Peilin Yu,Zhenming Liu,Xiafei Yu,Peiwu Ye,Huan Liu,Xiwen Xue,Lixin Yang,Zhongtang Li,Yang Wu,Cheng Fang,Yong Juan Zhao,Fan Yang,Jian Hong Luo,Lin-Hua Jiang,Liangren Zhang,Lihe Zhang,Wei Yang
Summary cADPR is a well-recognized signaling molecule by modulating the RyRs, but considerable debate exists regarding whether cADPR can bind to and gate the TRPM2 channel, which mediates oxidative stress signaling in diverse physiological and pathological processes. Here, we show that purified cADPR evoked TRPM2 channel currents in both whole-cell and cell-free single-channel recordings and specific binding of cADPR to the purified NUDT9-H domain of TRPM2 by surface plasmon resonance. Furthermore, by combining computational modeling with electrophysiological recordings, we show that the TRPM2 channels carrying point mutations at H1346, T1347, L1379, S1391, E1409, and L1484 possess distinct sensitivity profiles for ADPR and cADPR. These results clearly indicate cADPR is a bona fide activator at the TRPM2 channel and clearly delineate the structural basis for cADPR binding, which not only lead to a better understanding in the gating mechanism of TRPM2 channel but also shed light on a cADPR-induced RyRs-independent Ca 2+ signaling mechanism.
Cadmium (Cd) is a major contaminant in natural environments and exerts adverse effects on aquatic biota at low concentrations. Gill is as vital respiratory organ and may cause pollutants to enter fish during gas exchange. Baicalein (BAI), as a kind of flavonoids, possess antioxidant properties through inactivating free radicals. To confirm the potential effects and approaches of BAI addition in maintaining the gill stability, 90 common carps ( Cyprinus carpio L.) were selected and randomly divided into water environment exposure group (0.22 mg/L Cd) and/or feed added with 0.10 g/kg BAI for 30 days. The analysis of ion content in serum showed that Cd exposure disturbed ion homeostasis , and BAI could reduce serum Cd concentration. The histopathological results of gills showed that Cd exposure caused gill tissue lesions and structural damage, and BAI feeding effectively alleviated this damage. In addition, BAI could enhance antioxidant activity and activate Nrf2/HO-1 axis, thereby reducing oxidative stress and endoplasmic reticulum (ER) stress. Moreover, BAI lightened cytokine imbalance, inflammatory response, and necroptosis. Overall, the results indicated that BAI feeding could maintain gill homeostasis against Cd poisoning via the ROS/ER stress signaling. This trial revealed the properties of BAI resistance to metal Cd in aquaculture and partially elucidated its mechanism.
Weikang Sun,Ke Ren,Jingjing Li,Mengyu Zhang,Qishen Jiang,Lingling Wang,Erguang Li
(199 words) The c-Jun N-terminal kinase (JNK) signaling pathway is required for herpes simplex virus 1 lytic infection and reactivation from latency. JNK signaling regulates cellular processes in response to stress through transcriptional regulation. However, the mechanisms by which JNK regulates HSV-1 infection are less defined. We show here that HSV-1 infection triggers BRD4 transition from chromosome association to transcriptional regulation for viral infection. Specifically, HSV-1 infection induces JNK activation which mediates redistribution of BRD4, an epigenetic reader protein, from chromatin-targeting to association with proteins of transcriptional regulation. BRD4 transitions to viral infection regulation by complexing with P-TEFb, a positive transcription elongation factor, and association with viral DNA. Genetic ablation or perturbation of JNK with chemical inhibitors or siRNA leads to impediment of BRD4 release and inhibition of HSV-1 infection. Both chemotherapeutic agents and irradiation are known to promote JNK activation and HSV reactivation. We show further that JNK agonist or chemotherapeutic agents known to activate JNK have the ability to enhance HSV-1 infection. Our study reveals a novel mechanism by which JNK regulates HSV-1 infection through stress-induced BRD4 function transition from host chromosome association to viral gene expression. The work links recurrent HSV infection by chemotherapeutic agents to JNK activation.
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