bims-stacyt 2019-08-04 papers

bims-stacyt

Biomed News

on Metabolism and the paracrine crosstalk between cancer and the organism

Issue of 2019–08–04
nine papers selected by
Cristina Muñoz Pinedo, L’Institut d’Investigació Biomèdica de Bellvitge

SIRT1-regulated HMGB1 release is partially involved in TLR4 signal transduction: A possible anti-neuroinflammatory mechanism of resveratrol in neonatal hypoxic-ischemic brain injury.
Oncogenic KRAS Reduces Expression of FGF21 in Acinar Cells to Promote Pancreatic Tumorigenesis in Mice on a High-Fat Diet.
The protective effects of orexin a against high glucose-induced activation of NLRP3 inflammasome in human vascular endothelial cells.
The role of pro-inflammatory cytokines in lipid metabolism of metabolic diseases.
Systemic Immuno-metabolic alterations in chronic obstructive pulmonary disease (COPD).
Microenvironmental Metabolism Regulates Antitumor Immunity.
Bidirectional crosstalk between neutrophils and adipocytes promotes adipose tissue inflammation.
Cancer and ER stress: Mutual crosstalk between autophagy, oxidative stress and inflammatory response.
The effect of palmitic acid on inflammatory response in macrophages: an overview of molecular mechanisms.

Int Immunopharmacol. 2019 Jul 27. pii: S1567-5769(19)31358-X. [Epub ahead of print]75 105779

SIRT1-regulated HMGB1 release is partially involved in TLR4 signal transduction: A possible anti-neuroinflammatory mechanism of resveratrol in neonatal hypoxic-ischemic brain injury.

Kai Le, Enkhmurun Chibaatar Daliv, Shanshan Wu, Fangyuan Qian, Abdoulaye Idriss Ali, Dafan Yu, Yijing Guo.

  Neonatal hypoxic-ischemic brain injury (HIBI) is a knotty disease that lacks appropriate treatment. Inflammation is an important contributor to brain damage, and microglia are responsible for eliciting early and pronounced inflammatory reactions in the immature brain after hypoxic-ischemic (HI) insult. Acetylated HMGB1 can be released from immune cells into the extracellular space, where it acts as a danger-associated molecular pattern molecule to activate TLR4 signalling-mediated inflammatory responses. Resveratrol has neuroprotective and anti-inflammatory effects against HIBI, but whether these effects involve the regulation of the TLR4 signalling pathway and whether HMGB1 participates in this process is still unclear. We investigated the anti-inflammatory effects of resveratrol in HIBI and the molecular mechanisms potentially involved in the effect. The in vivo and in vitro results indicated that the level of cytoplasmic HMGB1 in microglia increased after insult and that treating experimental animals or mouse BV2 microglial cells with resveratrol attenuated HI insult-induced neuroinflammation, which was characterized by improved behavioural defects, reduced microglial activation and TLR4/MyD88/NF-κB signalling, and attenuated primary neuronal damage; this was accompanied by the inhibition of HMGB1 nucleoplasmic transfer and extracellular release. EX527 pretreatment reversed these effects. In addition, co-immunoprecipitation confirmed that SIRT1 was directly involved in the HMGB1 acetylation process in BV2 cells after oxygen glucose deprivation. These data demonstrate that resveratrol plays a neuroprotective role in neonatal HIBI by activating SIRT1 to inhibit HMGB1/TLR4/MyD88/NF-κB signalling and subsequent neuroinflammatory responses.

Keywords:  HMGB1; Hypoxic-ischemic brain injury; Microglia; Resveratrol; SIRT1; TLR4

DOI:  https://doi.org/10.1016/j.intimp.2019.105779
Gastroenterology. 2019 Jul 25. pii: S0016-5085(19)41127-X. [Epub ahead of print]

Oncogenic KRAS Reduces Expression of FGF21 in Acinar Cells to Promote Pancreatic Tumorigenesis in Mice on a High-Fat Diet.

