bims-stacyt 2024-08-04 papers

bims-stacyt

Biomed News

on Metabolism and the paracrine crosstalk between cancer and the organism

Issue of 2024–08–04
seven papers selected by
Cristina Muñoz Pinedo, L’Institut d’Investigació Biomèdica de Bellvitge

CDK5RAP3 Inhibition by Hypoxia Activates P38MAPK to Facilitate Angiogenesis.
TAX1BP1/A20 inhibited TLR2-NF-κB activation to induce tolerant expression of IL-6 in endothelial cells.
Targeting TXNIP in endothelial progenitors mitigates IL-8-induced neutrophil recruitment under metabolic stress.
Mechanisms by which obesity regulates inflammation and anti-tumor immunity in cancer.
Lactate contributes to remote ischemic preconditioning-mediated protection against myocardial ischemia reperfusion injury by facilitating autophagy via AMPK-mTOR-TFEB-CX43 axis.
Metabolic control of collagen synthesis.
Endoplasmic reticulum stress and autophagy in cerebral ischemia/reperfusion injury: PERK as a potential target for intervention.

Int Heart J. 2024 ;65(4): 748-757

CDK5RAP3 Inhibition by Hypoxia Activates P38MAPK to Facilitate Angiogenesis.

Mengmeng Zhang, Liu Yang, Jun Shu, Xin Gu, Yan Han.

  CDK5RAP3 is a recognized tumor suppressor that inhibits Chk1 and Chk2 and activates p53, all of which are involved with mediating toxin-induced apoptosis of cancer cells. CDK5RAP3 also inhibits p38MAPK phosphorylation and activity via mediating a p38 interaction with wild-type p53-induced phosphatase 1. This study aimed to investigate the antiangiogenic activity of CDK5RAP3 and its molecular mechanisms in human umbilical vein endothelial cells (HUVECs) under conditions of hypoxic conditions. Angiogenesis was induced in HUVECs mainly by vascular endothelial growth factor (VEGF). The CDK5RAP3 levels of HUVECs were reduced in a time-dependent manner in response to hypoxic treatment at 2% O2. The reduction of CDK5RAP3 was accompanied with increased p38MAPK phosphorylation and activation. Moderate hypoxia was found to significantly increase secreted VEGF concentrations, and the hypoxic conditioned medium (HCM) markedly enhanced proliferation, migration, and tube formation. Our findings indicate that moderate hypoxia facilitates angiogenesis by inhibiting CDK5RAP3. CDK5RAP3 exhibits a clear regulatory role in vascular regeneration, as downregulating its expression in endothelial cells enhances VEGF synthesis and subsequently improves cell migration and lumen formation capability. This study presents evidence indicating that moderate hypoxia facilitates angiogenesis by inhibiting CDK5RAP3, demonstrating the potential for CKD5RAP3 to be a potent antiangiogenic agent in angiogenesis regulation of cancer, ischemic diseases, and wound healing.

Keywords:  Human umbilical vein endothelial cell; VEGF

DOI:  https://doi.org/10.1536/ihj.23-604
Int Immunopharmacol. 2024 Jul 29. pii: S1567-5769(24)01310-9. [Epub ahead of print]139 112789

TAX1BP1/A20 inhibited TLR2-NF-κB activation to induce tolerant expression of IL-6 in endothelial cells.

Mei Yang, Xueting Liu, Manli Jiang, Jinyue Hu, Zhilin Xiao.

