ß-Cyclodextrin and Hyaluronic Acid-Modified Targeted Nanodelivery System for Atherosclerosis Prevention.

Natural products have been widely recognized in clinical treatment because of their low toxicity and high activity. It is worth paying attention to modifying the biopolymer into nanostructures to give natural active ingredients additional targeting effects. In this study, based on the multifunctional modification of ß-cyclodextrin (ß-CD), a nanoplatform encapsulating the unstable drug (-)-epicatechin gallate (ECG) was designed to deliver to atherosclerotic plaques. Acetalization cyclodextrin (PH-CD), which responds to low-pH environments, and hyaluronic acid cyclodextrin, which targets the CD44 receptor on macrophage membranes, were synthesized from ß-CD and hyaluronic acid using acetalization and transesterification, respectively. The resulting dual-carrier nanoparticles (Double-NPs) loaded with ECG were prepared using a solvent evaporation method. The Double-NPs effectively scavenged reactive oxygen species, promoted macrophage migration, inhibited macrophage apoptosis, and suppressed abnormal proliferation and migration of vascular smooth muscle cells. Furthermore, the Double-NPs actively accumulated in atherosclerotic plaques in ApoE-/- mice fed with a high-fat diet, leading to a reduced plaque area, inflammatory infiltration, and plaque instability. Our findings demonstrate that the newly developed ECG nanopreparation represents an effective and safe nanotherapy for diseases such as atherosclerosis.

(-)-Epicatechin gallate prevented atherosclerosis by reducing abnormal proliferation of VSMCs and oxidative stress of AML 12 cells.

(-)-Epicatechin gallate (ECG) is beneficial to the treatment of cardiovascular diseases (CVDs), especially atherosclerosis (AS) through antioxidant stress, but there is a lack of detailed mechanism research. In this study, the therapeutic target of ECG was determined by crossing the drug target and disease target of CVDs and AS. The combination ability of ECG with important targets was verified by Discovery Studio software. The abnormal proliferation of vascular smooth muscle cells (VSMCs) induced by Ang-II and the oxidative damage of AML 12 induced by H2O2 were established to verify the reliability of ECG intervention on the target protein. A total of 120 ECG targets for the treatment of CVDs-AS were predicted by network pharmacology. The results of molecular docking showed that ECG has strong binding force with VEGFA, MMP-9, CASP3 and MMP-2 domains. In vitro experiments confirmed that ECG significantly reduced the expression of VEGFA, MMP-9, CASP3 and MMP-2 in Ang-II-induced VSMCs, and also blocked the abnormal proliferation, oxidative stress and inflammatory reaction of VSMCs by inhibiting the phosphorylation of PI3K signaling pathway. At the same time, ECG also interfered with H2O2-induced oxidative damage of AML 12 cells, decreased the expression of ROS and MDA and cell foaming, and increased the activities of antioxidant enzymes such as SOD, thus playing a protective role.

Secure output consensus for multi-agent systems under edge-based event-trigger against denial-of-service.

This paper is concerned with the secure output consensus problem for the heterogeneous multi-agent systems under the event-triggered scheme in the presence of the denial-of-service attack. Without detecting the attack, the hold-input controller update strategy is adopted when some transmission data may be lost due to the effect of the attack. Based on the tolerable duration of the attack, a novel edge-based event-triggered scheme is developed. The scheme can avoid continuous communication and exclude Zeno behavior. With the aid of the switched system theory, output consensus is preserved. An example shows the effectiveness.

Mobilizing endogenous neuroprotection: the mechanism of the protective effect of acupuncture on the brain after stroke.

Given its high morbidity, disability, and mortality rates, ischemic stroke (IS) is a severe disease posing a substantial public health threat. Although early thrombolytic therapy is effective in IS treatment, the limited time frame for its administration presents a formidable challenge. Upon occurrence, IS triggers an ischemic cascade response, inducing the brain to generate endogenous protective mechanisms against excitotoxicity and inflammation, among other pathological processes. Stroke patients often experience limited recovery stages. As a result, activating their innate self-protective capacity [endogenous brain protection (EBP)] is essential for neurological function recovery. Acupuncture has exhibited clinical efficacy in cerebral ischemic stroke (CIS) treatment by promoting the human body's self-preservation and "Zheng Qi" (a term in traditional Chinese medicine (TCM) describing positive capabilities such as self-immunity, self-recovery, and disease prevention). According to research, acupuncture can modulate astrocyte activity, decrease oxidative stress (OS), and protect neurons by inhibiting excitotoxicity, inflammation, and apoptosis via activating endogenous protective mechanisms within the brain. Furthermore, acupuncture was found to modulate microglia transformation, thereby reducing inflammation and autoimmune responses, as well as promoting blood flow restoration by regulating the vasculature or the blood-brain barrier (BBB). However, the precise mechanism underlying these processes remains unclear. Consequently, this review aims to shed light on the potential acupuncture-induced endogenous neuroprotective mechanisms by critically examining experimental evidence on the preventive and therapeutic effects exerted by acupuncture on CIS. This review offers a theoretical foundation for acupuncture-based stroke treatment.

