Exploration of the causal associations between circulating inflammatory proteins, immune cells, and neuromyelitis optica spectrum disorder: a bidirectional Mendelian randomization study and mediation analysis.

Background: An increasing body of research has demonstrated a robust correlation between circulating inflammatory proteins and neuromyelitis optica spectrum disorders (NMOSD). However, whether this association is causal or whether immune cells act as mediators currently remains unclear. Methods: We employed bidirectional two-sample Mendelian randomization (TSMR) analysis to examine the potential causal association between circulating inflammatory proteins, immune cells, and NMOSD using data from genome-wide association studies (GWAS). Five different methods for Mendelian randomization analyses were applied, with the inverse variance-weighted (IVW) method being the primary approach. Sensitivity analyses were further performed to assess the presence of horizontal pleiotropy and heterogeneity in the results. Finally, a two-step Mendelian randomization (MR) design was employed to examine the potential mediating effects of immune cells. Results: A notable causal relationship was observed between three circulating inflammatory proteins (CSF-1, IL-24, and TNFRSF9) and genetically predicted NMOSD. Furthermore, two immune cell phenotypes, genetically predicted CD8 on naive CD8+ T cells, and Hematopoietic Stem Cell Absolute Count were negatively and positively associated with genetically predicted NMOSD, respectively, although they did not appear to function as mediators. Conclusion: Circulating inflammatory proteins and immune cells are causally associated with NMOSD. Immune cells do not appear to mediate the pathway linking circulating inflammatory proteins to NMOSD.

Design, synthesis and biological evaluation of novel podophyllotoxin derivatives as tubulin-targeting anticancer agents.

CONTEXT: Podophyllotoxin (PPT) derivatives, used in cancer therapy, require development toward enhanced efficacy and reduced toxicity. OBJECTIVE: This study synthesizes PPT derivatives to assess their anticancer activities. MATERIALS AND METHODS: Compounds E1-E16 antiproliferative activity was tested against four human cancer cell lines (H446, MCF-7, HeLa, A549) and two normal cell lines (L02, BEAS-2B) using the CCK-8 assay. The effects of compound E5 on A549 cell growth were evaluated through molecular docking, in vitro assays (flow cytometry, wound healing, Transwell, colony formation, Western blot), and in vivo tests in female BALB/c nude mice treated with E5 (2 and 4 mg/kg). E5 (4 mg/kg) significantly reduced xenograft tumor growth compared to the DMSO control group. RESULTS: Among the 16 PPT derivatives tested for cytotoxicity, E5 exhibited potent effects against A549 cells (IC50: 0.35 ± 0.13 µM) and exceeded the reference drugs PPT and etoposide to inhibit the growth of xenograft tumours. E5-induced cell cycle arrest in the S and G2/M phases accelerated tubulin depolymerization and triggered apoptosis and mitochondrial depolarization while regulating the expression of apoptosis-related proteins and effectively inhibited cell migration and invasion, suggesting a potential to limit metastasis. Molecular docking showed binding of E5 to tubulin at the colchicine site and to Akt, with a consequent down-regulation of PI3K/Akt pathway proteins. DISCUSSION AND CONCLUSIONS: This research lays the groundwork for advancing cancer treatment through developing and using PPT derivatives. The encouraging results associated with E5 call for extended research and clinical validation, leading to novel and more effective cancer therapies.

6-Gingerol regulates triglyceride and cholesterol biosynthesis to improve hepatic steatosis in MAFLD by activating the AMPK-SREBPs signaling pathway.