  The inflammatory cascadedriven by interleukin-6 (IL-6) plays a crucial role in the initiation and progression of chronic inflammatory conditions such as atherosclerosis. Research has demonstrated that prolonged exposure to inflammatory stimuli leads to the development of "immune tolerance" in specialized immune cells such as monocytes and macrophages, serving as a mechanism to prevent tissue damage and curb the inflammatory cascade. However, our recent investigation revealed that immune tolerance did not effectively regulate the production of IL-6 in human umbilical vein endothelial cells (HUVECs) when stimulated by a Toll-like receptor 2 (TLR2) ligand Pam3CSK4, which is a potent activator of the pro-inflammatory transcription factor NF-κB. Furthermore, the negative regulator of NF-κB signaling, A20, was ineffective in suppressing TLR2-induced IL-6 synthesis in this context. Notably, all A20 auxiliary molecules, with the exception of TAX1BP1, were found to be significantly expressed in HUVECs. DNA methylation in TAX1BP1 was confirmed in GEO database. According to the information provided, it is hypothesized that altered DNA methylation in HUVECs could potentially lead to decreased expression of TAX1BP1, thereby impeding A20's capacity to modulate continuous activation of the TLR2-NF-κB pathway. This may consequently lead to unregulated production of IL-6, evading immune tolerance mechanisms. Subsequent investigations suggested that demethylating TAX1BP1 could enhance its expression, potentially reducing the endogenous IL-6 levels induced by repeated TLR2 stimulation and restoring A20's inhibitory role in NF-κB signaling. Additionally, over-expression of TAX1BP1 coulddecrease the production of atherosclerosis-associated cytokines like IL-6, MCP-1, ICAM-1, and VCAM-1, while increasing NO release following repeated Pam3cks4 stimulation, along with enhanced co-localization of TAX1BP1 and A20. These findings indicate that inducing immune tolerance in endothelial cells may effectively suppress endogenous IL-6 production and halt the IL-6-mediated inflammatory cascade, with TAX1BP1/A20 identified as crucial components in this process.These insights provide novel perspectives and potential targets for therapeutic strategies in inflammatoryimmunological disorders involving the overproduction of IL-6.

Keywords:  Endothelial cells; Immune-tolerance; Interleukin-6; NF-κB signaling; Tax1-binding protein 1/A20

DOI:  https://doi.org/10.1016/j.intimp.2024.112789
Stem Cell Res Ther. 2024 Jul 29. 15(1): 225

Targeting TXNIP in endothelial progenitors mitigates IL-8-induced neutrophil recruitment under metabolic stress.

Julia Jolibois, Alison Domingues, Divina El Hamaoui, Raphaël Awaida, Mathilde Berger-de-Gaillardo, Daniel Guérin, David M Smadja, Perrine Marquet-DeRougé, Isabelle Margaill, Elisa Rossi, Valérie Nivet-Antoine.

   BACKGROUND: This study explores the potential role of Thioredoxin-interacting protein (TXNIP) silencing in endothelial colony-forming cells (ECFCs) within the scope of age-related comorbidities and impaired vascular repair. We aim to elucidate the effects of TXNIP silencing on vasculogenic properties, paracrine secretion, and neutrophil recruitment under conditions of metabolic stress.
METHODS: ECFCs, isolated from human blood cord, were transfected with TXNIP siRNA and exposed to a high glucose and β-hydroxybutyrate (BHB) medium to simulate metabolic stress. We evaluated the effects of TXNIP silencing on ECFCs' functional and secretory responses under these conditions. Assessments included analyses of gene and protein expression profiles, vasculogenic properties, cytokine secretion and neutrophil recruitment both in vitro and in vivo. The in vivo effects were examined using a murine model of hindlimb ischemia to observe the physiological relevance of TXNIP modulation under metabolic disorders.
RESULTS: TXNIP silencing did not mitigate the adverse effects on cell recruitment, vasculogenic properties, or senescence induced by metabolic stress in ECFCs. However, it significantly reduced IL-8 secretion and consequent neutrophil recruitment under these conditions. In a mouse model of hindlimb ischemia, endothelial deletion of TXNIP reduced MIP-2 secretion and prevented increased neutrophil recruitment induced by age-related comorbidities.
CONCLUSIONS: Our findings suggest that targeting TXNIP in ECFCs may alleviate ischemic complications exacerbated by metabolic stress, offering potential clinical benefits for patients suffering from age-related comorbidities.

