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Weijie Chen, Junlian Wang, Yong Luo, Tao Wang, Xiaochun Li, Aiyun Li, Jia Li, Kang Liu, Baolin Liu
BACKGROUND: This study was designed to investigate whether ginsenoside Rb1 (Rb1) and compound K (CK) ameliorated insulin resistance by suppressing endoplasmic reticulum (ER) stress-induced inflammation in adipose tissue. METHODS: To induce ER stress, epididymal adipose tissue from mice or differentiated 3T3 adipocytes were exposed to high glucose. The effects of Rb1 and CK on reactive oxygen species production, ER stress, TXNIP/NLRP3 inflammasome activation, inflammation, insulin signaling activation, and glucose uptake were detected by western blot, emzyme-linked immunosorbent assay, or fluorometry...
October 2016: Journal of Ginseng Research
Takujiro Homma, Junichi Fujii
Heat stress induces intracellular protein denaturation and endoplasmic reticulum (ER) stress, which elicits unfolded protein response (UPR) in cells. UPR involves three ER-localized sensor proteins: the inositol-requiring protein 1α (IRE1α), the dsRNA-activated protein kinase-like ER kinase (PERK), and activating transcription factor-6 (ATF6). However, the precise mechanism by which cells deal with heat stress remains to be elucidated. We report herein that heat stress effectively activates all branches of the UPR...
October 12, 2016: Experimental Cell Research
Craig A Erickson, Balmiki Ray, Logan K Wink, Baindu L Bayon, Ernest V Pedapati, Rebecca Shaffer, Tori L Schaefer, Debomoy K Lahiri
BACKGROUND: Dysregulation of extracellular signal-related kinase (ERK) activity has been potentially implicated in the pathophysiology of autistic disorder (autism). ERK is part of a central intracellular signaling cascade responsible for a myriad of cellular functions. ERK is expressed in peripheral blood lymphocytes, and measurement of activated (phosphorylated) lymphocytic ERK is commonly executed in many areas of medicine. We sought to conduct the first study of ERK activation in humans with autism by utilizing a lymphocytic ERK activation assay...
September 9, 2016: Journal of Psychiatric Research
Zhenpeng Song, Bingrui Xiong, Hua Zheng, Anne Manyande, Xuehai Guan, Fei Cao, Lifang Ren, Yaqun Zhou, Dawei Ye, Yuke Tian
Major histocompatibility class II (MHC II)-specific activation of CD4(+) T helper cells generates specific and persistent adaptive immunity against tumors. Emerging evidence demonstrates that MHC II is also involved in basic pain perception; however, little is known regarding its role in the development of cancer-induced bone pain (CIBP). In this study, we demonstrate that MHC II expression was markedly induced on the spinal microglia of CIBP rats in response to STAT1 phosphorylation. Mechanical allodynia was ameliorated by either pharmacological or genetic inhibition of MHC II upregulation, which was also attenuated by the inhibition of pSTAT1 and pERK but was deteriorated by intrathecal injection of IFNγ...
October 11, 2016: Brain, Behavior, and Immunity
Marat R Talipov, Jaladhi Nayak, Michael Lepley, Robert D Bongard, Daniel S Sem, Ramani Ramchandran, Rajendra Rathore
DUSP5 is an inducible nuclear dual-specificity phosphatase that specifically interacts with and deactivates extracellular signal-regulated kinases ERK1 and ERK2, which are responsible for cell proliferation, differentiation, and survival. The phosphatase domain (PD) of DUSP5 has unique structural features absent in other nuclear DUSPs, such as presence of a secondary anion-binding site in the proximity to the reaction center and a glutamic acid E264 positioned next to the catalytic cysteine C263, as well as a remote intra-molecular disulfide linkage...