Excessive synthesis of triglycerides and cholesterol accelerates the progression of hepatic steatosis in metabolic-associated fatty liver disease (MAFLD). However, the precise mechanism by which 6-gingerol mitigates hepatic steatosis in MAFLD model mice has yet to be fully understood. The present study observed that 6-gingerol administration exhibited significant protective effects against obesity, insulin resistance, and hepatic steatosis in mice subjected to a high-fat diet (HFD), and mitigated lipid accumulation in HepG2 cells treated with palmitate (PA). Following the hepatic lipidomic analysis, we confirmed that the AMPK-SREBPs signaling pathway as the underlying molecular mechanism by which 6-gingerol inhibited triglyceride and cholesterol biosynthesis, both in vivo and in vitro, through Western blot and immunofluorescence assay. Additionally, the application of an AMPK agonist/inhibitor further validated that 6-gingerol promoted AMPK activation by increasing the phosphorylation level of AMPK in vitro. Notably, the inhibitory effect of 6-gingerol on cholesterol biosynthesis, rather than triglyceride biosynthesis, was significantly diminished after silencing SREBP2 using a lentiviral plasmid shRNA in HepG2 cells. Our study demonstrates that 6-gingerol mitigates hepatic triglyceride and cholesterol biosynthesis to alleviate hepatic steatosis by activating the AMPK-SREBPs signaling pathway, indicating that 6-gingerol may be a potential candidate in the therapy of MAFLD.

The Intestinal Redox System and Its Significance in Chemotherapy-Induced Intestinal Mucositis.

Chemotherapy-induced intestinal mucositis (CIM) is a significant dose-limiting adverse reaction brought on by the cancer treatment. Multiple studies reported that reactive oxygen species (ROS) is rapidly produced during the initial stages of chemotherapy, when the drugs elicit direct damage to intestinal mucosal cells, which, in turn, results in necrosis, mitochondrial dysfunction, and ROS production. However, the mechanism behind the intestinal redox system-based induction of intestinal mucosal injury and necrosis of CIM is still undetermined. In this article, we summarized relevant information regarding the intestinal redox system, including the composition and regulation of redox enzymes, ROS generation, and its regulation in the intestine. We innovatively proposed the intestinal redox "Tai Chi" theory and revealed its significance in the pathogenesis of CIM. We also conducted an extensive review of the English language-based literatures involving oxidative stress (OS) and its involvement in the pathological mechanisms of CIM. From the date of inception till July 31, 2021, 51 related articles were selected. Based on our analysis of these articles, only five chemotherapeutic drugs, namely, MTX, 5-FU, cisplatin, CPT-11, and oxaliplatin were shown to trigger the ROS-based pathological mechanisms of CIM. We also discussed the redox system-mediated modulation of CIM pathogenesis via elaboration of the relationship between chemotherapeutic drugs and the redox system. It is our belief that this overview of the intestinal redox system and its role in CIM pathogenesis will greatly enhance research direction and improve CIM management in the future.

Curcumin Relieves Chronic Unpredictable Mild Stress-Induced Depression-Like Behavior through the PGC-1α/FNDC5/BDNF Pathway.

METHODS: All rats were randomly divided into four groups, namely, control, CUMS, CUMS + CUR, and CUMS + CUR + SR18292 (PGC-1α inhibitor). Behavioral tests were conducted to assess the antidepressant-like effects of CUR. The expressions of PGC-1α, estrogen-related receptor alpha (ERRα), FNDC5, and BDNF were determined to investigate the regulatory effects of CUR on the PGC-1α/FNDC5/BDNF pathway. The PGC-1α inhibitor SR18292 was used to explore the role of PGC-1α in the induction of BDNF by CUR. RESULTS: Daily gavage of 100 mg/kg CUR successfully attenuated the abnormal behaviors induced by CUMS and effectively prevented CUMS-induced reduction of PGC-1α, ERRα, FNDC5, and BDNF expressions. CUR also enhanced PGC-1α and ERRα translocation from cytoplasm to nucleus. Furthermore, we found that CUR supplementation effectively promoted neurocyte proliferation and suppressed neuronal apoptosis induced by CUMS. Of note, the PGC-1α inhibitor SR18292 remarkably reversed the beneficial effects of CUR on depressed rats, indicating an important role of PGC-1α in the antidepressant-like effects of CUR. CONCLUSION: Collectively, our data evaluating the neuroprotective action of CUR in the CUMS rats highlights the involvement of the PGC-1α/FNDC5/BDNF pathway in the antidepressant-like effects of CUR.