Yongde Luo, Yaying Yang, Muyun Liu, Dan Wang, Feng Wang, Yawei Bi, Juntao Ji, Suyun Li, Yan Liu, Rong Chen, Haojie Huang, Xiaojie Wang, Agnieszka K Swidnicka-Siergiejko, Tobias Janowitz, Semir Beyaz, Guoqiang Wang, Sulan Xu, Agnieszka B Bialkowska, Catherine K Luo, Christoph L Pin, Guang Liang, Xiongbin Lu, Maoxin Wu, Kenneth R Shroyer, Robert A Wolff, William Plunkett, Baoan Ji, Zhaoshen Li, Ellen Li, Xiaokun Li, Vincent W Yang, Craig D Logsdon, James L Abbruzzese, Weiqin Lu.

   BACKGROUND & AIMS: Obesity is a risk factor for pancreatic cancer. In mice, a high-fat diet (HFD) and expression of oncogenic KRAS lead to development of invasive pancreatic ductal adenocarcinoma (PDAC) by unknown mechanisms. We investigated how oncogenic KRAS regulates the expression of fibroblast growth factor 21 (FGF21), a metabolic regulator that prevents obesity, and the effects of recombinant human FGF21 (rhFGF21) on pancreatic tumorigenesis.
METHODS: We performed immunohistochemical analyses of FGF21 levels in human pancreatic tissue arrays, comprising 59 PDAC specimens and 45 non-tumor tissues. We also studied mice with tamoxifen-inducible expression of oncogenic KRAS in acinar cells (KrasG12D/+ mice) and fElasCreERT mice (controls). KrasG12D/+ mice were placed on a HFD or regular chow diet (control) and given injections of rhFGF21 or vehicle; pancreata were collected and analyzed by histology, immunoblots, quantitative PCR, and immunohistochemistry. We measured markers of inflammation in the pancreas, liver, and adipose tissue. Activity of RAS was measured based on the amount of bound GTP.
RESULTS: Pancreatic tissues of mice expressed high levels of FGF21 compared with liver. FGF21 and its receptor proteins were expressed by acinar cells. Acinar cells that expressed KrasG12D/+ had significantly lower expression of Fgf21 mRNA, compared with acinar cells from control mice, partly due to downregulation of PPARG expression-a transcription factor that activates Fgf21 transcription. Pancreata from KrasG12D/+ mice on a control diet and given injections of rhFGF21 had reduced pancreatic inflammation, infiltration by immune cells, and acinar-to-ductal metaplasia compared with mice given injections of vehicle. HFD-fed KrasG12D/+ mice given injections of vehicle accumulated abdominal fat, developed extensive inflammation, pancreatic cysts, and high-grade pancreatic intraepithelial neoplasias (PanINs); half the mice developed PDAC with liver metastases. HFD-fed KrasG12D/+ mice given injections of rhFGF21 had reduced accumulation of abdominal fat and pancreatic triglycerides, fewer pancreatic cysts, reduced systemic and pancreatic markers of inflammation, fewer PanINs, and longer survival-only about 12% of mice developed PDACs and none of the mice had metastases. Pancreata from HFD-fed KrasG12D/+ mice given injections of rhFGF21 had lower levels of active RAS than from mice given vehicle.
CONCLUSIONS: Normal acinar cells from mice and humans express high levels of FGF21. In mice, acinar expression of oncogenic KRAS significantly reduces FGF21 expression. When these mice are placed on a HFD, they develop extensive inflammation, pancreatic cysts, PanINs, and PDACs, which are reduced by injection of FGF21. FGF21 also reduces the GTP binding capacity of RAS. FGF21 might be used in prevention or treatment of pancreatic cancer.

Keywords:  FGFR1; KLB; gene regulation; signaling

DOI:  https://doi.org/10.1053/j.gastro.2019.07.030
Arch Biochem Biophys. 2019 Jul 24. pii: S0003-9861(19)30383-2. [Epub ahead of print]

The protective effects of orexin a against high glucose-induced activation of NLRP3 inflammasome in human vascular endothelial cells.

Chengxi Zhang, Mamately Abdukerim, Mulati Abilailieti, Leile Tang, Yesheng Ling, Sinian Pan.

