Juvenile hormone promotes paracellular transport of yolk proteins via remodeling zonula adherens at tricellular junctions in the follicular epithelium.

Juvenile hormone (JH) acts as a gonadotrophic hormone stimulating insect vitellogenesis and oogenesis. Paracellular transport of yolk proteins through intercellular channels (patency) in the follicular epithelium is a developmentally regulated and evolutionarily conserved process during vitellogenesis. However, the mechanisms underlying patency opening are poorly understood. Using the migratory locust Locusta migratoria as a model system, we report here that JH-regulated remodeling of zonula adherens (ZA), the belt-like adherens junction maintaining physical linking between follicle cells controlled the opening of patency. JH triggered phosphorylation of Partitioning defective protein 3 (Par3) via a signaling cascade including G protein-coupled receptor (GPCR), small GTPase Cell division cycle 42 (Cdc42) and atypical Protein kinase C (aPKC). Par3 phosphorylation resulted in its disassociation from ß-Catenin, the cytoplasmic partner of ZA core component E-Cadherin. Release of Par3 from the ß-Catenin/E-Cadherin complex caused ZA disassembly at tricellular contacts, consequently leading to patency enlargement. This study provides new insight into how JH stimulates insect vitellogenesis and egg production via inducing the opening of paracellular route for vitellogenin transport crossing the follicular epithelium barrier.

High level of ANO1 promotes pancreatic cancer growth in concert with oncogenic KRAS.

BACKGROUND: Anoctamin-1 (ANO1) was identified as an unfavorable prognostic marker in pancreatic cancer. However, the exact implication of ANO1 in pancreatic cancer is still poorly understood. Here we investigated the effect of ANO1 in pancreatic cancer progression under the context of oncogenic KRAS, aiming at finding a new therapeutic target. METHODS: Knockdown and overexpression of oncogenic KRAS as well as ANO1 in PDAC cell lines were performed by lentivirus infection. Cell proliferation and migration assay, RNA seq analysis were performed in PDAC cells bearing different status of ANO1 and KRAS. In vivo mice model was used to investigate the xenograft tumor growth with different status of KRAS and ANO1. RESULTS: Our results showed that ANO1 expression level is elevated in poorly differentiated cancer cells. Overexpression of ANO1 in PDAC cancer cells was found to promote cancer cell proliferation in vitro and in vivo, which synergized with the introduction of oncogenic KRAS. Consistently, knockdown of ANO1 expression was found to suppress cancer growth in vitro and in vivo. RNA seq analysis revealed that the observed synergistic cancer-promoting effect from ANO1 and oncogenic KRAS is likely due to concurrent activating key genes involved in lipid metabolism including HMGCS1. CONCLUSION: The outcome from our study suggests that ANO1 plays an important role in promoting pancreatic cancer development, especially at the presence of oncogenic KRAS. Considering the prevalence of KRAS mutation in pancreatic cancer patients, suppression ANO1 may represent a potential effective therapeutic measure in pancreatic cancer treatment.

FGF10 mitigates doxorubicin-induced myocardial toxicity in mice via activation of FGFR2b/PHLDA1/AKT axis.

Doxorubicin is a common chemotherapeutic agent in clinic, but myocardial toxicity limits its use. Fibroblast growth factor (FGF) 10, a multifunctional paracrine growth factor, plays diverse roles in embryonic and postnatal heart development as well as in cardiac regeneration and repair. In this study we investigated the role of FGF10 as a potential modulator of doxorubicin-induced cardiac cytotoxicity and the underlying molecular mechanisms. Fgf10+/- mice and an inducible dominant negative FGFR2b transgenic mouse model (Rosa26rtTA; tet(O)sFgfr2b) were used to determine the effect of Fgf10 hypomorph or blocking of endogenous FGFR2b ligands activity on doxorubicin-induced myocardial injury. Acute myocardial injury was induced by a single injection of doxorubicin (25 mg/kg, i.p.). Then cardiac function was evaluated using echocardiography, and DNA damage, oxidative stress and apoptosis in cardiac tissue were assessed. We showed that doxorubicin treatment markedly decreased the expression of FGFR2b ligands including FGF10 in cardiac tissue of wild type mice, whereas Fgf10+/- mice exhibited a greater degree of oxidative stress, DNA damage and apoptosis as compared with the Fgf10+/+ control. Pre-treatment with recombinant FGF10 protein significantly attenuated doxorubicin-induced oxidative stress, DNA damage and apoptosis both in doxorubicin-treated mice and in doxorubicin-treated HL-1 cells and NRCMs. We demonstrated that FGF10 protected against doxorubicin-induced myocardial toxicity via activation of FGFR2/Pleckstrin homology-like domain family A member 1 (PHLDA1)/Akt axis. Overall, our results unveil a potent protective effect of FGF10 against doxorubicin-induced myocardial injury and identify FGFR2b/PHLDA1/Akt axis as a potential therapeutic target for patients receiving doxorubicin treatment.

