Ying Xing

Postoperative pain is a type of pain that occurs in clinical patients after surgery. Among the factors influencing the transition from acute postoperative pain to chronic postoperative pain, chronic stress has received much attention in recent years. Here, we investigated the role of dopamine receptor D1/D2 expressing pyramidal neurons in the prelimbic cortex (PrL) in modulating chronic social defeat stress (CSDS)-induced anxiety-like behavior comorbidity with postoperative hyperalgesia in male mice. Our results showed that preoperative CSDS induced anxiety-like behavior and significantly prolonged postoperative pain caused by plantar incision, but did not affect plantar wound recovery and inflammation. Reduced activation of dopamine receptor D1 or D2 expressing neurons in the PrL is a remarkable feature of male mice after CSDS, and chronic inhibition of dopamine receptor D1 or D2 expressing neurons in the PrL induced anxiety-like behavior and persistent postoperative pain. Further studies found that activation of D1 expressing but not D2 expressing neurons in the PrL ameliorated CSDS-induced anxiety-like behavior and postoperative hyperalgesia. Our results suggest that dopamine receptor D1 expressing neurons in the PrL play a crucial role in CSDS-induced anxiety-like behavior comorbidity with postoperative hyperalgesia in male mice.

Zinc finger and BTB domain containing 20 (ZBTB20) is a key transcription repressor that regulates multiple physiological and pathophysiological processes. Thus far, the role of ZBTB20 in glioblastoma (GBM), a World Health Organization grade IV glioma, remains unclear. In the present study, the expression profile data of ZBTB20 in GBM tissues from public databases was analyzed. It was found that ZBTB20 expression in GBM tissues was significantly lower than that measured in lower grade glioma tissues. Furthermore, patients with GBM with lower ZBTB20 expression were associated with a shorter overall survival time. Gain‑ and loss‑of‑function experiments in GBM cells were also performed. The results demonstrated that ZBTB20 overexpression decreased GBM cell proliferation, while ZBTB20 knockdown significantly enhanced it. Cell cycle analysis showed the ZBTB20 overexpression may have inhibited proliferation through cell cycle arrest at the G2/M phase, while ZBTB20 knockdown increased the percentages of cells in both the S phase and G2/M phase. Ten‑eleven translocation 1 (TET1) is an important tumor suppressor involved in the formation of various types of tumor, and it was upregulated in ZBTB20‑overexpressing GBM cells. It was further demonstrated that ZBTB20 activated the TET1/FAS/caspase‑3 pathway. The results of the present study therefore indicated the potential role of ZBTB20 as a tumor suppressor and therapeutic target for GBM.

Glucagon-like peptide 1 (GLP-1) analogues have been commercialized for the management of type 2 diabetes. Recent studies have underscored GLP-1’s role as a modulator of alcohol-related behavior. However, the role of the GLP-1 analogue liraglutide on alcohol-withdrawal responses have not been fully elucidated. Liraglutide binds to the G-protein-coupled receptor and activates an adenylyl cyclase and the associated classic growth factor signaling pathway, which acts growth factor-like and neuroprotective properties. The underlying neurobiological mechanisms of liraglutide on alcohol withdrawal remains unknown. This study endeavored to explore the effects of liraglutide on the emotion and memory ability of alcohol-withdrawal mice, and synaptic morphology in the medial prefrontal cortex (mPFC) and the hippocampus (HP), and thus affects the relapse-like drinking of alcohol-withdrawal mice. The alcohol-withdrawal group was reintroduced to a 20% v/v alcohol and water through the two-bottle choice for four consecutive days, a period referred to as alcohol re-drinking. Male C57BL/6J mice were exposed to a regimen of 20% alcohol and water for a duration of 6 weeks. This regimen established the two-bottle choice model of alcohol exposure. Learning capabilities, memory proficiency, and anxiety-like behavior were evaluated using the Morris water maze, open field, and elevated plus maze paradigms. Furthermore, synaptic morphology and the levels of synaptic transport-related proteins were assessed via Golgi staining and Western Blot analysis after a two-week alcohol deprivation period. Alcohol re-drinking of alcohol-withdrawal mice was also evaluated using a two-bottle choice paradigm. Our findings indicate that liraglutide can substantially decrease alcohol consumption and preference (p < 0.05) in the alcohol group and enhance learning and memory performance (p < 0.01), as well as alleviate anxiety-like behavior (p < 0.01) of alcohol-withdrawal mice. Alcohol consumption led to a reduction in dendritic spine density in the mPFC and HP, which was restored to normal levels by liraglutide (p < 0.001). Furthermore, liraglutide was found to augment the levels of synaptic transport-related proteins in mice subjected to alcohol withdrawal (p < 0.01). The study findings corroborate that liraglutide has the potential to mitigate alcohol consumption and ameliorate the memory impairments and anxiety induced by alcohol withdrawal. The therapeutic efficacy of liraglutide might be attributed to its role in counteracting synapse loss in the mPFC and HP regions and thus prevented relapse-like drinking in alcohol-withdrawal mice.

