bims-stacyt 2018-01-14 papers

Biochem Biophys Res Commun. 2018 Jan 03. pii: S0006-291X(18)30006-8. [Epub ahead of print]

STIM1 deficiency protects the liver from ischemia/reperfusion injury in mice.

Hepatic ischemia reperfusion (I/R) injury is unavoidable in various clinical conditions. Despite considerable investigation, the underlying molecular mechanism revealing liver I/R injury remains elusive. Stromal interaction molecule 1 (STIM1) plays essential role in regulating the induction of cellular responses to a number of stress conditions, including temperature changes, elevated ROS, and hypoxia. Here, to explore if STIM1 is involved in hepatic injury, wild type (WT) and STIM1-knockout (STIM1-/-) mice were subjected to I/R. Our results indicated that the WT mice with hepatic I/R injury showed higher STIM1 expressions from gene and protein levels in liver tissue samples. Similar results were observed in hypoxia-exposed cells in vitro. Significantly, STIM1-/- attenuated hepatic injury compared to the WT mice after I/R, as evidenced by the improved pathological alterations in liver sections. WT mice subjected to liver I/R showed higher serum alanine aminotransferase (ALT) and aminotransferase (AST) levels, as well as pro-inflammatory cytokines, tumor necrosis factor-α (TNF-α), interleukin (IL)-6 and IL-1β, which were significantly reduced by STIM1-/-. In addition, STIM1-/- also decreased the liver mRNA levels of pro-inflammatory cytokines in mice after I/R injury. Furthermore, significantly decreased oxidative stress was found in STIM1-/- mice after I/R injury compared to the WT group of mice, evidenced by the enhanced superoxide dismutase (SOD) activity and the reduced malondialdehyde (MDA) and reactive oxygen species (ROS) levels in liver tissue samples. Moreover, STIM1-/- mice with hepatic I/R injury displayed the down-regulated nuclear factor of activated T cell (NFAT1), Orai1 and cleaved Caspase-3 levels in liver, contributing to apoptosis suppression. The results above were confirmed in hypoxia-treated cells lacking of STIM1 expression. Together, the findings suggested that STIM1-deletion protects the liver from I/R injury in mice through inhibiting inflammation, oxidative stress and apoptosis. STIM1 could be considered as a potential therapeutic target to ameliorate I/R injury.

Keywords: Apoptosis; I/R injury; Inflammation; Oxidative stress; STIM1

DOI: https://doi.org/10.1016/j.bbrc.2018.01.006

J Biol Chem. 2018 Jan 05. pii: jbc.M117.813675. [Epub ahead of print]

Regulation of gammaherpesvirus lytic replication by endoplasmic reticulum stress-induced transcription factors ATF4 and CHOP.

Xing-Chen Zhou, Si-Han Dong, Zhong-Shun Liu, Shuai Liu, Chao-Can Zhang, Xiao-Zhen Liang.

The stress-induced unfolded protein response (UPR) in the endoplasmic reticulum (ER) involves various signaling crosstalks and controls cell fate. B-cell receptor (BCR) signaling, which can trigger UPR, induces gammaherpesvirus lytic replication and serves as a physiological mechanism for gammaherpesvirus reactivation in vivo. However, how the UPR regulates BCR-mediated gammaherpesvirus infection is unknown. Here, we demonstrate that the ER stressors tunicamycin and thapsigargin inhibit BCR-mediated murine gammaherpesvirus 68 (MHV68) lytic replication by inducing expression of the UPR mediator Bip and blocking activation of Akt, ERK, and JNK. Both Bip and the downstream transcription factor ATF4 inhibited BCR-mediated MHV68 lytic gene expression, whereas UPR-induced C/EBP homologous protein (CHOP) was required for and promoted BCR-mediated MHV68 lytic replication by suppressing upstream Bip and ATF4 expression. Bip knockout was sufficient to rescue BCR-mediated MHV68 lytic gene expression in CHOP-knockout cells, and this rescue was blocked by ectopic ATF4 expression. Furthermore, ATF4 directly inhibited promoter activity of the MHV68 lytic switch transactivator RTA. Altogether, we show that ER stress-induced CHOP inhibits Bip and ATF4 expression and that ATF4, in turn, plays a critical role in CHOP-mediated regulation of BCR-controlled MHV68 lytic replication. We conclude that ER stress-mediated UPR and BCR signaling pathways are interconnected and form a complex network to regulate the gammaherpesvirus infection cycle.