October 14, 2016: Biochemistry
Wioletta Rozpędek, Dariusz Pytel, J Alan Diehl, Ireneusz Majsterek
Nowadays more than 24 million people suffer from Alzheimer's disease (AD) that is the most common progressive cause of dementia. Molecular mechanisms of neurodegeneration in Alzheimer's disease is closely link with accumulation of misfolded proteins in the lumen of the endoplasmic reticulum (ER). Deposition of senile plaques is one of the main feature of Alzheimer's disease as well as is strictly correlated with impairment of cognitive abilities. The accumulation of misfolded proteins in the lumen of the ER triggers activation of the ER stress, and subsequently unfolded protein response (UPR) signaling branches, which consists of a cascade of events on the molecular level of nerve cell...
July 29, 2016: Polski Merkuriusz Lekarski: Organ Polskiego Towarzystwa Lekarskiego
Claire M Perks, H A Zielinska, Jing Wang, Caroline Jarrett, A Frankow, Michael R Ladomery, Amit Bahl, Anthony Rhodes, Jon Oxley, Jeff M P Holly
Men who develop prostate cancer (PCa) increasingly have one of the co-morbidities associated with a Western lifestyle that are characterized by hyperinsulinemia, hyperglycemia and increased expression of insulin-like growth factors-I (IGF-I) and IGF-II. Each have been associated with poor prognosis and more aggressive cancers that exhibit increased metabolism and increased glucose uptake. The insulin receptor (IR) has two splice isoforms IR-A and IR-B: IR-A has a higher affinity for IGF-II comparable to that for insulin, whereas the IR-B isoform predominantly just binds to insulin...
2016: Frontiers in Endocrinology
Grace Gar-Lee Yue, Sida Xie, Julia Kin-Ming Lee, Hin-Fai Kwok, Si Gao, Yin Nian, Xiao-Xiao Wu, Chun-Kwok Wong, Ming-Hua Qiu, Clara Bik-San Lau
Actein is a triterpene glycoside isolated from the rhizomes of Cimicifuga foetida (Chinese herb "shengma") which could inhibit the growth of breast cancer cells. Nevertheless, the effect of actein on angiogenesis, which is an essential step for tumor growth and metastasis, has never been reported. Hence, this study aimed to investigate the in vitro and in vivo effects of actein on angiogenesis using human microvascular endothelial cells (HMEC-1), matrigel plug and tumor-bearing mouse models. Our results showed that actein significantly inhibited the proliferation, reduced the migration and motility of endothelial cells, and it could suppress the protein expressions of VEGFR1, pJNK and pERK, suggesting that JNK/ERK pathways were involved...
October 12, 2016: Scientific Reports
Boyu Yang, Yue Xu, Yaguang Hu, Yiwen Luo, Xi Lu, Ching Kit Tsui, Lin Lu, Xiaoling Liang
Madecassic acid (MA) is an abundant triterpenoid in Centella asiatica (L.) Urban. (Apiaceae) that has been used as a wound-healing, anti-inflammatory and anti-cancer agent. Up to now, the effects of MA against oxidative stress remain unclear. In this study, we investigated the effect of MA and its mechanisms on hypoxia-induced human Retinal Microvascular Endothelial Cells (hRMECs). hRMECs were pre-treated with different concentrations of MA (0-50μM) for 30min before being incubated under hypoxia condition (37°C, 5% CO2 and 95% N2)...
October 8, 2016: Biomedicine & Pharmacotherapy, Biomédecine & Pharmacothérapie
Noriyoshi Iriyama, Yoshihiro Hatta, Masami Takei
It has been shown that an increase in cytotoxic lymphocyte counts in the peripheral blood occurs rapidly after taking dasatinib, but the underlying mechanism is not yet elucidated. To investigate the influence of dasatinib on signal transduction pathways, we investigated the changes in JAK-STAT, mitogen-activated protein kinase (MAPK), and AKT in cytotoxic lymphocytes, including natural killer (NK) cells and cytotoxic T lymphocytes (CTLs), before and after dasatinib treatment in chronic myeloid leukemia patients...
