies that target UPR pathways.

DOI: https://doi.org/10.14348/molcells.2018.0241

J Cell Physiol. 2018 Aug 04.

Adipose tissue dysfunction in cancer cachexia.

Sahar I Daas, Balsam R Rizeq, Gheyath K Nasrallah.

Cancer cachexia is a complex disorder that is driven by inflammation and metabolic imbalances, resulting in extreme weight loss. Adipose tissue, a main player in cancer cachexia, is an essential metabolic and secretory organ consisting of both white adipose tissue (WAT) and brown adipose tissue. Its secretory products, including adipokines and cytokines, affect a wide variety of central and peripheral organs, such as the skeletal muscle, brain, pancreas, and liver. Therefore, a combination of metabolic alterations, and systemic inflammation dysregulation of both anti-inflammatory and proinflammatory modulators contribute toward adipose tissue wasting in cancer cachexia. Growing evidence suggests that, during cancer cachexia, WAT undergoes a browning process, resulting in increased lipid mobilization and energy expenditure. In this review, we have summarized the characteristics of cancer cachexia and WAT browning. Furthermore, this review describes how adipose tissue becomes inflamed in cancer, shedding light on the combinatorial action of multiple secreted macromolecules, cytokines, hormones, and tumor mediators on adipose tissue dysfunction. We also highlight the inflammatory responses, energy utilization defects, and molecular mechanisms underlying the WAT dysfunction and browning in cancer cachexia. Further, the actual mechanisms behind the loss of adipose tissue are unknown, but have been attributed to increased adipocyte lipolysis, systemic inflammation, and apoptosis or reduced lipogenesis. The understanding of adipose tissue dysfunction in cancer cachexia will hopefully promote the development of new therapeutic approaches to prevent or treat this wasting syndrome.

Keywords: WAT browning; brown adipocytes; cancer cachexia; inflammation; white adipocytes

DOI: https://doi.org/10.1002/jcp.26811

Immunol Lett. 2018 Aug 01. pii: S0165-2478(18)30276-1. [Epub ahead of print]202 23-30

Vitamin D inhibits palmitate-induced macrophage pro-inflammatory cytokine production by targeting the MAPK pathway.

Wei Li, Zhuo Liu, Renqiao Tang, Shengrong Ouyang, Sen Li, Jianxin Wu.

Vitamin D insufficiency is associated with chronic inflammatory diseases. However, the mechanism by which vitamin D reduces obesity-related inflammation remains poorly understood. In this study, we investigated the inhibitory effects of vitamin D on palmitate-induced inflammatory response in macrophages and explored the potential mechanisms of vitamin D action. The effect of vitamin D on the expression of inflammatory factors induced by palmitate, a saturated fatty acid, was investigated using human THP-1 macrophages and murine RAW 264.7 cells. To elucidate the mechanism by which vitamin D affects palmitate-induced inflammatory cytokine production, we investigated the activity of stress kinase-related proteins. Palmitate significantly increased TNF-α and IL-6 expression and secretion in THP-1 and RAW 264.7 macrophages. Treatment with the active form of vitamin D inhibited palmitate-induced TNF-α and IL-6 production in macrophages. Furthermore, vitamin D significantly reduced palmitate-stimulated activation of c-Jun N-terminal kinase (JNK) and extracellular signal-regulated kinase 1/2 (ERK1/2). The mitogen-activated protein kinase signaling pathway partly accounts for the induction of pro-inflammatory cytokines by palmitate. Our data suggest that the attenuation of palmitate-induced TNF-α and IL-6 gene expression and protein secretion by vitamin D are associated with reduced activation of JNK and ERK1/2.

Keywords: MAPK signaling pathway; Macrophage; Pro-inflammatory cytokines; Saturated fatty acids; Vitamin D

DOI: https://doi.org/10.1016/j.imlet.2018.07.009

Life Sci. 2018 Aug 01. pii: S0024-3205(18)30441-7. [Epub ahead of print]

Pharmacological evaluation of novel PKR inhibitor indirubin-3-hydrazone in-vitro in cardiac myocytes and in-vivo in wistar rats.

Mary Priyanka Udumula, Audesh Bhat, Sureshbabu Mangali, Jaspreet Kalra, Indu Dhar, Dharamrajan Sriram, Arti Dhar.

AIMS: Double stranded protein kinase R cellular response is associated with various stress signals such as nutrients, endoplasmic stress, cytokines and mechanical stress. Increased PKR activity has been observed under diabetic and cardiovascular disease conditions. Most of the currently available PKR inhibitors are non-specific and have other effects as well. Thus, the aim of the present study was to examine the effect of novel PKR inhibitor indirubin-3-hydrazone (IHZ) in cultured rat H9C2 cardiomyocytes and wistar rats.MATERIALS AND METHODS: PKR expression was determined by Q-PCR, immunofluorescence and immunoblotting. The expression of different gene markers for apoptosis was measured by RT-PCR. Apoptosis and oxidative stress were determined by flow cytometry.
KEY FINDINGS: High glucose (HG) treated H9C2 cardiomyocytes and high fructose (HF) treated wistar rats developed a significant increase in PKR expression. A significant increase in apoptosis and generation of reactive oxygen species was also observed in HG treated H9C2 cells and HF treated rats. Reduced vacuole formation and prominent nuclei were also observed in high glucose treated cells. Cardiac hypertrophy and increased fibrosis were observed in HF treated rats. All these effects of HG and HF were attenuated by novel PKR inhibitor, indirubin-3-hydrazone.
SIGNIFICANCE: Our results indicate IHZ as an effective inhibitor of PKR in vitro and in-vivo, thus it may prove very useful in blocking the multiple harmful effects of PKR.

Keywords: Cardiomyocytes; High fructose; High glucose; Indirubin-3-hydrazone

DOI: https://doi.org/10.1016/j.lfs.2018.07.055