A 512-Channel Multi-Layer Polymer-Based Neural Probe Array.

We present for the first time the design, fabrication, and preliminary bench-top characterization of a high-density, polymer-based penetrating microelectrode array, developed for chronic, large-scale recording in the cortices and hippocampi of behaving rats. We present two architectures for these targeted brain regions, both featuring 512 Pt recording electrodes patterned front-and-back on micromachined eight-shank arrays of thin-film Parylene C. These devices represent an order of magnitude improvement in both number and density of recording electrodes compared with prior work on polymer-based microelectrode arrays. We present enabling advances in polymer micro-machining related to lithographic resolution and a new method for back-side patterning of electrodes. In vitro electrochemical data verifies suitable electrode function and surface properties. Finally, we describe next steps toward the implementation of these arrays in chronic, large-scale recording studies in free-moving animal models.

A Parylene Neural Probe Array for Multi-Region Deep Brain Recordings.

A Parylene C polymer neural probe array with 64 electrodes purposefully positioned across 8 individual shanks to anatomically match specific regions of the hippocampus was designed, fabricated, characterized, and implemented in vivo for enabling recording in deep brain regions in freely moving rats. Thin film polymer arrays were fabricated using surface micromachining techniques and mechanically braced to prevent buckling during surgical implantation. Importantly, the mechanical bracing technique developed in this work involves a novel biodegradable polymer brace that temporarily reduces shank length and consequently, increases its stiffness during implantation, therefore enabling access to deeper brain regions while preserving a low original cross-sectional area of the shanks. The resulting mechanical properties of braced shanks were evaluated at the benchtop. Arrays were then implemented in vivo in freely moving rats, achieving both acute and chronic recordings from the pyramidal cells in the cornu ammonis (CA) 1 and CA3 regions of the hippocampus which are responsible for memory encoding. This work demonstrated the potential for minimally invasive polymer-based neural probe arrays for multi-region recording in deep brain structures.

The Anti-Inflammatory Effects of Vitamin D in Tumorigenesis.

In conjunction with the classical functions of regulating intestinal, bone, and kidney calcium and phosphorus absorption, as well as bone mineralization of vitamin D, the population-based association between low vitamin D status and increased cancer risk is now generally accepted. Inflammation is causally related to oncogenesis. It is widely thought that vitamin D plays an important role in the modulation of the inflammation system by regulating the production of inflammatory cytokines and immune cells, which are crucial for the pathogenesis of many immune-related diseases. Mechanistic studies have shown that vitamin D influences inflammatory processes involved in cancer progression, including cytokines, prostaglandins, MAP kinase phosphatase 5 (MKP5), the nuclear factor kappa B (NF-κB) pathway, and immune cells. Multiple studies have shown that vitamin D has the potential to inhibit tumor development by interfering with the inflammation system. The present review summarizes recent studies of the mechanisms of vitamin D on regulating the inflammation system, which contributes to its potential for cancer prevention and therapy. This review helps answer whether inflammation mediates a causal relationship between vitamin D and tumorigenesis.

[Effect of enhanced green fluorescent protein fusion on Ano1 physiological feature].

The aim of the present study was to investigate whether the physiological features of Ano1 were affected by enhanced green fluorescent protein (EGFP) fusing at Ano1 C-terminal. The eukaryotic expression vectors of Ano1 and EGFP-Ano1 were constructed, and these plasmids were transfected into Fischer rat thyroid follicular epithelial (FRT) cells using liposome. The expression and location of Ano1 were examined by using inverted fluorescence microscope. The ability of Ano1 to transport iodide was detected by kinetics experiment of fluorescence quenching. The results showed that both Ano1 and EGFP-Ano1 were expressed on FRT cell membrane and could be activated by Ca(2+). There was no significant difference of the ability to transport iodide between Ano1 and EGFP-Ano1. These results suggest Ano1 and EGFP-Ano1 have similar physiological feature.

