bims-unfpre 2023-12-10 papers

bims-unfpre

Biomed News

on Unfolded protein response

Issue of 2023–12–10
seven papers selected by
Susan Logue, University of Manitoba

Sestrin2 can alleviate endoplasmic reticulum stress to improve traumatic brain injury by activating AMPK/mTORC1 signaling pathway.
Modulating endoplasmic reticulum stress attenuates mast cell degranulation.
miR-616-3p alleviates inflammatory response by targeting C-X-C motif chemokine ligand 5.
Imaging peroxynitrite in endoplasmic reticulum stress and acute lung injury with a near-infrared fluorescent probe.
Apoptosis/Necroptosis Inducing Thiazole-Containing Artificial Polypeptide for Immunogenic Cell Death of Cancer.
A review on the mechanisms underlying the antitumor effects of natural products by targeting the endoplasmic reticulum stress apoptosis pathway.
Cell surface GRP78: A potential therapeutic target for high glucose-induced endothelial injury.

Metab Brain Dis. 2023 Dec 04.

Sestrin2 can alleviate endoplasmic reticulum stress to improve traumatic brain injury by activating AMPK/mTORC1 signaling pathway.

Yu Zhou, Yong Zhang, Benson O A Botchway, Min Huang, Xuehong Liu.

  Traumatic brain injury (TBI), as a serious central nervous system disease, can result in severe neurological dysfunction or even disability and death of patients. The early and effective intervention of secondary brain injury can improve the prognosis of TBI. Endoplasmic reticulum (ER) stress is one of the main reasons to recover TBI. ER stress inhibition may be beneficial in treating TBI. Sestrin2 is a crucial regulator of ER stress, and its activation can significantly improve TBI. In this paper, we analyze the biological function of sestrin2, the latest findings on ER stress, and the relationship between ER stress and TBI. We elucidate the relationship of sestrin2 inhibiting ER stress via activating the AMP-activated protein kinase (AMPK)/mammalian target of rapamycin complex 1 (MTORC1) signaling. Finally, we elaborate on the possible role of sestrin2 in TBI and explain how its activation potentially improves TBI.

Keywords:  Apoptosis; Inflammatory response; Injury; Mitochondrial dysfunction; Neurological dysfunction

DOI:  https://doi.org/10.1007/s11011-023-01323-2
Int Immunopharmacol. 2023 Dec 05. pii: S1567-5769(23)01663-6. [Epub ahead of print]126 111336

Modulating endoplasmic reticulum stress attenuates mast cell degranulation.

Jialiang Fan, Longpeng Ma, Bailing Xie, Shuyao Qiu, Shuo Song, Zhiyuan Tang, Yongjin Wu, Hui Huangfu, Yan Feng, Xiangqian Luo, Pingchang Yang.

   OBJECTIVES: Degranulation of mast cells leads to direct allergic symptoms. The underlying mechanism needs to be explored further. Endoplasmic reticulum (ER) stress is involved in the pathogenesis of allergic conditions. The objective of this study is to gain a better understanding of the mechanism of mast cell degranulation.
METHODS: Bone marrow derived mast cells and mast cells isolated from the airway tissues were prepared. The role of ER stress in mediating the release of mast cells was tested. RNA sequencing (RNAseq) was used to investigate the genetic activities of mast cells.
RESULTS: Our observation showed that sensitization increased ER stress in mast cells. X-box-1 binding protein (XBP1) activity was linked to mast cell degranulation. Modulation of ER stress or XBP1 expression regulates the release of the mast cell mediator. XBP1 promoted the mediator release of mast cells by activating spleen tyrosine kinase (Syk). Activation of eukaryotic initiation factor 2a (eIF2a) inhibited XBP1 in mast cells. Semaphorin 3A was effective in preventing experimental allergic rhinitis (AR) due to its ability to suppress the release of mast cell mediators.
CONCLUSIONS: ER stress is associated with the mast cell degranulation. By inhibiting XBP1, the crucial molecule of ER stress, mast cell degranulation can be suppressed and experimental AR can be mitigated.

Keywords:  Airway; Allergy; Endoplasmic reticulum; Mast cell; Mucosa

DOI:  https://doi.org/10.1016/j.intimp.2023.111336
Biochem Biophys Res Commun. 2023 Nov 28. pii: S0006-291X(23)01429-8. [Epub ahead of print]691 149335

miR-616-3p alleviates inflammatory response by targeting C-X-C motif chemokine ligand 5.