Anti-inflammatory effect of proanthocyanidins from blueberry through NF-κß/NLRP3 signaling pathway in vivo and in vitro.

BACKGROUND: Systemic inflammatory response syndrome (SIRS) is an uncontrolled systemic inflammatory response. Proanthocyanidins (PC) is a general term of polyphenol compounds widely existed in blueberry fruits and can treat inflammation-related diseases. This study aimed to explore the regulatory effect of PC on lipopolysaccharide (LPS)-induced systemic inflammation and its potential mechanism, providing effective strategies for the further development of PC. METHODS: Here, RAW264.7 macrophages were stimulated with LPS to establish an inflammation model in vitro, while endotoxin shock mouse models were constructed by LPS in vivo. The function of PC was investigated by MTT, ELISA kits, H&E staining, immunohistochemistry, and Western blot analysis. RESULTS: Functionally, PC could demonstrate the potential to mitigate mortality in mice with endotoxin shock, as well as attenuated the levels of inflammatory cytokines (IL-6, TNF-α) and biochemical indicators (AST, ALT, CRE and BUN). Moreover, it had a significant protective effect on lung and kidney tissues damage. Mechanistically, PC exerted anti-inflammatory effects by inhibiting the activation of the NF-κB/NLRP3 signaling pathway. CONCLUSION: PC might have the potential ability of anti-inflammatory effects via modulation of the NF-κB/NLRP3 signaling pathway.

TRPA1 Ion Channel Mediates the Analgesic Effects of Acupuncture at the ST36 Acupoint in Mice Suffering from Arthritis.

Purpose: Acupuncture (ACU) has been demonstrated to alleviate inflammatory pain. Mechanoreceptors are present in acupuncture points. When acupuncture exerts mechanical force, these ion channels open and convert the mechanical signals into biochemical signals. TRPA1 (T ransient receptor potential ankyrin 1) is capable of sensing various physical and chemical stimuli and serves as a sensor for inflammation and pain. This protein is expressed in immune cells and contributes to local defense mechanisms during early tissue damage and inflammation. In this study, we investigated the role of TRPA1 in acupuncture analgesia. Patients and Methods: We injected complete Freund's adjuvant (CFA) into the mouse plantars to establish a hyperalgesia model. Immunohistochemistry and immunofluorescence analyses were performed to determine the effect of acupuncture on the TRPA1 expression in the Zusanli (ST36). We used TRPA1-/- mouse and pharmacological methods to antagonize TRPA1 to observe the effect on acupuncture analgesia. On this basis, collagenase was used to destroy collagen fibers at ST36 to observe the effect on TRPA1. Results: We found that the ACU group vs the CFA group, the number of TRPA1-positive mast cells, macrophages, and fibroblasts at the ST36 increased significantly. In CFA- inflammatory pain models, the TRPA1-/- ACU vs TRPA1+/+ ACU groups, the paw withdrawal latency (PWL) and paw withdrawal threshold (PWT) downregulated significantly. In the ACU + high-, ACU + medium-, ACU + low-dose HC-030031 vs ACU groups, the PWL and PWT were downregulated, and in carrageenan-induced inflammatory pain models were consistent with these results. We further found the ACU + collagenase vs ACU groups, the numbers of TRPA1-positive mast cells, macrophages, and fibroblasts at the ST36 were downregulated. Conclusion: These findings together imply that TRPA1 plays a significant role in the analgesic effects produced via acupuncture at the ST36. This provides new evidence for acupuncture treatment of painful diseases.

Predictors of In-Stent Stenosis Following the Implantation of Pipeline Embolization Devices for the Treatment of Aneurysms Located at or beyond the Circle of Willis in the Anterior Circulation.