High-level expression, purification, and characterization of bifunctional ScFv-9R fusion protein.

Fibroblast growth factor receptor 3 (FGFR3) is a noted proto-oncogene involved in the pathogenesis of many tumors, so more and more studies focus on the potential use of receptor kinase inhibitor and therapeutic antibodies against FGFR3. In this study, we designed a novel fusion protein containing the single-chain Fv (ScFv) against FGFR3 and 9-arginine, denoted as ScFv-9R. To achieve the high-level production and soluble expression, ScFv and ScFv-9R were fused with small ubiquitin-related modifier (Sumo) by polymerase chain reaction and expressed in Escherichia coli BL21 (DE3). The recombinant bacteria was induced by 0.5 mM isopropyl-ß-D-thiogalactopyranoside for 20 h at 20 °C; supernatants of Sumo-ScFv was harvested and purified by DEAE Sepharose FF and Ni-NTA orderly, and supernatants of Sumo-ScFv-9R was harvested and purified by Ni-NTA. After cleaved by the Sumo protease, the recombinant ScFv or ScFv-9R was released from the fusion protein, respectively. The purity of ScFv or ScFV-9R was shown to be higher than 90 %, and their yield reached 3-5 mg per liter of bacterial culture. In vitro data showed that ScFV-9R can attenuate the phosphorylation of FGFR3 and ERK in the absence or presence of FGF9. Gel retardation assay showed that 1 µg of ScFv-9R could efficiently bind to about 4 pmol siRNA. Fluorescent microscope analysis showed that ScFv-9R can efficiently bind and deliver siRNA into RT112 cells. In conclusion, we use Sumo fusion system to acquire high-level production, soluble expression, and bifunctional activity of ScFv-9R in E. coli. Our results also revealed that ScFv-9R, as a novel carrier, may have potential applications in antitumor studies and pharmaceutical development.

Single session of interpretation bias modification helped to improve fear of COVID-19 and COVID-19-related post-traumatic stress symptoms.

BACKGROUND: Post-traumatic stress symptoms (PTSS) are frequently observed in those who have experienced trauma events like the COVID-19 outbreak. The cognitive model of PTSS highlights the relationship between PTSS and negative interpretation bias. OBJECTIVE: The present study aimed to modify interpretation bias and to improve PTSS as well as PTSS-related fear. METHODS: 59 participants with high PTSS levels were recruited and randomly allocated to either the interpretation modification programme (IMP) intervention group or the interpretation control condition (ICC) control group. PTSS, negative interpretation bias, fear of COVID-19, and depression and anxiety symptoms were assessed before and after training. FINDINGS: Intention-to-treat analyses showed that compared with ICC, participants receiving IMP generated fewer negative interpretations for ambiguous scenarios, and the group-by-time interaction effect was significant. IMP also illustrated a more significant change in fear after training compared with ICC. Although no effects of training conditions were found on PTSS, the interaction of training conditions with fear reduction could predict PTSS improvement. CONCLUSIONS: IMP could improve negative interpretations and fear related to COVID-19 and might help to ameliorate PTSS. CLINICAL IMPLICATIONS: The role of PTSS-related emotion should be considered when exploring the effectiveness of IMP. IMP is a flexible approach that can be tailored to the specific characteristics of the traumatic event, which makes it suitable for a broader range of traumatised individuals.

Physicochemical characterization, rheological properties, and hypolipidemic and antioxidant activities of compound polysaccharides in Chinese herbal medicines by fractional precipitation.

This study aimed to investigate the effects of different compound polysaccharides (CPs) extracted from Folium nelumbinis, Fructus crataegi, Fagopyrum tataricum, Lycium barbarum, Semen cassiae, and Poria cocos (w/w, 2:4:2:1:1.5:1) by gradient ethanol precipitation on the physicochemical properties and biological activities. Three CPs (CP50, CP70, and CP80) were obtained and comprised rhamnose, arabinose, xylose, mannose, glucose, and galactose in different proportions. The CPs contained different amounts of total sugar, uronic acid, and proteins. These also exhibited different physical properties, including particle size, molecular weight, microstructure, and apparent viscosity. Scavenging abilities of 2,2'-azino-bis(3-ethylbenzthiazoline-6-sulphonic acid) (ABTS), 1,1'-diphenyl-2-picrylhydrazyl (DPPH), hydroxyl, and superoxide radicals of CP80 were more potent compared to those of the other two CPs. Furthermore, CP80 significantly increased serum levels of high-density lipoprotein cholesterol (HDL-C) and lipoprotein lipase (LPL), and hepatic lipase (HL) activity in the liver, while decreasing the serum levels of total cholesterol (TC), triglyceride (TG), and low-density lipoprotein cholesterol (LDL-C), along with LPS activity. Therefore, CP80 may serve as a natural novel lipid regulator in the field of medicinal and functional food.