  Vascular disease is one of the most significant threats to the lives of patients suffering from diabetes, and chronic exposure of vascular endothelial cells to high glucose has been shown to significantly contribute to the process of endothelial cell dysfunction, one of the earliest events in diabetes-associated vascular disease. Nucleotide oligomerization domain (NOD)-like receptor pyrin domain-containing 3 (NLRP3) inflammasome plays a key role in initiating the inflammatory process by facilitating the production of interleukin-1β (IL-1β) and IL-18. ASC and caspase 1 are also implicated in NLRP3 inflammasome-mediated chronic inflammation. While under normal conditions, a balance exists between oxidants and antioxidants, exposure to high glucose significantly increases the production of ROS, which is enhanced by NOX4 expression. In the present study, we explored the role of orexin A, an endogenous peptide produced in the hypothalamus, in high glucose-induced activation of the NLRP3 inflammasome, oxidative stress, and expression of several key cytokines. Our findings demonstrate that orexin A exerts potent antioxidant effects in human aortic endothelial cells exposed to high glucose by inhibiting mitochondrial ROS and expression of NOX4 at both the mRNA and protein levels as revealed by MitoSOX staining, real-time PCR, and Western blot analysis. We also show that orexin A inhibits high glucose-induced expression of TxNIP, which is crucial to the activation of the NLRP3 inflammasome, as well as that of HMGB1. We confirmed via real-time PCR and Western blot analysis that orexin A suppressed the production of the inflammatory cytokines IL-1β and IL-18. Additionally, through SIRT1 knockdown siRNA experimentation, we confirmed that SIRT1 knockdown abolishes the effects of orexin A described above, thereby indicating a critical role of SIRT in the capacity of orexin A to ameliorate high glucose-induced oxidative stress and activation of NLRP3 inflammasome.

Keywords:  Endothelial dysfunction; HMGB1; High glucose; IL-18; IL-1β; NLRP3 inflammasome; Orexin A; SIRT1; TxNIP

DOI:  https://doi.org/10.1016/j.abb.2019.07.017
Int Rev Immunol. 2019 Jul 28. 1-18

The role of pro-inflammatory cytokines in lipid metabolism of metabolic diseases.

Yan Chen, Chun-Yan Yu, Wei-Min Deng.

  Adipose tissue has been considered as a crucial source of certain pro-inflammatory cytokines; conversely, these pro-inflammatory cytokines are involved in regulating the proliferation and apoptosis of adipocytes, promoting lipolysis, inhibiting lipid synthesis and decreasing blood lipids, etc. In recent decades, extensive studies have indicated that pro-inflammatory cytokines play important roles in the development of lipid metabolism of metabolic diseases, including obesity, atherosclerosis, steatohepatitis and hyperlipoproteinemia. However, the involved pro-inflammatory cytokines types and the underlying mechanisms remain largely unknown. The "re-discovery" of cancer as a metabolic disorder largely occurred in the last five years. Although pro-inflammatory cytokines have been intensively investigated in cancer research, there are very few studies about the roles of pro-inflammatory cytokines in the lipid metabolism of cancer. In the current review, we provide an overview of the progress that has been made in the roles of different pro-inflammatory cytokines in lipid metabolism of metabolic diseases including cancer.

Keywords:  Lipid metabolism; atherosclerosis; cytokine; fatty acid; obesity; steatohepatitis

DOI:  https://doi.org/10.1080/08830185.2019.1645138
Respir Res. 2019 Jul 30. 20(1): 171

Systemic Immuno-metabolic alterations in chronic obstructive pulmonary disease (COPD).

Amit R Agarwal, Smita Kadam, Ankita Brahme, Manas Agrawal, Komalkirti Apte, Govinda Narke, Kushal Kekan, Sapna Madas, Sundeep Salvi.