BACKGROUND AND PURPOSE: In-stent stenosis is commonly observed after stent implantation. There is no consensus on the contributing factors for in-stent stenosis, especially for aneurysms located at or beyond the circle of Willis in the anterior circulation. This study aimed to investigate the morbidity and determinants of in-stent stenosis in distal anterior circulation aneurysms following the implantation of Pipeline Embolization Devices. MATERIALS AND METHODS: Patients who underwent Pipeline Embolization Device treatment at our center between January 1, 2018, and June 15, 2023, were enrolled. Distal anterior circulation aneurysms were defined as those occurring at or beyond the circle of Willis, including anterior communicating artery aneurysms, anterior cerebral artery aneurysms, and MCA aneurysms. Baseline information, aneurysm characteristics, and follow-up data of patients were analyzed. Patients were divided into 2 groups: the in-stent stenosis group (patients with a loss of >25% of the lumen diameter of the parent artery) and the non-in-stent stenosis group. Binary logistic regression and restricted cubic spline curves were used to explore risk factors. RESULTS: We included 85 cases of 1213 patients treated with flow-diverter devices at our hospital. During an average follow-up period of 9.07 months, the complete occlusion rate was 77.64%. The overall incidence of in-stent stenosis was 36.47% (31/85), of which moderate stenosis accounted for 9.41% (8/85), and severe stenosis, 5.88% (5/85) (triglyceride-glucose index ≥ 8.95; OR = 6.883, P = .006). The difference in diameters between the stent and parent artery of ≥0.09 mm (OR = 6.534, P = .015) and 55 years of age or older (OR = 3.507, P = .036) were risk factors for in-stent stenosis. The restricted cubic spline curves indicated that the risk of in-stent stenosis increased as the difference in diameter between stent and parent artery and the triglyceride-glucose index increased. CONCLUSIONS: Compared with the on-label use of Pipeline Embolization Devices, the rate of in-stent stenosis did not obviously increase when treating distal anterior circulation aneurysms with these devices. The incidence of in-stent stenosis was 36.47% when defined as a lumen diameter loss of >25%, and 15.2% when defined as a lumen diameter loss of >50%. Stent-size selection and biochemical indicators can potentially impact the incidence of in-stent stenosis.

Harmine ameliorates CCl4-induced acute liver injury through suppression of autophagy and inflammation.

CCl4-induced acute liver injury (ALI) is characterized by heightened autophagy, inflammation, and oxidative damage. Accumulating evidence suggests that harmine exerts beneficial effects in countering CCl4-induced ALI by mitigating inflammation and oxidative stress. However, the impact of autophagy on CCl4-induced ALI and the protective role of harmine remain unclear. This study aimed to investigate the potential protective effects of harmine against CCl4-induced ALI in mice by suppressing autophagy and inflammation. Male Kunming mice were orally administered harmine or bifendate for seven days. Subsequently, one hour after the final administration, the model group and treatment groups were intraperitoneally injected with CCl4 to induce ALI. The findings revealed that harmine significantly reduced the levels of aspartate aminotransferase (AST) and alanine aminotransferase (ALT) in serum, and ameliorated the liver histopathological changes induced by CCl4. Furthermore, harmine diminished the levels of TNF-α and IL-6, restored the levels of glutathione (GSH) and superoxide dismutase (SOD), and suppressed the production of nitric oxide (NO) and malondialdehyde (MDA) in the liver. Mechanistically, harmine down-regulated LC3B II/I, p38 MAPK, TLR4, and NF-κB levels, while upregulating p62, Bcl-2, Beclin1, ULK1, and p-mTOR expression. In conclusion, harmine mitigated CCl4-induced ALI by inhibiting autophagy and inflammation through the p38 MAPK/mTOR autophagy pathway, the Bcl-2/Beclin1 pathway, and the TLR4/NF-κB pathway.

Bletilla striata polysaccharide attenuated the progression of pulmonary fibrosis by inhibiting TGF-ß1/Smad signaling pathway.

ETHNOPHARMACOLOGICAL RELEVANCE: Bletilla striata, a traditional medicinal plant, has been utilized as a folk medicine for many years because of its superior biological activity in China. However, Bletilla striata polysaccharide (BSP) has received less attention, and its specific mechanism for ameliorating pulmonary fibrosis is completely unclear. AIMS OF THE STUDY: In this study, we aim to assess BSP on the treatment of PF and explore potential mechanisms. MATERIALS AND METHODS: BSP was successfully extracted and purified from Bletilla striata. The mechanisms were assessed in bleomycin-induced pulmonary fibrosis model and lung fibroblasts activated by transforming growth factor-ß1 (TGF-ß1). Histological analysis, immunofluorescence, Western blot and flow cytometry were used to explore the alterations after BSP intervention. RESULTS: The results in vivo showed an anti-PF effect of BSP treatment, which reduced pathogenic damages. Furthermore, TGF-ß1-induced abnormal migration and upregulated expression of collagen I (COL1A1), vimentin and α-smooth muscle actin (α-SMA) were suppressed by BSP in L929 cells. Moreover, the abnormal proliferation was retarded by inhibiting the cell cycle of G1 to S phase. Immunofluorescence assay showed that BSP activated autophagy and played an antifibrotic role by inhibiting the expression of p62 and phospho-mammalian target of rapamycin (p-mTOR). Last but not least, the suppression of TGF-ß1/Smad signaling pathway was critical for BSP to perform therapeutic effects in vitro and in vivo. CONCLUSION: The possible mechanisms were involved in improving ECM deposition, regulating cell migration and proliferation, and promoting cellular autophagy. Briefly, all of the above revealed that BSP might be a novel therapy for treating pulmonary fibrosis.