A Library of Polymer-based Microelectrode Array Designs for Recording from the Brain of Different Animal Models.

Large-scale network recording technology is critical in linking neural activity to behavior. Stable, long-term recordings collected from behaving animals are the foundation for understanding neural dynamics and the plasticity of neural circuits. Penetrating microelectrode arrays (MEAs) can obtain high-resolution neural activity from different brain regions. However, ensuring the longevity of implantable devices and the consistency of neural signals over time remains one big challenge. A potential solution is to use flexible, polymer-based MEAs to minimize the foreign body response and prolong the lifetime of neural interfacing devices. Rodents and nonhuman primates (NHP) are commonly used animal models in neuroscience and neuroengineering studies. Specially designed MEAs that capture morphological features of different animal brains and various brain structures are powerful tools to simultaneously obtain neural activities from multiple brain regions. In this work, we develop a set of prototype designs of polymer MEAs that cover cortical, sub-cortical, and multiple brain regions of rodents and NHP.

Inhibition of Neuromyelitis Optica Immunoglobulin G Binding to Aquaporin-4 by the Small Molecule Blocker Melanthioidine.

BACKGROUND: Neuromyelitis optica (NMO) is a severe neurological demyelinating autoimmune disease affecting the optic nerves and spinal cord. The binding of neuromyelitis optica immunoglobulin G (NMO- IgG) and aquaporin-4 (AQP4) on the surface of astrocytes in the serum and cerebrospinal fluid is the main pathogenesis of NMO. Currently, therapeutic strategies for NMO include a reduction of the secondary inflammation response and the number of NMO-IgG, which can only alleviate clinical symptoms rather than fundamentally preventing a series of pathological processes caused by NMO-IgG binding to AQP4. OBJECTIVE: The purpose of this study was to investigate the blocking effect of melanthioidine on the binding of NMO-IgG to AQP4 and its potential cytotoxicity. METHODS: The current study developed a cell-based high-throughput screening approach to identify a molecular blocker of NMO-IgG binding to AQP4 using the Chinese hamster lung fibroblast (V79) cells expressing M23- AQP4. By screening ~400 small molecules, we identified melanthioidine with blocking effects without affecting AQP4 expression or its water permeability. RESULTS: Melanthioidine effectively blocked the binding of NMO-IgG to AQP4 in immunofluorescence assays and reduced complement-dependent cytotoxicity against both NMO-IgG/complement-treated Fischer rat thyroid- AQP4 cells and primary astrocytes. The docking computations identified the putative sites of blocker binding at the extracellular surface of AQP4. CONCLUSION: This study serves as proof of a potential NMO therapy by using a small-molecule blocker to target NMO pathogenesis.

Polymer Implantable Electrode Foundry: A shared resource for manufacturing polymer-based microelectrodes for neural interfaces.

Large scale monitoring of neural activity at the single unit level can be achieved via electrophysiological recording using implanted microelectrodes. While neuroscience researchers have widely employed chronically implanted electrode-based interfaces for this purpose, a commonly encountered limitation is loss of highly resolved signals arising from immunological response over time. Next generation electrode-based interfaces improve longitudinal signal quality using the strategy of stabilizing the device-tissue interface with microelectrode arrays constructed from soft and flexible polymer materials. The limited availability of such polymer microelectrode arrays has restricted access to a small number of researchers able to build their own custom devices or who have developed specific collaborations with engineering researchers who can produce them. Here, a new technology resource model is introduced that seeks to widely increase access to polymer microelectrode arrays by the neuroscience research community. The Polymer Implantable Electrode (PIE) Foundry provides custom and standardized polymer microelectrode arrays as well as training and guidance on best-practices for implantation and chronic experiments.

Making a case for endovascular approaches for neural recording and stimulation.

