Author: Pei, Gaiqin ; Shen, Jiayu ; Wei, Quan ; Fan, Qingwen ; Cheng, Hongxin ; Chen, Tingyu ; Pei, Hongliang ; Fu, Chenying ; He, Chengqi ; Wang, Lu ; Feng, Qipu ; Fang, Zhi ; Wang, Shiqi ; Guo, Yingqiang ; Li, Hanbin

INTRODUCTIONIschemic heart disease (IHD) is a prominent contributor to mortality worldwide, with myocardial infarction (MI) representing its most severe manifestation. Pulsed electromagnetic fields (PEMF) treatment shows promise for treating IHD. Nevertheless, the therapeutic impact and underlying mechanism of PEMF in MI are not fully understood.OBJECTIVESTo investigate the efficacy, safety, and mechanisms of PEMF for MI.METHODSWe established MI models in both mice and pigs and performed serial echocardiography and cardiac magnetic resonance follow-up to demonstrate the benefit of PEMF treatment after MI. The pathological environment after myocardial infarction was simulated in vitro to observe changes in various cells exposed to PEMF. Gene knockout (TLR4^-/-) mice and inhibitors were used to compare the differences in the efficacy of PEMF treatment relative to that of gene knockout/inhibitor treatments. Agonists were used to further explore the mechanism of PEMF treatment.RESULTSIn post-MI mice, PEMF treatment enhanced cardiac function and reduced scar formation. PEMF reduced the macrophage inflammatory response, improved cardiomyocyte survival in an inflammatory environment, and decreased collagen secretion by fibroblasts in vitro. Importantly, in the clinically relevant porcine model, PEMF treatment inhibited the inflammatory response and alleviated adverse left ventricular remodeling. Moreover, PEMF could exert therapeutic effects similar to those of gene knockout or inhibitor treatments. In the presence of TLR4 knockout or pyrrolidine dithiocarbamate (an NF-κB inhibitor) administration, PEMF could still improve cardiac function in post-MI mice. Mechanistically, the anti-inflammatory effect of PEMF was reversed when RS09 (a TLR4 agonist) was administered, and the antifibrotic effect of PEMF was attenuated after treatment with SRI-011381 (a TGF-β signaling pathway agonist).CONCLUSIONSPEMF treatment exhibits considerable promise as a noninvasive physical therapy modality, warranting further investigation into its potential implications for managing patients with IHD.

01 Apr 2025·Molecular Therapy

Development of RelB-targeting small-molecule inhibitors of non-canonical NF-κB signaling with antitumor efficacy

Article

Author: Yang, Zhuo ; Tao, Yu ; Shi, Yufang ; Li, Lingling ; Wang, Qi ; Liu, Zhanjie ; Xie, Ningxia ; Jiang, Yuhang ; Liu, Yongzhong ; Chen, Xi ; Li, Bo ; Zhu, Weiliang ; Xu, Zhijian ; Liu, Dandan ; Sun, Donglin ; Zhang, Haohao ; Lin, Han ; Ye, Deji ; Hu, Yiming ; Zhang, Jie ; Zhang, Xiaoren ; Wei, Shuqi ; Liu, Sanhong ; Li, Cuifeng

Dysfunction of the non-canonical nuclear factor κB (NF-κB) signaling pathway has been causally associated with numbers of cancers and autoimmune diseases. However, specific inhibitors for this signaling pathway remain to be developed. Here, we showed that structure-based cell-based screening yielded a potent and specific small molecule targeting RelB to inhibit the non-canonical NF-κB signaling pathway, while it had no inhibitory effect on the canonical NF-κB signaling pathway. Mechanistically, the inhibitor directly interacted with RelB protein and disrupted RelB binding to its target DNA, thus repressing RelB transactivity on target genes. Through blocking oncogenic activity of the non-canonical NF-κB signaling pathway in colorectal cancer or B lymphoma, the inhibitor efficiently exerted a potent antitumor effect in vitro and in vivo. Thus, our study provided a new RelB-targeting inhibitor that inhibited the non-canonical NF-κB signaling pathway and facilitated precise therapeutic applications in cancers and possibly other diseases.

05 Mar 2025·ACS Chemical Neuroscience

Corilagin Attenuates Neuronal Apoptosis and Ferroptosis of Parkinson’s Disease through Regulating the TLR4/Src/NOX2 Signaling Pathway

Article

Author: Zhou, Jiabin ; Lei, Yu ; Xiong, Nanxiang ; Chai, Songshan ; Xu, Dongyuan

Corilagin has shown neuroprotective potential in various neurological disorders, but its effects in Parkinson's disease (PD) have not been fully explored. In this study, we investigated the therapeutic impact and underlying mechanism of corilagin on PD using MPTP-induced mice and MPP⁺-treated N2a cells. Behavioral tests and immunohistochemical analysis demonstrated that corilagin significantly reduced MPTP-induced loss of TH-positive neurons in the substantia nigra. In vitro, corilagin improved cell viability, decreased MPP⁺-induced apoptosis, and mitigated the associated oxidative stress by lowering intracellular ROS levels and preserving mitochondrial membrane potential. Moreover, corilagin reversed MPP⁺-induced iron accumulation and lipid peroxidation in N2a cells. Mechanistically, Western blotting revealed that the protective effects of corilagin are linked to the TLR4/Src/NOX2 signaling pathway. The TLR4 agonist RS 09 impaired the neuroprotective effects of corilagin, further supporting its role in modulating ferroptosis via this pathway. These findings suggest that corilagin could be a promising therapeutic agent for PD by targeting the TLR4/Src/NOX2 signaling axis to inhibit ferroptosis.

100 Deals associated with RS-09

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Indication	Highest Phase	Country/Location	Organization	Date
B-Cell Lymphoma	Preclinical	China	Tsinghua University	04 Feb 2025
B-Cell Lymphoma	Preclinical	China	Guangzhou Medical University	04 Feb 2025
B-Cell Lymphoma	Preclinical	China	Shanghai Institute of Nutrition and Health	04 Feb 2025
Colorectal Cancer	Preclinical	China	Guangzhou Medical University	04 Feb 2025
Colorectal Cancer	Preclinical	China	Tsinghua University	04 Feb 2025
Colorectal Cancer	Preclinical	China	Shanghai Institute of Nutrition and Health	04 Feb 2025

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