Yujin Guo

Dysregulation of Neuregulin-1/ErbB signaling in the prefrontal cortex and hippocampus of rats exposed to chronic unpredictable mild stress.

Exposure to chronic stress increases the likelihood of developing depression, but the underlying mechanisms remain equivocal. While recent evidence has indicated that Neuregulin-1 (NRG1) and its ErbB receptors play an essential role in neural development and function, and NRG1 has emerged as a novel modulator involved in the response of brain to stress, there is limited evidence concerning the effects of chronic stress exposure on NRG1/ErbB signaling. To fill this critical gap, we examined the protein expression of NRG1 and ErbB receptors in the brain of rats following chronic unpredictable mild stress (CUMS) exposure. After 6weeks of CUMS procedures, the rats were induced to a depression-like state. The stressed rats displayed elevated expression of NRG1 and phosphorylated ErbB4 (pErbB4) in the prefrontal cortex, whereas ErbB2 and pErbB2 were inhibited. In the hippocampus, CUMS also attenuated activation of the both ErbB receptors and suppressed the downstream Akt and ERK phosphorylation. Meanwhile, administration of sertraline enhanced NRG1/ErbB signaling and partly normalized the stress-induced behavioral changes and the disturbances of NRG1/ErbB system in CUMS rats. Combined, our data firstly showed the aberrant changes of NRG1/ErbB system in the brain of the animal model of depression, providing new evidence for the involvement of NRG1/ErbB pathway in the development and treatment of depression.

Association between NLPR1, NLPR3, and P2X7R Gene Polymorphisms with Partial Seizures

Objectives. Clinical and experimental evidence has clarified that the inflammatory processes within the brain play a pivotal role in the pathophysiology of seizures and epilepsy. Inflammasomes and P2X7 purinergic receptor (P2X7R) are important mediators during the inflammatory process. Therefore, we investigated the possible association between partial seizures and inflammasomes NLPR1, NLRP3, and P2X7R gene polymorphisms in the present study. Method. A total of 163 patients and 201 health controls were enrolled in this study and polymorphisms of NLPR1, NLRP3, and P2X7R genes were detected using polymerase chain reaction- (PCR-) ligase detection reaction method. Result. The frequency of rs878329 (G>C) genotype with C (CG + CC) was significantly lower among patients with partial seizures relative to controls (OR = 2.033, 95% CI = 1.290–3.204, p = 0.002 for GC + CC versus GG). Intriguingly, we found that the significant difference of rs878329 (G>C) genotype and allele frequency only existed among males (OR = 2.542, 95% CI = 1.344–4.810, p = 0.004 for GC + CC versus GG), while there was no statistically significant difference among females. However, no significant results were presented for the genotype distributions of rs8079034, rs4612666, rs10754558, rs2027432, rs3751143, and rs208294 polymorphisms between patients and controls. Conclusion. Our study demonstrated the potentially significant role of NLRP1 rs878329 (G>C) in developing susceptibility to the partial seizures in a Chinese Han population.

Quantitative profiling of neurotransmitter abnormalities in the hippocampus of rats treated with lipopolysaccharide: Focusing on kynurenine pathway and implications for depression

Peripheral administration of lipopolysaccharide (LPS) can induce the rodents to a depression-like state accompanied with remarkable changes of neurotransmitter systems. In this study, the effect of an intraperitoneal LPS injection (3mg/kg) on the concentrations of neurotransmitters was investigated by in vivo microdialysis in rat hippocampus. To further explore dysregulation pattern of the neurotransmitters following continuous inflammatory process, we then analyzed the neurotransmitters in the hippocampus of rats after 2-week LPS exposure (500μg/kg every other day). Acute treatment of LPS quickly enhanced glutamate release and increased the extracellular levels of dopamine, serotonin and their metabolites. Elevated glutamate status was also found in the chronic inflamed hippocampus, whereas dopamine and serotonin was decreased following prolonged LPS exposure. Interestingly, both acute and chronic treatment of LPS significantly elevated hippocampal kynurenine concentrations and altered the balance between the serotonin and kynurenine branches of tryptophan metabolism-increasing kynurenine/tryptophan ratio, but decreasing serotonin/tryptophan ratio. Additionally, kynurenic acid, the endogenous NMDA receptor antagonist, and the ratio of kynurenic acid/kynurenine were significantly decreased by acute treatment of LPS, which may further strengthen NMDA receptor activation. Since that NMDA activation can exacerbate inflammatory and neurodegenerative process, the enhanced glutamate release and dysregulated kynurenine pathway might constitute a vicious cycle playing a pivotal role in the neuropsychiatric disorders associated with inflammation, such as depression.