   BACKGROUND: Metabolic adaptation in immune cells is necessary to modulate immune cell function as it is intricately coupled with intracellular metabolism. We aimed to characterize the metabolic state of human peripheral blood mononuclear cells (PBMCs) after long-term exposure to tobacco smoke in smokers with preserved lung function and COPD subjects.
METHODS: PBMCs were isolated from healthy non-smokers (HNS), healthy smokers (HS) and COPD subjects, cultured and the mitochondrial respiration while utilizing glucose (glycolysis), fatty acids (β-oxidation) or pyruvate (direct Krebs' cycle substrate) was measured using the XFp Extracellular Flux Analyzer. Plasma levels of inflammatory cytokines IFN-γ, IL-17, TNF-α, IL-5, IL-9 and IFN-α were measured using flow cytometry. RAW264.7 cells were exposed to cigarette smoke condensate (CSC) for 1 h and its effect on cell viability, cellular metabolism and phagocytosis ability were also studied. Patient's data was analyzed using the Mann Whitney U test, whereas Student's t test was performed to analyze the in-vitro data.
RESULTS: PBMCs from COPD subjects showed a significant decrease in extracellular acidification rate (ECAR) while utilizing glucose as compared to HNS (151.9 Vs 215%). Mitochondrial oxygen consumption rate (OCR) on palmitate or pyruvate was also found to be significantly lower in COPD subjects as compared to HS and a strong positive correlation between palmitate OCR in PBMCs and FEV1 (r = 0.74, p < 0.05) and FVC (r = 0.79, p < 0.05) values in HS was observed. The metabolic shift towards fatty acid metabolism in healthy smokers promoted an inflammatory cytokine response with a greater increase in the levels of IL-5, IL-9 and IFN-α as compared to IFN-γ, IL-17 and TNF-α. In-vitro experiments with RAW 264.7 cells showed similar metabolic alterations and a reduced ability to phagocytose Streptococcus pneumonia and Haemophilus influenza after cigarette smoke exposure in the presence of glucose or palmitate.
CONCLUSIONS: These findings indicate a metabolic basis for the inflammatory response in COPD and could suggest a new therapeutic target for controlling the immune response and delaying the onset of disease.
TRIAL REGISTRATION: This observational study was retrospectively registered in the Clinical Trails Registry - India (ICMR - NIMS) on 19th January 2018 with the registration number CTRI/2018/01/011441 .

Keywords:  Cigarette smoke; Fatty acids; Glucose; Metabolism; PBMCs

DOI:  https://doi.org/10.1186/s12931-019-1139-2
Cancer Res. 2019 Jul 30.

Microenvironmental Metabolism Regulates Antitumor Immunity.

Verra M Ngwa, Deanna N Edwards, Mary Philip, Jin Chen.

Metabolic reprogramming of cancer cells and the tumor microenvironment are emerging as key factors governing tumor growth, metastasis, and response to therapies including immune checkpoint inhibitors. It has been recognized that rapidly proliferating cancer cells, tumor-infiltrating lymphocytes, and vascular endothelial cells compete for oxygen and nutrients. Tumor cells and other cell types in the microenvironment not only compete for nutrients, but they also simultaneously produce immunosuppressive metabolites, leading to immune escape. In addition, commensal microbial metabolites can influence regulatory T cells and inflammation in the intestine, thus playing an essential role in cancer prevention or cancer promotion. In this review, we summarize recent advances on metabolic interactions among various cell types in the tumor microenvironment, with a focus on how these interactions affect tumor immunity. We also discuss the potential role of blood vessel metabolism in regulating immune cell trafficking and activation.

DOI: https://doi.org/10.1158/0008-5472.CAN-19-0617
FASEB J. 2019 Jul 29. fj201900477RR

Bidirectional crosstalk between neutrophils and adipocytes promotes adipose tissue inflammation.

Yasuharu Watanabe, Yoshinori Nagai, Hiroe Honda, Naoki Okamoto, Tsutomu Yanagibashi, Masaru Ogasawara, Seiji Yamamoto, Ryu Imamura, Ichiro Takasaki, Hiromitsu Hara, Masakiyo Sasahara, Makoto Arita, Shigeaki Hida, Shun'ichiro Taniguchi, Takashi Suda, Kiyoshi Takatsu.

  Chronic activation of the IL-1β system in adipose tissue on metabolic disorders is well demonstrated. However, a mechanism for its expression and activation in the tissue has remained unexplored. Here, we demonstrate that IL-1β transcript was enriched in neutrophils of white adipose tissue (WAT) from lean mice. Mechanistically, the interaction of neutrophils with adipocytes induced IL-1β expression via NF-κB pathway. Lipolysis of adipocytes accumulated neutrophils prior to macrophages in WAT and produced high levels of IL-1β via an inflammasome pathway. Leukotriene B4 (LTB4) production in WAT also contributed to neutrophil accumulation. Furthermore, an LTB4-inflammasome axis contributed to the expression of chemotactic molecules involved in high-fat diet-induced macrophage infiltration into WAT. We have identified previously unappreciated roles for neutrophils in the development of adipose tissue inflammation: robust IL-1β production and infiltration of macrophages to initiate chronic inflammation.-Watanabe, Y., Nagai, Y., Honda, H., Okamoto, N., Yanagibashi, T., Ogasawara, M., Yamamoto, S., Imamura, R., Takasaki, I., Hara, H., Sasahara, M., Arita, M., Hida, S., Taniguchi, S., Suda, T., Takatsu, K. Bidirectional crosstalk between neutrophils and adipocytes promotes adipose tissue inflammation.