Nobiletin Ameliorates NLRP3 Inflammasome-Mediated Inflammation Through Promoting Autophagy via the AMPK Pathway.

Multiple lines of evidence have shown that neuroinflammation and autophagy are highly involved in the process of depression. Nobiletin (NOB) displays neuroprotective effects and anti-depressant-like effects. Given the evidence that NOB exerts anti-inflammatory effects and regulates autophagy, we investigate the anti-neuroinflammatory properties and the effect of regulating the autophagy of NOB and subsequently uncover the potential anti-depressant mechanisms of NOB. The behavioral changes of rats were observed after prolonged lipopolysaccharide (LPS) treatment and NOB administration. Rat hippocampus and BV2 cells treated by LPS and NOB were evaluated. The methods of real-time PCR analysis, Western blot, immunostaining, and adenovirus transfection were employed to determine neuroinflammation, autophagic markers, and nucleotide-binding oligomerization domain-like receptor 3 (NLRP3) activation. Our study showed LPS enhanced the expression of pro-inflammatory cytokines and NLRP3 inflammasome activation but inhibited autophagy in both rat hippocampus and BV2 cells. NOB significantly improved the behavioral deficits and ameliorated the neuroinflammation induced by LPS in rats. Furthermore, NOB promoted autophagy and attenuated NLRP3 inflammasome activation induced by LPS, involving in the process the adenosine monophosphate-activated protein kinase (AMPK) pathway. Neuroprotective and anti-depressant actions of NOB relied on its effects of promoting autophagy and suppressing the activation of NLRP3, in which process of AMPK pathway may be involved.

Neuroprotective effects of vitamin D and 17ß-estradiol against ovariectomy-induced neuroinflammation and depressive-like state: Role of the AMPK/NF-κB pathway.

Estrogen replacement therapy (ERT) has been proven to relieve menopausal-related mental disorders including depression in postmenopausal women. However, the unsafety of ERT hinders its clinical use. In this study, we would evaluate whether vitamin D (VD), a hormone with optimal safety profile, could relieve the depressive-like symptom in ovariectomized (OVX) rats. Furthermore, we would determine whether vitamin D and 17ß-estradiol (E2) exert neurological function through their immunomodulatory effect in OVX rats. Middle-aged female SD rats were randomly divided into four groups, namely, control (SHAM), OVX, OVX + VD, and OVX + E2. Vitamin D (calcitriol, 100 ng/kg) and 17ß-estradiol (30 µg/kg) had been daily gavaged in the OVX + VD and OVX + E2 group, respectively. After 10-week administration, vitamin D and 17ß-estradiol both showed anti-depressive-like activity in the OVX rats. Using the method of immunofluorescent staining and western blot, vitamin D and 17ß-estradiol were demonstrated to upregulate each other's receptors, including VDR, ERα, and ERß in the hippocampus of OVX rats. Additionally, the upregulation of VDR, calbindin-D28k, and calbindin-D9k suggested that the vitamin D signaling system was amplified by vitamin D and 17ß-estradiol. Vitamin D and 17ß-estradiol showed neuroprotective effects by decreasing OVX-induced apoptosis and neuronal damage, regulating the AMPK/NF-κB signaling pathway, and reducing the proinflammatory cytokines (IL-1ß, IL-6, and TNFα), as well as iNOS and COX-2 in the hippocampus of OVX rats. Collectively, the present study demonstrated that vitamin D and 17ß-estradiol could upregulate each other's receptors and regulate the AMPK/NF-κB pathway to relieve the OVX-induced depressive-like state. The results could stimulate translational research towards the vitamin D potential for prevention or treatment of menopause-related depression.