October 10, 2016: Cancer Medicine
Ritesh K Srivastava, Changzhao Li, Zhiping Weng, Anupam Agarwal, Craig A Elmets, Farrukh Afaq, Mohammad Athar
Arsenicals are painful, inflammatory and blistering causing agents developed as chemical weapons in World War I/II. However, their large stockpiles still exist posing threat to public health. Phenylarsine oxide (PAO), a strong oxidant and a prototype arsenical is tested for its suitability to defining molecular mechanisms underlying arsenicals-mediated tissue injury. Topically applied PAO induces cutaneous erythema, edema and micro-blisters. These gross inflammatory responses were accompanied by the enhanced production of pro-inflammatory cytokines, ROS and unfolded protein response (UPR) signaling activation...
October 11, 2016: Scientific Reports
Soshi Kanemoto, Ryota Nitani, Tatsuhiko Murakami, Masayuki Kaneko, Rie Asada, Koji Matsuhisa, Atsushi Saito, Kazunori Imaizumi
The endoplasmic reticulum (ER) plays a pivotal role in maintaining cellular homeostasis. However, numerous environmental and genetic factors give rise to ER stress by inducing an accumulation of unfolded proteins. Under ER stress conditions, cells initiate the unfolded protein response (UPR). Here, we demonstrate a novel aspect of the UPR by electron microscopy and immunostaining analyses, whereby multivesicular body (MVB) formation was enhanced after ER stress. This MVB formation was influenced by inhibition of ER stress transducers inositol required enzyme 1 (IRE1) and PKR-like ER kinase (PERK)...
October 7, 2016: Biochemical and Biophysical Research Communications
Junnan Liu, Maolin Xiao, Jianjun Li, Delin Wang, Yunfeng He, Jiang He, Fei Gao, Li Mai, Ying Li, Yong Liang, Yuejiang Liu, Xiaoni Zhong
BACKGROUND: Currently, the role of UPR signaling in prostate cancer (PCa) is unclear. To evaluate the relationship between UPR signaling pathway and the prognosis of PCa, we explored the expression of IRE1, PERK, and ATF6 in tissues. METHODS: A total of 160 PCa and 30 benign prostate hyperplasia (BPH) tissues were collected. The expression of UPR signaling factors was assessed by immunohistochemistry. The staining characteristics were identified and evaluated for associations with clinicopathologic parameters, PSA recurrence survival, and prostate cancer-specific morality...
October 8, 2016: Prostate
Silvina Laura Lompardía, Mariángeles Díaz, Daniela Laura Papademetrio, Matías Pibuel, Élida Álvarez, Silvia Elvira Hajos
Chronic myeloid leukemia (CML) is a myeloproliferative syndrome characterized by the presence of the Philadelphia chromosome which encodes a constitutively activated tyrosine kinase (BCR-ABL). The first line treatment for CML consists on BCR-ABL inhibitors such as Imatinib. Nevertheless, such treatment may lead to the selection of resistant cells. Therefore, it is of great value to find molecules that enhance the anti-proliferative effect of first-line drugs. Hyaluronan is the main glycosaminglican of the extracellular matrix which is involved in tumor progression and multidrug resistance...
October 8, 2016: Investigational New Drugs
Zhuofeng Ding, Wei Xu, Jie Zhang, Wangyuan Zou, Qulian Guo, Changsheng Huang, Chang Liu, Tao Zhong, Jun-Ming Zhang, Zongbin Song
Bone cancer pain (BCP) is the most common complication in patients with bone cancer. Glial cell line-derived neurotrophic factor (GDNF) is believed to be involved in chronic pain conditions. In this article, the expression and roles of GDNF were studied in a rat model of BCP induced by tibia injection of Walker 256 rat mammary gland carcinoma cells. Significant mechanical and thermal hyperalgesia and ongoing pain were observed beginning as early as day 5 post injection. The expression level of GDNF protein examined on day 16 after tibia injection was decreased in the L3 dorsal root ganglion (DRG) and lumbar spinal cord, but not in other spinal levels or the anterior cingulate cortex...
