Inhibition of acid-sensing receptor GPR4 attenuates neuronal ferroptosis via RhoA/YAP signaling in a rat model of subarachnoid hemorrhage DOI Creative Commons
Qiuguang He, You Zhou, Lei Wu

et al.

Free Radical Biology and Medicine, Journal Year: 2024, Volume and Issue: 225, P. 333 - 345

Published: Oct. 10, 2024

Subarachnoid hemorrhage (SAH) is a devastating stroke, in which acidosis one of detrimental complications. The extracellular pH reduction can activate G protein-coupled receptor 4 (GPR4) the brain. Yet, extent to proton-activated GPR4 contributes early brain injury (EBI) post-SAH remains largely unexplored. Ferroptosis, iron-dependent programmed cell death, has recently been shown contribute EBI. We aimed investigate effects inhibition on neurological deficits and neuronal ferroptosis after SAH rats. A total 253 Sprague Dawley (SD) male rats (weighing 275-330g) were utilized this study. was induced by endovascular perforation. NE-52-QQ57 (NE), selective antagonist administered intraperitoneally 1-h post-SAH. To explore mechanisms, RhoA activator U-46619 YAP PY-60 delivered intracerebroventricularly. Short- long-term neurobehavior, grading, Western blot assay, ELISA immunofluorescence staining, transmission electron microscopy performed Following SAH, there an upregulation expression neurons. NE improved both short-term outcomes also reduced ferroptosis, as evidenced decreased lipid peroxidation products 4HNE MDA levels tissues, mitochondrial shrinkage, increased mitochondria crista membrane density. application either or partially offset neuroprotective This study demonstrated that acid-sensing contributed via RhoA/YAP pathway, may be potential therapeutic strategy attenuate mediated EBI SAH.

Language: Английский

Acid‐sensing receptor GPR4 plays a crucial role in lymphatic cancer metastasis DOI Creative Commons
Masako Nakanishi,

Akiya Ibe,

Kiyoto Morishita

et al.

Cancer Science, Journal Year: 2024, Volume and Issue: 115(5), P. 1551 - 1563

Published: Feb. 27, 2024

Cancer tissues exhibit an acidic microenvironment owing to the accumulation of protons and lactic acid produced by cancer inflammatory cells. To examine role in lymphatic metastasis, gene expression profiling was conducted using human dermal endothelial cells (HDLECs) treated with a low pH medium. Microarray set enrichment analysis revealed that treatment induced inflammation-related genes HDLECs, including encoding chemokines adhesion molecules. Acid treatment-induced C-X3-C motif chemokine ligand 1 (CX3CL1) C-X-C 6 (CXCL6) autocrinally promoted growth tube formation HDLECs. The vascular cell molecule (VCAM-1) increased HDLECs after time-dependent manner, which, turn, enhanced their melanoma Among various acid-sensing receptors, basally expressed G protein-coupled receptor 4 (GPR4), which augmented under microenvironment. induction or VCAM-1 conditions attenuated GPR4 knockdown In addition, lymph node metastases mouse model were suppressed administering anti-VCAM-1 antibody antagonist. These results suggest modifies function via GPR4, thereby promoting metastasis. Acid-sensing receptors downstream molecules might serve as preventive therapeutic targets cancer.

Language: Английский

Citations

4
An acidic microenvironment promotes lymphatic metastasis of melanoma by Thy-1 in endothelial cells and integrin αvβ3 in tumor cells DOI Creative Commons

Akiya Ibe,

Masako Nakanishi,

Ken Higashimoto

et al.

Discover Oncology, Journal Year: 2025, Volume and Issue: 16(1)

Published: April 9, 2025

Melanoma tissues exhibit an acidic microenvironment compared with that of surrounding normal tissues. However, the effects conditions on lymphatic metastasis, a crucial prognostic factor for patients melanoma, are unclear. In present study, we aimed to investigate role in function endothelial cells. We first conducted gene expression profiling using human dermal cells (HDLECs) treated low pH media. Based these results, focused Thy-1/CD90, whose increased time-dependent manner HDLECs under conditions. Immunohistochemical analysis primary tumor mouse melanoma model revealed Thy-1 The integrin αvβ3, receptor Thy-1, was also up-regulated adhesion accelerated conditions, which reduced by knockdown HDLECs. Furthermore, metastasis significantly attenuated when inoculated αv-silenced These results suggest acid-induced cells, as well αvβ3 may promote their mutual cellular adhesion, contributing metastasis.

Language: Английский

Citations

0
The Roles of Proton-Sensing G-Protein-Coupled Receptors in Inflammation and Cancer DOI Open Access

Calvin R. Justus,

Mona A. Marie, Edward J. Sanderlin

et al.

Genes, Journal Year: 2024, Volume and Issue: 15(9), P. 1151 - 1151

Published: Sept. 1, 2024

The precise regulation of pH homeostasis is crucial for normal physiology. However, in tissue microenvironments, it can be impacted by pathological conditions such as inflammation and cancer. Due to the overproduction accumulation acids (protons), extracellular characteristically more acidic inflamed tissues tumors comparison tissues. A family proton-sensing G-protein-coupled receptors (GPCRs) has been identified molecular sensors cells responding microenvironments. Herein, we review current research progress pertaining these GPCRs, including GPR4, GPR65 (TDAG8), GPR68 (OGR1), Growing evidence suggests that GPR4 are mainly pro-inflammatory, whereas primarily anti-inflammatory, various inflammatory disorders. Both anti- pro-tumorigenic effects have reported this receptors. Moreover, antagonists agonists targeting GPCRs developed evaluated preclinical models. Further warranted better understand roles pathophysiology required order exploit them potential therapeutic targets disease treatment.

Language: Английский

Citations

3
Inhibition of acid-sensing receptor GPR4 attenuates neuronal ferroptosis via RhoA/YAP signaling in a rat model of subarachnoid hemorrhage DOI Creative Commons
Qiuguang He, You Zhou, Lei Wu

et al.

Free Radical Biology and Medicine, Journal Year: 2024, Volume and Issue: 225, P. 333 - 345

Published: Oct. 10, 2024

Subarachnoid hemorrhage (SAH) is a devastating stroke, in which acidosis one of detrimental complications. The extracellular pH reduction can activate G protein-coupled receptor 4 (GPR4) the brain. Yet, extent to proton-activated GPR4 contributes early brain injury (EBI) post-SAH remains largely unexplored. Ferroptosis, iron-dependent programmed cell death, has recently been shown contribute EBI. We aimed investigate effects inhibition on neurological deficits and neuronal ferroptosis after SAH rats. A total 253 Sprague Dawley (SD) male rats (weighing 275-330g) were utilized this study. was induced by endovascular perforation. NE-52-QQ57 (NE), selective antagonist administered intraperitoneally 1-h post-SAH. To explore mechanisms, RhoA activator U-46619 YAP PY-60 delivered intracerebroventricularly. Short- long-term neurobehavior, grading, Western blot assay, ELISA immunofluorescence staining, transmission electron microscopy performed Following SAH, there an upregulation expression neurons. NE improved both short-term outcomes also reduced ferroptosis, as evidenced decreased lipid peroxidation products 4HNE MDA levels tissues, mitochondrial shrinkage, increased mitochondria crista membrane density. application either or partially offset neuroprotective This study demonstrated that acid-sensing contributed via RhoA/YAP pathway, may be potential therapeutic strategy attenuate mediated EBI SAH.

Language: Английский

Citations

1