Background: Chronic postsurgical pain (CPP) markedly impairs patients’ quality of life. Research has shown that chronic stress may extend incisional nociception in male mice. Dopaminergic (DAergic) neurons in the ventral tegmental area (VTA) are integral to stress-related mental disorders (including major depressive disorder, anxiety disorders, and PTSD) and pain. However, the impact of chronic social defeat stress (CSDS) on mesolimbic dopamine (DA) transmission in the development of CPP is yet to be established. It remains uncertain whether the dopamine signals in the rostral anterior cingulate cortex (rACC), which regulate pain, derive from the VTA. This study aims to explore the role of VTA-rACC dopaminergic circuits in a mouse model of CPP induced by CSDS. Methods: We conducted CSDS on C57BL/6 J wild-type male mice (n = 12–16 mice/group) and DAT-cre male mice (n = 10–12 mice/group). After 10 days of CSDS, a left posterior plantar incision was made to establish a mouse model of CPP. Paw withdrawal thresholds (PWTs) were evaluated using Von-Frey fibre stimulation. The open field test (OFT) and elevated plus maze test (EPM) were used to assess pain-related negative emotions. We used immunofluorescence staining and Western Blot to analyse D1, D2, c-Fos, and TH expression. DAergic fibre projections in the VTA-rACC neural pathway were traced using retrograde tracing and immunofluorescence staining. Optogenetics and Chemogenetics were employed to manipulate DAergic neurons in the VTA and their axons in the rACC. Results: The ipsilateral PWTs in male C57BL/6 J mice significantly decreased after surgery, returning to baseline after seven days. Conversely, in CSDS mice, ipsilateral PWTs remained reduced for at least 30 days post-incision. A significant reduction in TH-positive neurons expressing c-Fos in the VTA of CPP mice was observed 15 days post-incision. Activating DAergic neurons significantly improved ipsilateral PWTs and locomotor performance in the OFT and EPM in CPP mice post-incision. Additionally, D1 expression in the rACC was found to decrease in CPP mice, and this reduction counteracted the increase in PWTs caused by activating DAergic neuron axon terminals in the rACC. Conclusion: CSDS results in chronicity of postsurgical nociception and anxiety-like negative emotions, with alterations in DA transmission playing a role in CPP. Specific activation of DAergic neurons mitigates nociceptive responses and anxiety-like bahaviors, possibly mediated by D1 receptors in the rACC.

Alzheimer’s disease (AD) is a chronic and progressive neurodegenerative disease and clinically manifests with cognitive decline and behavioral disabilities. Over the past years, mounting studies have demonstrated that the inflammatory response plays a key role in the onset and development of AD, and neuroinflammation has been proposed as the third major pathological driving factor of AD, ranking after the two well-known core pathologies, amyloid β (Aβ) deposits and neurofibrillary tangles (NFTs). Epigenetic mechanisms, referring to heritable changes in gene expression independent of DNA sequence alterations, are crucial regulators of neuroinflammation which have emerged as potential therapeutic targets for AD. Upon regulation of transcriptional repression or activation, epigenetic modification profiles are closely involved in inflammatory gene expression and signaling pathways of neuronal differentiation and cognitive function in central nervous system disorders. In this review, we summarize the current knowledge about epigenetic control mechanisms with a focus on DNA and histone modifications involved in the regulation of inflammatory genes and signaling pathways in AD, and the inhibitors under clinical assessment are also discussed.