Keywords: cell signaling; endoplasmic reticulum stress (ER stress); gene regulation; lymphocyte; microbiology; viral transcription; virology

DOI: https://doi.org/10.1074/jbc.M117.813675

J Exp Med. 2018 Jan 05. pii: jem.20171012. [Epub ahead of print]

Ablation of endothelial VEGFR1 improves metabolic dysfunction by inducing adipose tissue browning.

Takahiro Seki, Kayoko Hosaka, Carina Fischer, Sharon Lim, Patrik Andersson, Mitsuhiko Abe, Hideki Iwamoto, Yanyan Gao, Xinsheng Wang, Guo-Hua Fong, Yihai Cao.

Angiogenesis plays an instrumental role in the modulation of adipose tissue mass and metabolism. Targeting adipose vasculature provides an outstanding opportunity for treatment of obesity and metabolic disorders. Here, we report the physiological functions of VEGFR1 in the modulation of adipose angiogenesis, obesity, and global metabolism. Pharmacological inhibition and genetic deletion of endothelial VEGFR1 augmented adipose angiogenesis and browning of subcutaneous white adipose tissue, leading to elevated thermogenesis. In a diet-induced obesity model, endothelial-VEGFR1 deficiency demonstrated a potent anti-obesity effect by improving global metabolism. Along with metabolic changes, fatty liver and insulin sensitivity were also markedly improved in VEGFR1-deficient high fat diet (HFD)-fed mice. Together, our data indicate that targeting of VEGFR1 provides an exciting new opportunity for treatment of obesity and metabolic diseases, such as liver steatosis and type 2 diabetes.

DOI: https://doi.org/10.1084/jem.20171012

Int Rev Cell Mol Biol. 2018 ;pii: S1937-6448(17)30082-5. [Epub ahead of print]335 41-84

NF-κB and the Transcriptional Control of Inflammation.

Jennifer P Mitchell, Ruaidhrí J Carmody.

The NF-κB transcription factor was discovered 30 years ago and has since emerged as the master regulator of inflammation and immune homeostasis. It achieves this status by means of the large number of important pro- and antiinflammatory factors under its transcriptional control. NF-κB has a central role in inflammatory diseases such as rheumatoid arthritis, inflammatory bowel disease, and autoimmunity, as well as diseases comprising a significant inflammatory component such as cancer and atherosclerosis. Here, we provide an overview of the studies that form the basis of our understanding of the role of NF-κB subunits and their regulators in controlling inflammation. We also describe the emerging importance of posttranslational modifications of NF-κB in the regulation of inflammation, and highlight the future challenges faced by researchers who aim to target NF-κB transcriptional activity for therapeutic benefit in treating chronic inflammatory diseases.

Keywords: Autoimmune disease; Cancer; Inflammation; NF-κB; Regulation; Toll-like receptor tolerance; Transcription

DOI: https://doi.org/10.1016/bs.ircmb.2017.07.007

J Diabetes Complications. 2017 Dec 06. pii: S1056-8727(17)31366-1. [Epub ahead of print]

Oxidative stress-dependent MMP-13 activity underlies glucose neurotoxicity.

Ashley L Waldron, Patricia A Schroder, Kelly L Bourgon, Jessie K Bolduc, James L Miller, Adriana D Pellegrini, Amanda L Dubois, Magdalena Blaszkiewicz, Kristy L Townsend, Sandra Rieger.