Salvianolic Acid B Improves Chronic Mild Stress-Induced Depressive Behaviors in Rats: Involvement of AMPK/SIRT1 Signaling Pathway.

INTRODUCTION: Depression is one of the most common neuropsychiatric illnesses which leads to a huge social and economic burden on modern society. So, it is necessary to develop an effective and safe pharmacological intervention for depression. Accumulating evidence has shown that adenosine monophosphate-activated protein kinase/sirtuin 1 (AMPK/SIRT1) signaling pathway plays a pivotal role in the development of depression. Our present study aimed to investigate the antidepressant effect and possible mechanisms of salvianolic acid B (SalB) in a chronic mild stress (CMS)-induced depression model in rats. MATERIALS AND METHODS: The rats were randomly divided into three groups: control group with no stressor, CMS group and CMS+SalB (30 mg/kg/d) group. After administration for 28 consecutive days, the behavior tests were performed. The rats were sacrificed after behavior tests, and the brain tissues were collected for biochemical analysis. RESULTS: It was observed that the administration of SalB for 28 consecutive days successfully corrected the depressive-like behaviors in CMS-treated rats. SalB could effectively reduce the gene expression of pro-inflammatory cytokines such as interleukin-6 (IL-6), interleukin-1ß (IL-1ß) and tumor necrosis factor α (TNF-α), as well as nuclear factor-kappa B (NF-κB) p65 protein. In addition, inhibitor of NF-κB (IκB) protein expression was significantly increased after the administration of SalB. Moreover, SalB could effectively decrease protein expression of oxidative stress markers such as 4-hydroxynonenal (4-HNE) and malondialdehyde (MDA) and increase the activity of catalase (CAT). SalB treatment also reversed CMS-induced inhibition of Nrf2 signaling pathway, along with increasing the mRNA expression of NAD(P)H:quinone oxidoreductase (NQO-1) and heme oxygenase 1 (HO-1). Regarding the endoplasmic reticulum (ER) stress markers, the protein expressions of C/EBP-homologous protein (CHOP) and glucose-regulated protein 78 kD (GRP78) were also significantly reduced after SalB administration. Furthermore, the supplementation of SalB could effectively activate the AMPK/SIRT1 signaling pathway, which indicated significant increase in pAMPK/AMPK ratio and SIRT1 protein expression. CONCLUSION: Our study demonstrated that SalB relieved CMS-induced depressive-like state through the mitigation of inflammatory status, oxidative stress, and the activation of AMPK/SIRT1 signaling pathway.

Angiotensin-â ¡ and angiotensin-(1-7) imbalance affects comorbidity of depression and coronary heart disease.

A large body of evidence suggests a relationship between depression and coronary heart disease (CHD). Angiotensin-Ⅱ (Ang-Ⅱ) and angiotensin-(1-7) [Ang-(1-7)] are considered to exert biological effects in both conditions. Here, we aimed to determine the role of Ang-Ⅱ and Ang-(1-7) in the occurrence of comorbid depression in patients with CHD. Our study included 214 CHD patients and 100 matched healthy controls. Serum Ang-Ⅱ and Ang-(1-7) levels were assessed by ELISA, and the depression symptoms were evaluated by the nine-item Patient Health Questionnaire (PHQ-9). Linear regression and correlation analyses were used to estimate the associations between PHQ-9 scores and Ang-Ⅱ and Ang-(1-7) serum levels. Six single-nucleotide polymorphisms (SNPs) spanning the angiotensin converting enzyme 2 (ACE2) and MAS1 genes were genotyped. The associations between SNPs and depression risk in CHD patients were examined using logistic regression analysis with adjustment for age and gender. Decreased Ang-(1-7) (P < 0.05) and an elevated Ang-Ⅱ/Ang-(1-7) ratio (P < 0.01) were observed in CHD patients with depression compared to CHD patients without depression. PHQ-9 scores were negatively correlated with Ang-(1-7) level (r=-0.44, P < 0.01) and positively correlated with the Ang-Ⅱ/Ang-(1-7) ratio (r = 0.33, P < 0.05). Furthermore, carriers of risk allele T for CHD with depression had significantly higher PHQ-9 scores (P < 0.05), lower Ang-(1-7) level (P < 0.01), and higher Ang-Ⅱ/Ang-(1-7) ratio (P < 0.05) than those CC carriers. Collectively, our results firstly showed that Ang-(1-7) serum level in CHD patients may protect against comorbid depression. Moreover, the imbalance between Ang-Ⅱ and Ang-(1-7) may contribute to depression in CHD patients.