Suyeon Lee, Suji Kim, Tae-Jin Lee, Jae Hyang Lim, Chang-Hoon Woo.

  C/EBP homologous protein (CHOP) is a key regulator in ER stress-mediated signaling pathway via PERK-dependent unfolded protein response. It has been known that microRNA-616 (miR-616) is produced from the intron of the human DDIT3 gene encoding CHOP and increased by ER stress. However, the role of miR-616 and its targets are not fully addressed yet. Here we try to identify a novel target of miR-616 in human lung epithelial cells. Microarray analysis showed that CXCL5 is the most downregulated gene by miR-616 overexpression in A549 cells. We also found that CXCL5 mRNA and protein levels were significantly reduced by miR-616 mimic in the presence or absence of TNFα, while anti-miR-616 enhanced CXCL5 expression. In addition, miR-616-3p targeting sequence in 3'UTR of CXCL5 was confirmed by luciferase reporter assay suggesting that miR-616-3p directly binds to 3'UTR of CXCL5 and inhibits CXCL5 expression. Finally, we confirmed that conditioned medium from A549 cells treated with TNFα or Streptococcus pneumoniae lysates increased intra-alveolar neutrophil infiltration in a mouse model of pulmonary inflammation, while this induction was significantly reduced in a conditioned medium from cells transfected with miR-616-3p. These results suggest that miR-616-3p can alleviate CXCL5-induced pulmonary inflammatory response via targeting 3'UTR of CXCL5 gene.

Keywords:  CHOP; CXCL5; Inflammation; Lung epithelial cells; miR-616

DOI:  https://doi.org/10.1016/j.bbrc.2023.149335
Anal Chim Acta. 2024 Jan 15. pii: S0003-2670(23)01271-0. [Epub ahead of print]1286 342050

Imaging peroxynitrite in endoplasmic reticulum stress and acute lung injury with a near-infrared fluorescent probe.

Ke Yang, Ying Liu, Min Deng, Peipei Wang, Dan Cheng, Songjiao Li, Longwei He.

   BACKGROUND: The cellular endoplasmic reticulum (ER) is responsible for various functions, including protein synthesis, folding, distribution, and calcium ion storage. Studies have linked ER stress with acute lung injury (ALI), which can result in oxidative stress and even cell death. Peroxynitrite (ONOO-) is a well-known reactive oxygen species (ROS) that contributes to various physiological and pathological processes in oxidative stress diseases. To understand the role of ER ONOO- in ALI, it is crucial to accurately measure its level in the ER. Unfortunately, there is currently no probe available to detect ER ONOO- in an ALI model.
RESULTS: To address this, we developed three near-infrared (NIR) fluorescent probes (DCM-F-ONOO, DCM-Cl-ONOO, and DCM-Br-ONOO) for the detection of ONOO- using pentafluorobenzenesulfonate (PFBS) moieties as fluorescence quenchers. Through comprehensive testing, we selected DCM-Br-ONOO as the best NIR fluorescent probe due to its rapid response (within 3 min), high selectivity, good sensitivity (LOD = 2.3 nM), and approximately 66-fold enhanced response to ONOO- in fluorescence intensity. The probe was successfully applied to detect changes in ONOO- levels induced by different drugs in the ER of living cells. Importantly, a significant increase in the level of ONOO- was observed in the ER of an ALI cell model (4.5-fold) and an ALI mouse model (2.5-fold) using the probe, which is essential for understanding the role of ONOO- in ER-associated diseases.
SIGNIFICANCE: Using DCM-Br-ONOO as a probe, present work further validated that the elevated levels of ONOO- secretion were accompanied by the ALI progressed. These findings may provide valuable results for figuring out the biological roles that ONOO- played in ALI.

Keywords:  Acute lung injury; Endoplasmic reticulum stress; Fluorescent probe; Near-infrared

DOI:  https://doi.org/10.1016/j.aca.2023.342050
ACS Appl Bio Mater. 2023 Dec 03.

Apoptosis/Necroptosis Inducing Thiazole-Containing Artificial Polypeptide for Immunogenic Cell Death of Cancer.

Jeong Ho Park, Mun Sik Kim, Do Hyun Yun, Yeu-Chun Kim.