BACKGROUND: A complication of diabetes is neuropathy, a condition of sensory axon degeneration that originates in the epidermis. The mechanisms remain unknown but reactive oxygen species (ROS) have been implicated in this condition. In this study, we assessed the role of ROS and a candidate downstream target, MMP-13 in glucose-induced sensory axon degeneration in zebrafish and mice.
METHODS: The effects of glucose on metabolism and sensory axon degeneration were assessed using qPCR and live imaging. ROS were analyzed using pentafluorobenzene-sulfonyl fluorescein and activation of the NF-κB stress response was determined using Tg(NF-κB:GFP) zebrafish. The role of MMP-13 and ROS in glucose-dependent axon degeneration was determined in zebrafish following treatment with the antioxidant, N-acetylcysteine and the MMP-13 inhibitor, DB04760. Neuropathic mice fed on a high-fat/high-sugar diet were treated with the MMP-13 inhibitor, CL-82198 to assess sensory recovery.
RESULTS: Glucose treatment of zebrafish induced metabolic changes that resemble diabetes. Sensory axon degeneration was mediated by ROS-induced MMP-13 and prevented upon antioxidant treatment or MMP-13 inhibition. MMP-13 inhibition also reversed neuropathy in diabetic mice.
CONCLUSION: We demonstrate that zebrafish are suitable to study glucose-induced neurotoxicity. Given the effects in zebrafish and mice, MMP-13 inhibition may be beneficial in the treatment of human diabetic neuropathy.

Keywords: Epidermis; Glucose; MMP-13; Mice; Neuropathy; ROS

DOI: https://doi.org/10.1016/j.jdiacomp.2017.11.012

Diabetologia. 2018 Jan 05.

Hyperglycaemia is associated with cancer-related but not non-cancer-related deaths: evidence from the IPC cohort.

Jean-Marc Simon, Frederique Thomas, Sebastien Czernichow, Olivier Hanon, Cedric Lemogne, Tabassome Simon, Bruno Pannier, Nicolas Danchin.

AIMS/HYPOTHESIS: Hyperglycaemia has been associated with the incidence of all and specific types of cancer, distinct from the risks related to diabetes. The relationships between blood glucose and mortality rates related to all and specific cancers were analysed in comparison with all-cause or non-cancer-related mortality rates in a large, general primary care population in France.
METHODS: Between January 1991 and December 2008, 301,948 participants (193,221 men and 108,727 women), aged 16-95 years (mean ± SD 44.8 ± 12.0 years for men and 45.1 ± 14.2 years for women), had a health check at the IPC Centre. All data collected in standard conditions during the health checks-up were used for statistical analysis All examinations were performed under fasting conditions and included a blood glucose measurement. Participants with known diabetes (<9%) were excluded from the analysis. Participants were classified into quintiles based on their blood glucose measurement and were followed for a maximum of 17 years (mean ± SD 9.2 ± 4.7 years) to assess all-cause, cancer and non-cancer mortality rates.
RESULTS: A non-linear relationship was observed between cancer mortality rates and blood glucose quintile after adjustment for age and sex. There was a significant association between the group with the highest blood glucose level and cancer-related death (multivariate Cox model, HR [95% CI] 1.17 [1.03, 1.34]), while the group with normoglycaemia showed no association with cancer-related deaths. We did not observe a relationship between blood glucose and all-cause or non-cancer mortality rates. An excess risk of death was observed in the highest blood glucose quintile for gastrointestinal cancer and leukaemia. Adjustments for diabetes and aspirin use did not modify the results. However, this excess risk disappeared with use of glucose-lowering agents (HR [95% CI] 1.03 [0.74, 1.43]).
CONCLUSIONS/INTERPRETATION: Hyperglycaemia is associated with significantly higher rates of cancer-related deaths, particularly in gastrointestinal cancer and leukaemia, but not with non-cancer-related deaths. The association is retained when taking into account confounding factors, including chronic aspirin treatment.

Keywords: Cancer; Epidemiology; Hyperglycaemia; Mortality

DOI: https://doi.org/10.1007/s00125-017-4540-8