September 22, 2016: International Journal of Cancer. Journal International du Cancer
Siying Zhu, Barbara C McGrath, Yuting Bai, Xin Tang, Douglas R Cavener
PERK (EIF2AK3) is an ER-resident eIF2α kinase required for behavioral flexibility and metabotropic glutamate receptor-dependent long-term depression via its translational control. Motivated by the recent discoveries that PERK regulates Ca(2+) dynamics in insulin-secreting β-cells underlying glucose-stimulated insulin secretion, and modulates Ca(2+) signals-dependent working memory, we explored the role of PERK in regulating Gq protein-coupled Ca(2+) dynamics in pyramidal neurons. We found that acute PERK inhibition by the use of a highly specific PERK inhibitor reduced the intracellular Ca(2+) rise stimulated by the activation of acetylcholine, metabotropic glutamate and bradykinin-2 receptors in primary cortical neurons...
October 1, 2016: Molecular Brain
Ming-Jenn Chen, De-Wei Wu, Yao-Chen Wang, Chi-Yi Chen, Huei Lee
PAK1 confers resistance to the estrogen antagonist tamoxifen in breast cancer. However, a role for PAK1 remains to be elucidated for chemoresistance and prognosis in non-small cell lung cancer (NSCLC). We provide evidence that PAK1 confers cisplatin resistance by increasing β-catenin expression through ERK/GSK3β signaling. The increased β-catenin expression promotes sphere cell formation and expression of stemness markers and this β-catenin-induced stemness is responsible for PAK1-mediated cisplatin resistance...
October 7, 2016: Scientific Reports
Noll L Campbell, Anthony J Perkins, Pamela Bradt, Sinem Perk, Ronald C Wielage, Malaz A Boustani, Daniel B Ng
STUDY OBJECTIVE: To determine the association between Anticholinergic Cognitive Burden (ACB) score and both cognitive impairment and health care utilization among a diverse ambulatory older adult population. DESIGN: Retrospective cohort study. DATA SOURCE: Medication exposure and other clinical data were extracted from the Regenstrief Medical Record System (RMRS), and cognitive diagnosis derived from a dementia screening and diagnosis study...
October 6, 2016: Pharmacotherapy
Hsueh-Chun Wang, Yufeng Zhou, Shau-Ku Huang
Previously we reported that exposure of mouse and human mast cells to aryl hydrocarbon receptor (AhR) ligands resulted in reactive oxygen species (ROS)- and calcium (Ca(2+))-dependent activation of mast cells in vitro and in vivo. However, the mechanisms through which the AhR-ligand axis mediates stress response, Ca(2+) signaling and subsequent mast cell activation remain to be fully elucidated. Evidence is provided herein that SHP-2 is critical in regulating AhR-mediated ER stress response and intracellular Ca(2+) dynamics...
October 5, 2016: Archives of Toxicology
Sheng-Fan Wang, Meng-Shian Chen, Yueh-Ching Chou, Yune-Fang Ueng, Pen-Hui Yin, Tien-Shun Yeh, Hsin-Chen Lee
Mitochondrial DNA mutations and defects in mitochondrial enzymes have been identified in gastric cancers, and they might contribute to cancer progression. In previous studies, mitochondrial dysfunction was induced by oligomycin-enhanced chemoresistance to cisplatin. Herein, we dissected the regulatory mechanism for mitochondrial dysfunction-enhanced cisplatin resistance in human gastric cancer cells. Repeated cisplatin treatment-induced cisplatin-resistant cells exhibited high SLC7A11 (xCT) expression, and xCT inhibitors (sulfasalazine or erastin), xCT siRNA, or a GSH synthesis inhibitor (buthionine sulphoximine, BSO) could sensitize these cells to cisplatin...
September 30, 2016: Oncotarget
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