Keywords:  Age-related comorbidities; Cytokine secretion; Endothelial progenitors; Metabolic stress; Neutrophils; TXNIP

DOI:  https://doi.org/10.1186/s13287-024-03850-w
Biochem Biophys Res Commun. 2024 Jul 23. pii: S0006-291X(24)00973-2. [Epub ahead of print]733 150437

Mechanisms by which obesity regulates inflammation and anti-tumor immunity in cancer.

Cora E Miracle, Chelsea L McCallister, Richard D Egleton, Travis B Salisbury.

  Obesity is associated with an increased risk for 13 different cancers. The increased risk for cancer in obesity is mediated by obesity-associated changes in the immune system. Obesity has distinct effects on different types of inflammation that are tied to tumorigenesis. For example, obesity promotes chronic inflammation in adipose tissue that is tumor-promoting in peripheral tissues. Conversely, obesity inhibits acute inflammation that rejects tumors. Obesity therefore promotes cancer by differentially regulating chronic versus acute inflammation. Given that obesity is chronic, the initial inflammation in adipose tissue will lead to systemic inflammation that could induce compensatory anti-inflammatory reactions in peripheral tissues to suppress chronic inflammation. The overall effect of obesity in peripheral tissues is therefore dependent on the duration and severity of obesity. Adipose tissue is a complex tissue that is composed of many cell types in addition to adipocytes. Further, adipose tissue cellularity is different at different anatomical sites throughout the body. Consequently, the sensitivity of adipose tissue to obesity is dependent on the anatomical location of the adipose depot. For example, obesity induces more inflammation in visceral than subcutaneous adipose tissue. Based on these studies, the mechanisms by which obesity promotes tumorigenesis are multifactorial and immune cell type-specific. The objective of our paper is to discuss the cellular mechanisms by which obesity promotes tumorigenesis by regulating distinct types of inflammation in adipose tissue and the tumor microenvironment.

Keywords:  And myeloid-derived suppressor cells; Anti-Tumor immunity; CD8+T cells; Inflammation; Natural killer cells; Obesity

DOI:  https://doi.org/10.1016/j.bbrc.2024.150437
Am J Pathol. 2024 Jul 26. pii: S0002-9440(24)00247-5. [Epub ahead of print]

Lactate contributes to remote ischemic preconditioning-mediated protection against myocardial ischemia reperfusion injury by facilitating autophagy via AMPK-mTOR-TFEB-CX43 axis.

Zhang-Jian Yang, Wei-Fang Zhang, Qing-Qing Jin, Zhi-Rong Wu, Yun-Yan Du, Hao Shi, Zhen-Sheng Qu, Xiao-Jian Han, Li-Ping Jiang.

  Remote ischemic preconditioning (RIPC) exerts a protective role on myocardial ischemia reperfusion (I/R) injury by the release of various humoral factors. Lactate is a common metabolite in ischemic tissues. Nevertheless, little is known about the role lactate plays in myocardial I/R injury and its underlying mechanism. This investigation revealed that RIPC elevated the level of lactate in blood and myocardium. Furthermore, AZD3965, a selective monocarboxylate transporter 1 (MCT1) inhibitor and 2-Deoxy-D-glucose (2-DG), a glycolysis inhibitor, mitigated the effects of RIPC-induced elevated lactate in the myocardium and prevented RIPC against myocardial I/R injury. In an in vitro hypoxia reoxygenation (H/R) model, lactate markedly mitigated H/R-induced cell damage in H9c2 cells. Meanwhile, further studies suggested that lactate contributed to RIPC rescuing I/R-induced autophagy deficiency by promoting TFEB translocation to the nucleus through activating the AMPK-mTOR pathway without influencing the PI3K-Akt pathway, thus reducing cardiomyocytes damage. Interestingly, we also found that lactate upregulated the mRNA and protein expression of CX43 by facilitating the binding of TFEB to CX43 promoter in the myocardium. Functionally, silencing of TFEB attenuated the protective effect of lactate on cell damage, which was reversed by overexpression of CX43. Further mechanistic studies suggested lactate facilitated CX43-regulated autophagy via AMPK-mTOR-TFEB signaling pathway. Collectively, our research demonstrates that RIPC protects against myocardial I/R injury through lactate-mediated myocardial autophagy via AMPK-mTOR-TFEB-CX43 axis.