A dansyl-based fluorescent probe for the highly selective detection of cysteine based on a d-PeT switching mechanism

A novel fluorescent probe, DN-C, for detection of cysteine (Cys) based on a d-PeT switching mechanism is reported. In the presence of Cys, the probe exhibits a turn-on fluorescence signal and nearly 28-fold fluorescence intensity enhancement. The cellular imaging experiment indicated the DN-C possess desirable cell permeability for biological applications.

Chronic stress and excessive glucocorticoid exposure both lead to altered Neuregulin-1/ErbB signaling in rat myocardium.

Exposure to chronic stress or excess glucocorticoids is associated with the development of depression and heart disease, but the underlying mechanisms remain equivocal. While recent evidence has indicated that Neuregulin-1 (NRG1) and its ErbB receptors play an essential role in cardiac function, much is still unknown concerning the biological link between NRG1/ErbB pathway and the stress-induced comorbidity of depression and cardiac dysfunction. Therefore, we examined the protein expression of NRG1 and ErbB receptors in the myocardium of rats following chronic unpredictable mild stress (CUMS) or rats treated with two different doses (0.2 and 2mg/kg/day, respectively) of dexamethasone (Dex). The stressed rats showed elevated expression of NRG1 and phosphorylated ErbB4 (pErbB4) in the myocardium, whereas ErbB2 and pErbB2 were inhibited. The lower dose of Dex enhanced myocardial NRG1/ErbB signaling, but as the dose is increased, while ErbB4 remained activated, the expression of ErbB2 and pErbB2 became compromised. Both CUMS and 2mg/kg of Dex suppressed the downstream Akt and ERK phosphorylation. Although the lower dose of Dex increased myocardial antiapoptotic Bcl-xl expression, a significant decrease of Bcl-xl expression was found in rats treated with the higher dose. Meanwhile, both CUMS and two different doses of Dex induced proapoptotic Bax level. Combined, our data firstly showed (mal)adaptive responses of NRG1/ErbB system in the stressed heart, indicating the potential involvement of NRG1/ErbB pathway in the stress-induced cardiac dysfunction.

Effects of prolonged antipsychotic administration on neuregulin-1/ErbB signaling in rat prefrontal cortex and myocardium: implications for the therapeutic action and cardiac adverse effect

Patients with schizophrenia (SCZ) are at higher risk for developing cardiovascular disease (CVD) and neuregulin-1 (NRG1)/ErbB signaling has been identified as a common susceptibility pathway for the comorbidity. Antipsychotic treatment can change NRG1/ErbB signaling in the brain, which has been implicated in their therapeutic actions, whereas the drug-induced alterations of NRG1/ErbB pathway in cardiovascular system might be associated with the prominent cardiac side-effects of antipsychotic medication. To test this hypothesis, we examined NRG1/ErbB system in rat prefrontal cortex (PFC) and myocardium following 4-week intraperitoneal administration of haloperidol, risperidone or clozapine. Generally, the antipsychotics significantly enhanced NRG1/ErbB signaling with increased expression of NRG1 and phosphorylation of ErbB4 and ErbB2 in the brain and myocardium, except that clozapine partly blocked the cardiac NRG1/ErbB2 activation, which could be associated with its more severe cardiac adverse actions. Combined, our data firstly showed evidence of the effect of antipsychotic exposure on myocardial NRG1/ErbB signaling, along with the activated NRG1/ErbB system in brain, providing a potential link between the therapeutic actions and cardiotoxicity.