  Immunogenic cell death (ICD) has emerged as a promising approach to cancer immunotherapy. During ICD, cancer cell death and the release of damage-associated molecular pattern (DAMP) signals occur simultaneously. Increased production of reactive oxygen species (ROS) and severe endoplasmic reticulum stress are necessary for enhanced ICD. Furthermore, the levels of ROS and reduced glutathione (GSH) are involved in various cell death mechanisms. The thiazole ring structure has gained considerable interest as a functional moiety for anticancer agents. This study designed and synthesized a positively charged cell-penetrating polypeptide with a thiazole functional moiety (NS). The NS internalizes into the cancer cells through direct penetration and endo-lysosomal escape. The NS induces mitochondrial depolarization and ER stress in a concentration-dependent manner, leading to a significant ROS production and GSH depletion. Consequently, the ICD of cancer cells is activated, resulting in the release of DAMP signals. Furthermore, NS causes a shift in the cell death pathway from apoptosis to necroptosis as the concentration increases. In this study, we confirmed the possibility of NS as a promising ICD inducer that can be used while varying the concentration according to the cancer type.

Keywords:  cancer immunotherapy; cell-penetrating polypeptide; immunogenic cell death; reactive oxygen species; thiazole

DOI:  https://doi.org/10.1021/acsabm.3c00581
Front Pharmacol. 2023 ;14 1293130

A review on the mechanisms underlying the antitumor effects of natural products by targeting the endoplasmic reticulum stress apoptosis pathway.

Jie-Xiang Zhang, Wei-Chen Yuan, Cheng-Gang Li, Hai-Yan Zhang, Shu-Yan Han, Xiao-Hong Li.

  Cancer poses a substantial risk to human life and wellbeing as a result of its elevated incidence and fatality rates. Endoplasmic reticulum stress (ERS) is an important pathway that regulates cellular homeostasis. When ERS is under- or overexpressed, it activates the protein kinase R (PKR)-like endoplasmic reticulum kinase (PERK)-, inositol-requiring enzyme 1 (IRE1)- and activating transcription Factor 6 (ATF6)-related apoptotic pathways to induce apoptosis. Tumor cells and microenvironment are susceptible to ERS, making the modulation of ERS a potential therapeutic approach for treating tumors. The use of natural products to treat tumors has substantially progressed, with various extracts demonstrating antitumor effects. Nevertheless, there are few reports on the effectiveness of natural products in inducing apoptosis by specifically targeting and regulating the ERS pathway. Further investigation and elaboration of its mechanism of action are still needed. This paper examines the antitumor mechanism of action by which natural products exert antitumor effects from the perspective of ERS regulation to provide a theoretical basis and new research directions for tumor therapy.

Keywords:  antitumor; apoptosis; endoplasmic reticulum stress; natural products; review

DOI:  https://doi.org/10.3389/fphar.2023.1293130
Biochem Biophys Res Commun. 2023 Dec 01. pii: S0006-291X(23)01441-9. [Epub ahead of print]692 149347

Cell surface GRP78: A potential therapeutic target for high glucose-induced endothelial injury.

Bo Wang, Xin He, Jingliang Zhang, Yingjie Zhang.

  Endothelial cell inflammation and oxidative stress are critical to developing diabetic vascular complications. GRP78 translocation to the cell surface has been observed in different types of endothelial cells, but the potential role of cell surface GRP78 in modulating endothelial inflammation and oxidative stress remains uncertain. In this study, we investigated whether inhibiting cell surface GRP78 function using a novel anti-GRP78 monoclonal antibody (MAb159) could suppress high glucose (HG)-induced endothelial inflammation and oxidative stress. Our findings demonstrated that the expression of cell surface GRP78 was increased in HG-treated HUVECs. Inhibition of cell surface GRP78 using MAb159 attenuated HG-induced endothelial injury, inflammation and oxidative stress, while activation of GRP78 by recombinant GRP78 further amplified HG-induced endothelial damage, inflammation and oxidative stress. Additionally, we discovered that cell surface GRP78 promoted HG-induced inflammation and oxidative stress by activating the TLR4/NF-κB signalling pathway. Moreover, HG-induced GRP78 translocation to the cell surface is dependent on ER stress. Our data demonstrate that targeting cell surface GRP78 could be a promising therapeutic strategy for mitigating endothelial injury, inflammation and oxidative stress.

Keywords:  Cell surface GRP78; Endothelial injury; Inflammation; Oxidative stress; TLR4/NF-κB signalling pathway

DOI:  https://doi.org/10.1016/j.bbrc.2023.149347