Keywords:  autophagy; connexin 43; lactate; myocardial ischemia reperfusion injury; remote ischemic preconditioning

DOI:  https://doi.org/10.1016/j.ajpath.2024.07.005
Matrix Biol. 2024 Jul 29. pii: S0945-053X(24)00094-5. [Epub ahead of print]

Metabolic control of collagen synthesis.

Julien Guillard, Simon Schwörer.

  The extracellular matrix (ECM) is present in all tissues and crucial in maintaining normal tissue homeostasis and function. Defects in ECM synthesis and remodeling can lead to various diseases, while overproduction of ECM components can cause severe conditions like organ fibrosis and influence cancer progression and therapy resistance. Collagens are the most abundant core ECM proteins in physiological and pathological conditions and are predominantly synthesized by fibroblasts. Previous efforts to target aberrant collagen synthesis in fibroblasts by inhibiting pro-fibrotic signaling cascades have been ineffective. More recently, metabolic rewiring downstream of pro-fibrotic signaling has emerged as a critical regulator of collagen synthesis in fibroblasts. Here, we propose that targeting the metabolic pathways involved in ECM biomass generation provides a novel avenue for treating conditions characterized by excessive collagen accumulation. This review summarizes the unique metabolic challenges collagen synthesis imposes on fibroblasts and discusses how underlying metabolic networks could be exploited to create therapeutic opportunities in cancer and fibrotic disease. Finally, we provide a perspective on open questions in the field and how conceptual and technical advances will help address them to unlock novel metabolic vulnerabilities of collagen synthesis in fibroblasts and beyond.

Keywords:  ECM; collagen; fibroblasts; glycine; metabolism; proline

DOI:  https://doi.org/10.1016/j.matbio.2024.07.003
Neural Regen Res. 2025 May 01. 20(5): 1455-1466

Endoplasmic reticulum stress and autophagy in cerebral ischemia/reperfusion injury: PERK as a potential target for intervention.

Ju Zheng, Yixin Li, Ting Zhang, Yanlin Fu, Peiyan Long, Xiao Gao, Zhengwei Wang, Zhizhong Guan, Xiaolan Qi, Wei Hong, Yan Xiao.

JOURNAL/nrgr/04.03/01300535-202505000-00028/figure1/v/2024-07-28T173839Z/r/image-tiff Several studies have shown that activation of unfolded protein response and endoplasmic reticulum (ER) stress plays a crucial role in severe cerebral ischemia/reperfusion injury. Autophagy occurs within hours after cerebral ischemia, but the relationship between ER stress and autophagy remains unclear. In this study, we established experimental models using oxygen-glucose deprivation/reoxygenation in PC12 cells and primary neurons to simulate cerebral ischemia/reperfusion injury. We found that prolongation of oxygen-glucose deprivation activated the ER stress pathway protein kinase-like endoplasmic reticulum kinase (PERK)/eukaryotic translation initiation factor 2 subunit alpha (eIF2α)-activating transcription factor 4 (ATF4)-C/EBP homologous protein (CHOP), increased neuronal apoptosis, and induced autophagy. Furthermore, inhibition of ER stress using inhibitors or by siRNA knockdown of the PERK gene significantly attenuated excessive autophagy and neuronal apoptosis, indicating an interaction between autophagy and ER stress and suggesting PERK as an essential target for regulating autophagy. Blocking autophagy with chloroquine exacerbated ER stress-induced apoptosis, indicating that normal levels of autophagy play a protective role in neuronal injury following cerebral ischemia/reperfusion injury. Findings from this study indicate that cerebral ischemia/reperfusion injury can trigger neuronal ER stress and promote autophagy, and suggest that PERK is a possible target for inhibiting excessive autophagy in cerebral ischemia/reperfusion injury.

DOI: https://doi.org/10.4103/NRR.NRR-D-23-00794