Stress is the main cause of mood disorders such as depression and posttraumatic stress disorder. Individuals respond to stress differently, as some develop depressive symptoms, whereas others successfully cope with adversity, but it remains unclear what makes some particularly vulnerable to stress. The chronic social defeat stress (CSDS) mouse model, an ethologically valid rodent model that exhibits long-term physiological and behavioral phenotypes similar to depression and anxiety, can imitate individual differences in stress responses in humans. In this review, we not only summarize various behavioral deficits of the CSDS mouse model that were reported since its establishment but also concentrate on modified CSDS mouse models that have been developed in recent years, aiming at providing useful information for future research and application of this model. (PsycInfo Database Record (c) 2020 APA, all rights reserved).

Background: It has been reported that N-cadherin and cAMP response element binding protein (CREB) in the spinal cord are critical for synaptogenesis and regulation of excitatory synapse function, which could underlie chronic pain development. The aim of the present study was to investigate the role of spinal N-cadherin/CREB signaling in postsurgical pain chronicity following chronic alcohol consumption. Methods: C57BL/6 male mice were randomly assigned into different groups. Plantar incision was used to induce postsurgical pain. Chronic alcohol consumption was conducted by giving mice unlimited access to different concentrations of ethanol for five weeks. We measured paw withdrawal thresholds to test postsurgical pain. Using Western blotting, we examined the expression of N-Cadherin and CREB in the spinal dorsal horn. We further performed intrathecal injection of specific N-cadherin and CREB inhibitors to assess the role of spinal N-cadherin/CREB signaling in chronic alcohol consumption-enhanced postsurgical pain. Results: We observed that the chronic alcohol consumption significantly prolonged postsurgical pain and enhanced plantar incision-increased N-cadherin expression and CREB phosphorylation at the Ser133 in the spinal cord. Intrathecal injection of specific N-cadherin and CREB inhibitors attenuated chronic alcohol consumption-prolonged postsurgical pain. Conclusion: Our results suggest that spinal N-cadherin/CREB signaling is involved in chronic alcohol consumption-caused postsurgical pain chronicity.

To investigate the effect of metformin on the proliferation, apoptosis and energy metabolism of acute myeloid leukemia (AML) K562 cells and the possible mechanism. Different doses (0, 5, 10, 20 and 30 mmol/L) of metformin was added into the K562 cells, which were cultivated for 24 h, 48 h and 72 h. The inverted optical microscope was used to observe the cell growth, CCK 8 was used to detect the cell vitality. The appropriate metformin doses (0, 10, 20 and 30 mmol/L) and the best time (48 h) were selected for subsequent experiments. The flow cytometer with Annexin V-FITC /PI doulde staining was used to detect apoptosis; the glucose detection kit and lactate detection kit were used to detect glucose consumption and lactate production; fluorescence quantitative PCR was used to detect glycolysis-related gene expression, and Western blot was used to detect protein expression. Metformin inhibited the proliferation of K562 cells in a dose-dependent manner (r=0.92), and the relative survival in the 30 mmol/L group was as low as 19.84% at 72 h. When treated with metformin for 48 h, the apoptosis rates of 0, 10, 20 and 30 mmol/L groups were 5.14%, 12.19%, 26.29% and 35.5%, respectively. Compared with the control group, the glucose consumption and lactate secretion of K562 cells treated with metformin were significantly reduced (P<0.05), and showed a dose-dependent effect(r=0.94,r=0.93,respectively). Metformin inhibited the expression of GLUT1, LDHA, ALDOA, PDK1, and PGK1 genes of K562 cells (P<0.05) showing a dose-dependent manner(r=0.83，r=0.80，r=0.72，r=0.76，r=0.73,respectively). Metformin inhibited the expression of P-Akt, P-S6, GLUT1, LDHA proteins of K562 cells(P<0.05), showing a dose-dependent relationship(r=0.80，r=0.92，r=0.83，r=0.92,respectively). Metformin can inhibit the growth and proliferation of K562 cells and promote the apoptosis of K562 cells by inhibiting glycolysis energy metabolism. PI3K/Akt/mTOR signaling pathway may be one of the molecular mechanisms of metformin on k562 cells.