Calpain and PARP-NF-κB signaling are reported to participate in the ischemic brain injury. In this study, it was investigated whether calpain was contributed to the neurovascular unit (NVU) damage through up-regulating PARP-NF-κB signaling during experimental ischemic stroke. Male Sprague-Dawley rats were suffered from 90 min of middle cerebral artery occlusion, followed by reperfusion. The NVU damage was evaluated by the permeability of blood-brain barrier (BBB), the degradation of proteins in extracellular matrix and tight junctions, and ultrastructural changes. The inflammatory response was determined by the expression of inflammatory genes driven by PARP-NF-κB signaling and the activities of myeloperoxidase (MPO). Treatment with MDL 28,170, a calpain inhibitor, improved neurological functions, reduced TUNEL staining index, lessened brain swelling, and decreased infarct volume in ischemic rats. Moreover, it reduced the BBB permeability, enhanced the levels of laminin, collagen IV and occludin, and attenuated the ultrastructural damage of NVU in penumbra and core after induction of ischemia. Meanwhile, it enhanced the levels of cytosolic IκBα, lessened the levels of nuclear PARP and NF-κB p65, reduced the levels of ICAM-1, TNF-α, IL-1β, MMP-9, and MMP-2,and suppressed the activities of MPO in penumbra and core. These data showed that calpain inhibition suppressed PARP-NF-κB signaling-mediated inflammatory response, reduced NVU damage, and protected brain against ischemic stroke, suggesting the involvement of calpain in the NVU damage through up-regulating PARP-NF-κB signaling during brain ischemia.

2024-09-01·AMERICAN JOURNAL OF PATHOLOGY

Calpain-1 Up-Regulation Promotes Bleomycin-Induced Pulmonary Fibrosis by Activating Ferroptosis

Article

作者: Liu, Yu ; Lu, Meili ; Ran, Chenyang ; Tang, Bailin ; Li, Yunhan ; Wang, Hongxin ; Wei, Silin

Idiopathic pulmonary fibrosis (IPF) is a chronic, progressive, and fatal disease. Calpain-1 was shown to be an effective therapeutic target for vascular endothelial dysfunction and pulmonary hypertension. However, the role of calpain-1 in bleomycin (BLM)-induced IPF has not been defined. The aim of this study was to assess the targeting of calpain-1 by activating ferroptosis in BLM-treated knockout mice and murine lung epithelial-12 cells. In this study, the role of calpain-1 in the regulation of IPF was investigated using a BLM-induced IPF mouse model. The results of our study showed that increased expression of calpain-1 was accompanied by increased fibrosis, lipid peroxidation, iron ion accumulation, and YAP levels and decreased levels of p-AMPK in BLM-induced IPF. MDL-28170 (calpain-1 inhibition) treatment and calpain-1 knockdown alleviated ferroptosis and IPF induced by BLM. Overexpression of calpain-1 in murine lung epithelial-12 cells further exacerbated iron accumulation and IPF. Mechanistically, lentivirus-mediated up-regulation of calpain-1 inhibited AMPK activity and promoted the nuclear translocation of YAP, leading to high levels of acyl-CoA synthetase long-chain family 4 -and transferrin receptor protein 1 and triggering a ferroptosis response that ultimately exacerbated BLM-induced lung fibrosis. Calpain-1 inhibition reversed these results and ameliorated BLM-induced IPF. In conclusion, these findings suggest that the calpain-1-acyl-CoA synthetase long-chain family 4-transferrin receptor protein 1-ferroptosis-positive regulatory axis contributes to BLM-induced IPF, which indicates that calpain-1 has potential therapeutic value for the treatment of IPF.

2024-07-01·Journal of Ginseng Research

Ginsenoside Rg1 alleviates vascular remodeling in hypoxia-induced pulmonary hypertension mice through the calpain-1/STAT3 signaling pathway

Article

作者: Lu, Meili ; Ran, Chenyang ; Guo, Xinyu ; Su, Yuhong ; Hao, Yi ; Zhao, Fang ; Wang, Hongxin ; Li, Yunhan

Background:

Hypoxic pulmonary hypertension (HPH) is the main pathological change in vascular remodeling, a complex cardiopulmonary disease caused by hypoxia. Some research results have shown that ginsenoside Rg1 (Rg1) can improve vascular remodeling, but the effect and mechanism of Rg1 on hypoxia-induced pulmonary hypertension are not clear. The purpose of this study was to discuss the potential mechanism of action of Rg1 on HPH.

Methods:

C57BL/6 mice, calpain-1 knockout mice and Pulmonary artery smooth muscle cells (PASMCs) were exposed to a low oxygen environment with or without different treatments. The effect of Rg1 and calpain-1 silencing on inflammation, fibrosis, proliferation and the protein expression levels of calpain-1, STAT3 and p-STAT3 were determined at the animal and cellular levels.

Results:

At the mouse and cellular levels, hypoxia promotes inflammation, fibrosis, and cell proliferation, and the expression of calpain-1 and p-STAT3 is also increased. Ginsenoside Rg1 administration and calpain-1 knockdown, MDL-28170, and HY-13818 treatment showed protective effects on hypoxia-induced inflammation, fibrosis, and cell proliferation, which may be associated with the downregulation of calpain-1 and p-STAT3 expression in mice and cells. In addition, overexpression of calpain 1 increased p-STAT3 expression, accelerating the onset of inflammation, fibrosis and cell proliferation in hypoxic PASMCs.

Conclusion:

Ginsenoside Rg1 may ameliorate hypoxia-induced pulmonary vascular remodeling by suppressing the calpain-1/STAT3 signaling pathway.

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