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

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.

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.

Insight into resistance mechanisms of AZD4547 and E3810 to FGFR1 gatekeeper mutation via theoretical study.

Inhibitors targeting the amplification of the fibroblast growth factor receptor 1 (FGFR1) have found success in the treatment of FGFR1-positive squamous cell lung and breast cancers. A secondary mutation of gatekeeper residue (V561M) in the binding site has been linked to the acquired resistance. Recently, two well-known small molecule inhibitors of FGFR1, AZD4547 and E3810, reported that the V561M mutation confers significant resistance to E3810, while retaining affinity for AZD4547. FGFR1 is widely investigated as potential therapeutic target, while there are few computational studies made to understand the resistance mechanisms about FGFR1 V561M gatekeeper mutation. In this study, molecular docking, classical molecular dynamics simulations, molecular mechanics/generalized born surface area (MM/GBSA) free energy calculations, and umbrella sampling (US) simulations were carried out to make clear the principle of the binding preference of AZD4547 and E3810 toward FGFR1 V561M gatekeeper mutation. The results provided by MM/GBSA reveal that AZD4547 has similar binding affinity to both FGFR1WT and FGFR1V561M, whereas E3810 has much higher binding affinity to FGFR1WT than to FGFR1V561M. Comparison of individual energy terms indicates that the major variation of E3810 between FGFR1WT and FGFR1V561M are van der Waals interactions. In addition, US simulations prove that the potential of mean force (PMF) profile of AZD4547 toward FGFR1WT and FGFR1V561M has similar PMF depth. However, the PMF profile of E3810 toward FGFR1WT and FGFR1V561M has much higher PMF depth, suggesting that E3810 is more easily dissociated from FGFR1V561M than from FGFR1WT. The results not only show the drug-resistance determinants of FGFR1 gatekeeper mutation but also provide valuable implications and provide vital clues for the development of new inhibitors to combat drug resistance.

Chronic administration of calcitriol enhanced neuregulin-1/ErbB signaling in rat myocardium.

Although emerging evidence suggests that vitamin D has beneficial effects in the cardiovascular health, the underlying mechanisms are far from fully elucidated. Given the indispensable role of neuregulin-1 (NRG1)/ErbB signaling in the cardiovascular system, the present study investigated the influences of prolonged administration of calcitriol, the active form of vitamin D, on the NRG1/ErbB system. We examined the protein expression of NRG1, ErbB receptors (ErbB2 and ErbB4) and their phosphorylated forms in the myocardium of rats following 6-week administration of calcitriol (50 ng/kg/day or 100 ng/kg/day). We further assessed the myocardial vitamin D receptor (VDR) to confirm the effect of calcitriol treatment. Additionally, serum neuregulin-1 level was also analyzed. Generally, calcitriol enhanced myocardial VDR expression and NRG1/ErbB signaling. Calcitriol increased NRG1 protein level at the higher dose, while both doses promoted ErbB2 and phosphorylated ErbB2 expression. Although calcitriol has no significant influence on ErbB4 expression, phosphorylated ErbB4 receptors were enhanced at the higher dose. Furthermore, the serum neuregulin-1 concentration was increased at both doses. Overall, our data firstly showed that chronic calcitriol administration enhanced NRG1/ErbB signaling in the heart, indicating a novel mechanism underlying the cardiac effects of vitamin D.

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.

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.