There are many electrode types for recording and stimulating neural tissue, most of which necessitate direct contact with the target tissue. These electrodes range from large, scalp electrodes which are used to non-invasively record averaged, low frequency electrical signals from large areas/volumes of the brain, to penetrating microelectrodes which are implanted directly into neural tissue and interface with one or a few neurons. With the exception of scalp electrodes (which provide very low-resolution recordings), each of these electrodes requires a highly invasive, open brain surgical procedure for implantation, which is accompanied by significant risk to the patient. To mitigate this risk, a minimally invasive endovascular approach can be used. Several types of endovascular electrodes have been developed to be delivered into the blood vessels in the brain via a standard catheterization procedure. In this review, the existing body of research on the development and application of endovascular electrodes is presented. The capabilities of each of these endovascular electrodes is compared to commonly used direct-contact electrodes to demonstrate the relative efficacy of the devices. Potential clinical applications of endovascular recording and stimulation and the advantages of endovascular versus direct-contact approaches are presented.

ESE1/AGR2 axis antagonizes TGF-ß-induced epithelial-mesenchymal transition in low-grade pancreatic cancer.

Epithelium-specific ETS transcription factor 1 (ESE1) has been implicated in epithelial homeostasis, inflammation, as well as tumorigenesis, and cancer progression. However, numerous studies have reported contradictory roles-as an oncogene or a tumor suppressor of ESE1 in different cancers, and its function in the development and progression of pancreatic ductal adenocarcinoma (PDAC) has remained largely unexplored. Herein, we report that ESE1 was found upregulated in primary PDAC compared to normal pancreatic tissue, but high expression of ESE1 correlated to better relapse-free survival in patients with PDAC. Interestingly, ESE1 was found to exhibit dual roles in regulation of malignant properties of PDAC cells in that its overexpression promoted cell proliferation, whereas its downregulation enhanced epithelial-mesenchymal transition (EMT) phenotype. In the context of TGF-ß-induced EMT, ESE1 is markedly downregulated at post-transcriptional level, and reconstituted ESE1 expression partially reversed TGF-ß-induced EMT marker expression. Furthermore, we identify AGR2 as a novel transcriptional target of ESE1 that participates in TGF-ß-induced EMT in PDAC. Collectively, our findings reveal an ESE1/AGR2 axis that interacts with TGF-ß signaling to modulate EMT phenotype in PDAC.

Imaging features of eosinophilic solid and cystic renal cell carcinoma: An additional case report of a novel tumor entity.

Eosinophilic solid and cystic renal cell carcinoma (ESC RCC) is a special classification of indolent kidney tumors newly discovered in recent years. It is extremely uncommon, with only a few clinical and pathological reports, and its imaging description are very rare. Here, we present a case of ESC RCC.

Perceived stress and stress responses during COVID-19: The multiple mediating roles of coping style and resilience.

Although many studies have examined the effects of perceived stress on some specific stress responses during the COVID-19, a comprehensive study is still lacking. And the co-mediating role of coping style and resilience as important mediators of stress processes is also unclear. This study aimed to explore the effects of perceived stress on emotional, physical, and behavioral stress responses and the mediating roles of coping style and resilience in Chinese population during the recurrent outbreak of COVID-19 from a comprehensive perspective. 1087 participants were recruited to complete the anonymous online survey including the Perceived Stress Scale, the Stress Response Questionnaire, the Simplified Coping Style Questionnaire and the Emotional Resilience Questionnaire. Pearson's correlation and Hayes PROCESS macro 3.5 model 6 were used in the mediating effect analysis. Results showed that positive coping style and resilience both buffered the negative effects of perceived stress on emotional, physical, and behavioral responses through direct or indirect pathways, and resilience had the strongest mediating effects. The findings urged relevant authorities and individuals to take measures to promote positive coping style and resilience to combat the ongoing pandemic stress and protect public physical and mental health.

Quarantine and demographic characteristics as predictors of perceived stress and stress responses during the third year of COVID-19 in China.