Keywords:  IL-1β inflammasome; fatty acid; metabolic disorder

DOI:  https://doi.org/10.1096/fj.201900477RR
Biomed Pharmacother. 2019 Jul 23. pii: S0753-3322(19)32955-5. [Epub ahead of print]118 109249

Cancer and ER stress: Mutual crosstalk between autophagy, oxidative stress and inflammatory response.

Yuning Lin, Mei Jiang, Wanjun Chen, Tiejian Zhao, Yanfei Wei.

  The endoplasmic reticulum (ER) acts as a moving organelle with many important cellular functions. As the ER lacks sufficient nutrients under pathological conditions leading to uncontrolled protein synthesis, aggregation of unfolded/misfolded proteins in the ER lumen causes the unfolded protein response (UPR) to be activated. Chronic ER stress produces endogenous or exogenous damage to cells and activates UPR, which leads to impaired intracellular calcium and redox homeostasis. The UPR is capable of recognizing the accumulation of unfolded proteins in the ER. The protein response enhances the ability of the ER to fold proteins and causes apoptosis when the function of the ER fails to return to normal. In different malignancies, ER stress can effectively induce the occurrence of autophagy in cells because malignant tumor cells need to re-use their organelles to maintain growth. Autophagy simultaneously counteracts ER stress-induced ER expansion and has the effect of enhancing cell viability and non-apoptotic death. Oxidative stress also affects mitochondrial function of important proteins through protein overload. Mitochondrial reactive oxygen species (ROS) are produced by calcium-enhanced ER release. The accumulation of toxic substances in ER and mitochondria in mitochondria destroys basic organelle function. It is known that sustained ER stress can also trigger an inflammatory response through the UPR pathway. Inflammatory response is thought to be associated with tumor development. This review discusses the emerging links between UPR responses and autophagy, oxidative stress, and inflammatory response signals in ER stress, as well as the potential development of targeting this multifaceted signaling pathway in various cancers.

Keywords:  Autophagy; Cancer; Endoplasmic reticulum stress; Inflammatory; Oxidative stress

DOI:  https://doi.org/10.1016/j.biopha.2019.109249
Inflamm Res. 2019 Jul 30.

The effect of palmitic acid on inflammatory response in macrophages: an overview of molecular mechanisms.

Jan Korbecki, Karolina Bajdak-Rusinek.

  Palmitic acid is a saturated fatty acid whose blood concentration is elevated in obese patients. This causes inflammatory responses, where toll-like receptors (TLR), TLR2 and TLR4, play an important role. Nevertheless, palmitic acid is not only a TLR agonist. In the cell, this fatty acid is converted into phospholipids, diacylglycerol and ceramides. They trigger the activation of various signaling pathways that are common for LPS-mediated TLR4 activation. In particular, metabolic products of palmitic acid affect the activation of various PKCs, ER stress and cause an increase in ROS generation. Thanks to this, palmitic acid also strengthens the TLR4-induced signaling. In this review, we discuss the mechanisms of inflammatory response induced by palmitic acid. In particular, we focus on describing its effect on ER stress and IRE1α, and the mechanisms of NF-κB activation. We also present the mechanisms of inflammasome NLRP3 activation and the effect of palmitic acid on enhanced inflammatory response by increasing the expression of FABP4/aP2. Finally, we focus on the consequences of inflammatory responses, in particular, the effect of TNF-α, IL-1β and IL-6 on insulin resistance. Due to the high importance of macrophages and the production of proinflammatory cytokines by them, this work mainly focuses on these cells.

Keywords:  Inflammation; Insulin resistance; Macrophage; Obesity; Palmitic acid; Saturated fatty acid

DOI:  https://doi.org/10.1007/s00011-019-01273-5