Targeting GPR65 alleviates hepatic inflammation and fibrosis by suppressing the JNK and NF-κB pathways

Background:G-protein coupled receptors(GPCRs)are recognized as attractive targets for drug therapy.However,it remains poorly understood how GPCRs,except for a few chemokine receptors,regulate the progression of liver fibrosis.Here,we aimed to reveal the role of GPR65,a proton-sensing receptor,in liver fibrosis and to elucidate the underlying mechanism.Methods:The expression level of GPR65 was evaluated in both human and mouse fibrotic livers.Furthermore,Gpr65-deficient mice were treated with either bile duct ligation(BDL)for 21 d or carbon tetrachloride(CCl4)for 8 weeks to investigate the role of GPR65 in liver fibrosis.A combination of experimental approaches,including Western blotting,quantitative real-time reverse transcription-polymerase chain reaction(qRT-PCR),and enzyme-linked immunosorbent assay(ELISA),confocal microscopy and rescue studies,were used to explore the underlying mechanisms of GPR65’s action in liver fibrosis.Additionally,the therapeutic potential of GPR65 inhibitor in the development of liver fibrosis was investigated.Results:We found that hepatic macrophage(HM)-enriched GPR65 was upregulated in both human and mouse fibrotic livers.Moreover,knockout of Gpr65 significantly alleviated BDL-and CCl4-induced liver inflammation,injury and fibrosis in vivo,and mouse bone marrow transplantation(BMT)experiments further demonstrated that the protective effect of Gpr65knockout is primarily mediated by bone marrow-derived macrophages(BMMs).Additionally,in vitro data demonstrated that Gpr65 silencing and GPR65 antagonist inhibited,while GPR65 overexpression and application of GPR65 endogenous and exogenous agonists enhanced the expression and release of tumor necrosis factor-α(TNF-α),interleukin-6(IL-6)and transforming growth factor-β(TGF-β),all of which subsequently promoted the activation of hepatic stellate cells(HSCs)and the damage of hepatocytes(HCs).Mechanistically,GPR65 overexpression,the acidic pH and GPR65 exogenous agonist induced up-regulation of TNF-αand IL-6 via the Gαq-Ca^(2+)-JNK/NF-κB pathways,while promoted the expression of TGF-βthrough the Gαq-Ca^(2+)-MLK3-MKK7-JNK pathway.Notably,pharmacological GPR65 inhibition retarded the development of inflammation,HCs injury and fibrosis invivo.Conclusions:GPR65 is a major regulator that modulates the progression of liver fibrosis.Thus,targeting GPR65 could be an effective therapeutic strategy for the prevention of liver fibrosis.

Change-over switch for quantum states transfer with topological channels in a circuit-QED lattice

We propose schemes to realize robust quantum states transfer between distant resonators using the topological edge states of a one-dimensional circuit quantum electrodynamics(QED)lattice.Analyses show that the distribution of edge states can be regulated accordingly with the on-site defects added on the resonators.And we can achieve different types of quantum state transfer without adjusting the number of lattices.Numerical simulations demonstrate that the on-site defects can be used as a change-over switch for high-fidelity single-qubit and two-qubit quantum states transfer.This work provides a viable prospect for flexible quantum state transfer in solid-state topological quantum system.

Effects of ganglioside + aspirin + atorvastatin triple therapy on oxidative stress and inflammatory response in patients with cerebral infarction

Objective: To investigate the effects of ganglioside + aspirin + atorvastatin triple therapy on oxidative stress and inflammatory response in patients with cerebral infarction. Methods:A total of 138 patients with acute cerebral infarction between July 2016 and July 2017 were divided into control group (n=69) and triple group (n=69) by random number table method. Control group accepted conventional symptomatic treatment combined with aspirin and atorvastatin therapy, triple group accepted conventional symptomatic treatment combined with ganglioside, aspirin and atorvastatin triple therapy, and both groups were treated for 1 month. The differences in oxidative stress and inflammatory response were compared between the two groups before and after treatment. Results: Immediately after admission, There was no statistically significant difference in serum levels of oxidative stress indexes and inflammatory mediators between the two groups. After 1 week of treatment and after 4 weeks of treatment, serum oxidative stress indexes ROS and AOPPs levels of triple group were lower than those of control group whereas SOD and CAT contents were higher than those of control group;serum inflammatory mediators IL-6, TNF-α and TGF-β levels were lower than those of control group whereas IL-4, IL-10 and IL-13 levels were higher than those of control group. Conclusion: ganglioside + aspirin + atorvastatin triple therapy can effectively inhibit the systemic oxidative stress and inflammatory response in patients with cerebral infarction.