Background: Quarantine as one of the most effective epidemic prevention measures, significantly increased people's stress levels. Ongoing monitoring of the stress status of people under quarantine during the pandemic is an important part of assessing the long-term impact of COVID-19 on mental health. This study aimed to gain a more comprehensive understanding of the stress status of people under quarantine, including perceived stress and stress responses, during the third year of the COVID-19 pandemic in China. Methods: An anonymous online survey was conducted among 464 participants from 39 cities in China from March 31 to April 12, 2022. The survey included three questionnaires: a self-designed questionnaire collecting demographic information and quarantine characteristics, the Perceived Stress Scale (PSS-10) and the Stress Response Questionnaire (SRQ). The t-test or one-way ANOVA or the Welch F-test were used to examine the differences among demographic and quarantine variables of perceived stress and stress responses, then multiple linear regressions were performed to identify the predictors of perceived stress and stress responses. Results: 428 valid respondents were finally included. The average scores of perceived stress, total stress response, emotional response, physical response, and behavioral response were 14.70 ± 7.02, 50.24 ± 22.48, 20.35 ± 9.99, 15.23 ± 7.25, and 11.39 ± 5.27, respectively. The regression analysis showed that the degree of financial worries and days of continuous quarantine were the predictors of perceived stress. The degree of financial worries was a vital factor in predicting total stress response, emotional response, physical response and behavioral response, and in predicting emotional response, age was also a significant predictor. Conclusion: The stress status of individuals under quarantine was generally stable but still needs further attention during the third year of the COVID-19 pandemic. People who are young, have a high degree of financial worries and have been quarantined for a long time may be at a higher risk of perceived stress and stress responses. Relevant authorities should pay closer attention to the risk groups, and additional support and assistance might be required for those mostly worried about their financial situations under quarantine.

Subthreshold repetitive transcranial magnetic stimulation suppresses ketamine-induced poly population spikes in rat sensorimotor cortex.

Cortical oscillations within or across brain regions play fundamental roles in sensory, motor, and memory functions. It can be altered by neuromodulations such as repetitive transcranial magnetic stimulation (rTMS) and pharmacological manipulations such as ketamine. However, the neurobiological basis of the effects of rTMS and ketamine, as well as their interactions, on cortical oscillations is not understood. In this study, we developed and applied a rodent model that enabled simultaneous rTMS treatment, pharmacological manipulations, and invasive electrophysiological recordings, which is difficult in humans. Specifically, a miniaturized C-shaped coil was designed and fabricated to deliver focal subthreshold rTMS above the primary somatosensory (S1) and motor (M1) cortex in rats. Multi-electrode arrays (MEA) were implanted to record local field potentials (LFPs) and single unit activities. A novel form of synchronized activities, poly population spikes (PPS), was discovered as the biomarker of ketamine in LFPs. Brief subthreshold rTMS effectively and reversibly suppressed PPS while increasing the firing rates of single unit activities. These results suggest that ketamine and rTMS have convergent but opposing effects on cortical oscillations and circuits. This highly robust phenomenon has important implications to understanding the neurobiological mechanisms of rTMS and ketamine as well as developing new therapeutic strategies involving both neuromodulation and pharmacological agents.

Inhibition of Connexin 36 attenuates HMGB1-mediated depressive-like behaviors induced by chronic unpredictable mild stress.

BACKGROUND: High mobility group box 1 (HMGB1) released by neurons and microglia was demonstrated to be an important mediator in depressive-like behaviors induced by chronic unpredictable mild stress (CUMS), which could lead to the imbalance of two different metabolic approaches in kynurenine pathway (KP), thus enhancing glutamate transmission and exacerbating depressive-like behaviors. Evidence showed that HMGB1 signaling might be regulated by Connexin (Cx) 36 in inflammatory diseases of central nervous system (CNS). Our study aimed to further explore the role of Cx36 in depressive-like behaviors and its relationship with HMGB1. METHODS: After 4-week chronic stress, behavioral tests were conducted to evaluate depressive-like behaviors, including sucrose preference test (SPT), tail suspension test (TST), forced swimming test (FST), and open field test (OFT). Western blot analysis and immunofluorescence staining were used to observe the expression and location of Cx36. Enzyme-linked immunosorbent assay (ELISA) was adopted to detect the concentrations of inflammatory cytokines. And the excitability and inward currents of hippocampal neurons were recorded by whole-cell patch clamping. RESULTS: The expression of Cx36 was significantly increased in hippocampal neurons of mice exposed to CUMS, while treatment with glycyrrhizinic acid (GZA) or quinine could both down-regulate Cx36 and alleviate depressive-like behaviors. The proinflammatory cytokines like HMGB1, tumor necrosis factor alpha (TNF-α), and interleukin-1ß (IL-1ß) were all elevated by CUMS, and application of GZA and quinine could decrease them. In addition, the enhanced excitability and inward currents of hippocampal neurons induced by lipopolysaccharide (LPS) could be reduced by either GZA or quinine. CONCLUSIONS: Inhibition of Cx36 in hippocampal neurons might attenuates HMGB1-mediated depressive-like behaviors induced by CUMS through down-regulation of the proinflammatory cytokines and reduction of the excitability and intracellular ion overload.