Yongjun Chen

Excessive acetaminophen (APAP) application is a major cause of drug-induced liver injury (DILI). Febuxostat (Feb), a drug for reducing uric acid (UA) levels, was demonstrated to relieve hepatic inflammation and reverse organ functions. However, the effect of Feb on APAP-induced DILI and its mechanisms have not been fully explored. In this study, Feb (10 mg/kg) was given to mice by gavage 1 h after APAP (300 mg/kg, i.g.) induction. Serum and liver samples were collected 12 or 3 h after APAP challenge. Feb treatment was found to remarkably improve APAP-induced DILI, as evidenced by reduced serum ALT, AST and UA levels, pathomorphology, inflammatory, and oxidative responses. Consistently, treatment with Feb also reduced the cell injury induced by APAP in LO2 cells. Mechanistically, Feb induced GPX4 expression, activated the Keap1/Nrf2 pathway, and inhibited the TLR4/NF-κB p65 pathway. Feb also inhibited glutathione (GSH) depletion and Jun N-terminal kinase (JNK) activation in the early injury phase. Notably, pretreatment with Feb for 3 days also revealed preventive effects against APAP-induced DILI in mice. Overall, our data revealed a potential health impact of Feb on APAP-mediated DILI in vivo and in vitro, suggesting that Feb might be a potential candidate for treating DILI.

Neuroinflammation is considered as one of the crucial pathogenesis in promoting neurodegenerative progress of Alzheimers disease (AD). As complementary and alternative therapy, electroacupuncture (EA) stimulation has been widely used in clinical practice for anti-inflammation. However, whether EA promotes the cognitive deficits resulting from neuroinflammation in AD remains unclear. In this study, the presenilin 1 and 2 conditional double knockout (PS cDKO) mice, exhibited a series of AD-like pathology, robust neuroinflammatory responses, and memory deficits, were used to evaluate the potential neuroprotective effect of EA at Baihui (GV 20) and Shenting (GV 24) by behavioral testing, electrophysiology recording, and molecular biology analyzing. First, we observed that EA improved memory deficits and impaired synaptic plasticity. Moreover, EA possesses an ability to suppress the hyperphosphorylated tau and robust elevated NLRP3, ASC, Caspase-1, IL-1β, and IL-18 in PS cDKO mice. Importantly, MCC950, a potent and selective inhibitor of NLPR3 inflammasome, has similar effects on inhibiting the hyperphosphorylated tau and the robust elevated NLRP3 components and neuroinflammatory responses of PS cDKO mice as well as EA treatment. Furthermore, EA treatment is not able to further improve the AD-like phenotypes of PS cDKO mice in combination with the MCC950 administration. Therefore, EA stimulation at GV 20 and GV 24 acupoints may be a potential alternative therapy for deterring cognitive deficits in AD through suppression of NLRP3 inflammasome activation.

Background. Doxorubicin (DOX) is a commonly used chemotherapeutic drug but is limited in clinical applications by its cardiotoxicity. Neiguan acupoint (PC6) is a well‐recognized acupoint for the treatment of cardiothoracic disease. However, whether acupuncture at PC6 could be effective in preventing DOX‐induced cardiotoxicity is still unknown. Methods. A set of experiments were performed with myocardial cells, wild type, inducible nitric oxide synthase knockout (iNOS‐/‐), and myocardial‐specific ablation arginase 2 (Myh6‐ARG 2‐/‐) mice. We investigated the protective effect and the underlying mechanisms for electroacupuncture (EA) against DOX‐induced cardiotoxicity by echocardiography, immunostaining, biochemical analysis, and molecular biotechnology in vivo and in vitro analysis. Results. We found that DOX‐mediated nitric oxide (NO) production was positively correlated with the iNOS level but has a negative correlation with the arginase 2 (ARG 2) level in both myocardial cells and tissues. Meanwhile, EA at PC6 alleviated cardiac dysfunction and cardiac hypertrophy in DOX‐treated mice. EA at PC6 blocked the upregulation of NO production in accompanied with the downregulated iNOS and upregulated ARG 2 levels in myocardial tissue induced by DOX. Furthermore, knockout iNOS prevented cardiotoxicity and EA treatment did not cause the further improvement of cardiac function in iNOS‐/‐ mice treated by DOX. In contrast, deficiency of myocardial ARG 2 aggravated DOX‐induced cardiotoxicity and reduced EA protective effect. Conclusion. These results suggest that EA treatment at PC6 can prevent DOX‐induced cardiotoxicity through modulating NO production by modulating the iNOS/ARG 2 balance in myocardial cells.

The descending motor nerve conduction of voluntary swallowing is mainly launched by primary motor cortex (M1). M1 can activate and regulate peripheral nerves (hypoglossal) to control the swallowing. Acupuncture at “Lianquan” acupoint (CV23) has a positive effect against poststroke dysphagia (PSD). In previous work, we have demonstrated that electroacupuncture (EA) could regulate swallowing-related motor neurons and promote swallowing activity in the essential part of central pattern generator (CPG), containing nucleus ambiguus (NA), nucleus of the solitary tract (NTS), and ventrolateral medulla (VLM) under the physiological condition. In the present work, we have investigated the effects of EA on the PSD mice in vivo and sought evidence for PSD improvement by electrophysiology recording and laser speckle contrast imaging (LSCI). Four main conclusions can be drawn from our study: (i) EA may enhance the local field potential in noninfarction area of M1, activate the swallowing-related neurons (pyramidal cells), and increase the motor conduction of noninfarction area in voluntary swallowing; (ii) EA may improve the blood flow in both M1 on the healthy side and deglutition muscles and relieve PSD symptoms; (iii) EA could increase the motor conduction velocity (MCV) in hypoglossal nerve, enhance the EMG of mylohyoid muscle, alleviate the paralysis of swallowing muscles, release the substance P, and restore the ability to drink water; and (iv) EA can boost the functional compensation of M1 in the noninfarction side, strengthen the excitatory of hypoglossal nerve, and be involved in the voluntary swallowing neural control to improve PSD. This research provides a timely and necessary experimental evidence of the motor neural regulation in dysphagia after stroke by acupuncture in clinic.

Prenatal infection during pregnancy increases the risk for developing neuropsychiatric disorders such as schizophrenia. This is linked to an inflammatory microglial phenotype in the offspring induced by maternal immune activation (MIA). Microglia are crucial for brain development and maintenance of neuronal niches, however, whether and how their activation is involved in the regulation of neurodevelopment remains unclear. Here, we used a MIA rodent model in which polyinosinic: polycytidylic acid (poly (I:C)) was injected into pregnant mice. We found fewer parvalbumin positive (PV+) cells and impaired GABAergic transmission in the dentate gyrus (DG), accompanied by schizophrenia-like behavior in the adult offspring. Minocycline, a potent inhibitor of microglia activation, successfully prevented the above-mentioned deficits in the offspring. Furthermore, by using microglia-specific arginase 1 (Arg1) ablation as well as overexpression in DG, we identified a critical role of Arg1 in microglia activation to protect against poly (I:C) imparted neuropathology and altered behavior in offspring. Taken together, our results highlight that Arg1-mediated alternative activation of microglia are potential therapeutic targets for psychiatric disorders induced by MIA.