The involvement of autophagic flux in the development and recovery of doxorubicin-induced neurotoxicity

&NA; Doxorubicin (Dox) is an effective anti‐cancer agent, whose clinical use is limited by the cytotoxicity in non‐target tissues, especially the heart and brain. The drug‐induced neuronal damage is primarily mediated by oxidative stress, in which autophagy plays a central role. Although numerous studies indicate the involvement of autophagy in neurodegenerative diseases and brain injury, the evidence concerning autophagic process in Dox‐induced neuronal death is limited. We found that repeated Dox administration induced the protein expression of LC3II and P62 and impaired autophagic flux with enhanced autophagasome accumulation in rat hippocampus, whereas two weeks after the cessation of Dox treatment, the autophagic process was restored, even stimulated, with normalized protein levels of LC3II and P62 and enhanced expression of Becline‐1, indicating a compensatory response in the recovery state. Likewise, while repeated Dox exposure inhibited the hippocampal expression of lysosomal‐associated membrane protein 2 (LAMP2) and cathepsin D (CTSD), and suppressed CTSD activity, the Dox‐induced impaired autophagy‐lysosome pathway was also restored in rats following two weeks of recovery. To further verify the role of autophagy, the autophagy inhibitor, 3‐methyladenine (3‐MA), was administrated daily for the two weeks of recovery period. Our data demonstrated that while the animals in the recovery state showed a significant trend to decreased oxidative damage, normalized antioxidative system and ameliorated endoplasmic reticulum (ER) stress compared with Dox‐induced toxic model, 3‐MA treatment abrogated the recovering process, resulting in sustained oxidative and ER stress and neuronal apoptosis. Collectively, the present study firstly provided the evidence for the involvement of autophagy in both development and recovery of Dox‐induced neurotoxicity, highlighting a novel target for mitigating the chemotherapy‐induced neuronal damage. Graphical abstract Figure. No caption available. HighlightsDoxorubicin induced oxidative and ER stress, leading to neuronal apoptosis.Doxorubicin treatment enhanced autophagosome accumulation.Doxorubicin treatment impaired autophagic flux and lysosomal function.Autophagy was enhanced in the recovery state from doxorubicin‐induced neurotoxicity.Autophagy inhibition abrogated the recovery from doxorubicin‐induced neurotoxicity.

Dysregulation of Neuregulin-1/ErbB signaling in the hippocampus of rats after administration of doxorubicin

Objective Long-term use of doxorubicin (Dox) can cause neurobiological side effects associated with depression, but the underlying mechanisms remain equivocal. While recent evidence has indicated that Neuregulin-1 (NRG1) and its ErbB receptors play an essential role in neural function, much is still unknown concerning the biological link between the NRG1/ErbB pathway and the Dox-induced neurotoxicity. Therefore, we examined the protein expression of NRG1 and ErbB receptors in the hippocampus of rats following Dox treatment. Materials and methods The drug was administered every 2 days at a dose of 2.5 mg/kg, and the animals in different groups were treated with intraperitoneal injection for three or seven times, respectively. Results Our data showed that the rats treated with Dox for seven times (DoxL group) exhibited depression-like behaviors, whereas the short-term treatment (DoxS group) had no effect on the behavioral changes. Dox treatment also induced the neural apoptosis with more severe neurotoxicity. Intriguingly, the expression of NRG1 and the ratio of pErbB4/ErbB4 and pErbB2/ErbB2 were significantly decreased in the DoxL group, but enhanced activation of ErbB receptors was observed in the DoxS group. In parallel, administration of Dox for seven times suppressed the downstream Akt and ERK phosphorylation, while the Akt phosphorylation was enhanced with the administration of Dox for three times. Conclusion Our data first showed the Dox-induced alterations of the NRG1/ErbB system in the hippocampus, indicating the potential involvement of the NRG1/ErbB pathway in the Dox-induced nervous system dysfunction.