Tectoridin alleviates caerulein-induced severe acute pancreatitis by targeting ERK2 to promote macrophage M2 polarization.

Severe acute pancreatitis (SAP) is an inflammatory disease of the pancreas with a high mortality rate. Macrophages play a crucial role in the pathogenesis of pancreatitis. Tectoridin (Tec) is a highly active isoflavone with anti-inflammatory pharmacological activity. However, the role of Tec in the SAP process is not known. The purpose of this study was to investigate the therapeutic effect and potential mechanism of Tec on SAP. To establish SAP mice by intraperitoneal injection of caerulein and Lipopolysaccharide (LPS), the role of Tec in the course of SAP was investigated based on histopathology, biochemical indicators of amylase and lipase and inflammatory factors. The relationship between Tec and macrophage polarization was verified by immunofluorescence, real-time quantitative PCR and Western blot analysis. We then further predicted the possible targets and signal pathways of action of Tec by network pharmacology and molecular docking, and validated them by in vivo and in vitro. In this study, we demonstrated that Tec significantly reduced pancreatic injury in SAP mice, and decreased serum levels of amylase and lipase. The immunofluorescence and Western blot analysis showed that Tec promoted macrophage M2 polarization. Network pharmacology and molecular docking predicted that Tec may target ERK2 for the treatment of SAP, and in vivo and in vitro experiments proved that Tec inhibited the ERK MAPK signal pathway. In summary, Tec can target ERK2, promote macrophage M2 polarization and attenuate pancreatic injury, Tec may be a potential drug for the treatment of SAP.

Psychological experience of home-quarantined older women with COVID-19 in Hong Kong: A qualitative study.

BACKGROUND: The surge of positive COVID-19 cases taxed the local health care system and left many older adults initiating home self-care practices. The study aimed to explore the psychological experiences of home-quarantined older women diagnosed with COVID-19 in Hong Kong. METHODS: Ten semi-structured telephone interviews were held among older women from March to April 2022. Inductive thematic analysis was used to analyse the data. RESULTS: Older women experienced psychological distress, anxiety and depression after being infected with COVID-19. The source of their psychological difficulties included fear of losing control over one's health and dignity, feeling a burden to one's family, conflict in balancing risks and responsibilities, and being overwhelmed by the tragic news reported in media. Meanwhile, the participants demonstrated resilience following the infection and found meaning in their experiences, and grew mentally. CONCLUSIONS: The older women in this study have identified the negative impact having a diagnosis and being home-quarantine means to them and their family. Yet, they were also able to take some positives from this. Importantly, the older women report being able to build greater resilience, optimism and wisdom towards COVID-19 in general and feel better prepared for the potential of future positive diagnoses.

Family caregivers' lived experience of caring for hospitalised patients with cancer during the COVID-19 lockdown: A descriptive phenomenological study.

AIMS: This study aimed to capture and explore family caregivers' lived experience of caring for hospitalised patients with cancer during the lockdown. BACKGROUND: The unprecedented lockdown episodes due to COVID-19 have brought significant changes in the hospital visiting policies and caregiving practices. As part of the precautionary measures for hospital visits, the bedside companion was restricted to one caregiver for patients with cancer in Shanghai hospitals. DESIGN: This study adopted a descriptive phenomenological approach. METHODS: Data were collected among 20 family caregivers recruited from the Oncology department of a tertiary hospital in Shanghai in May 2022, using purposive sampling method and followed by unstructured, open-ended interviews. Colaizzi's seven-step data analysis method was used to analyse the data to reveal the emergent themes and subthemes of the phenomenon. RESULTS: Four themes were generated on family caregivers' lived experience of caring for hospitalised patients with cancer during the lockdown, including (1) Feeling scared for the patient; (2) Living a life feeling trapped under COVID-19 surveillance; (3) Feeling neglected and unseen; (4) Growing resilience and appreciation. CONCLUSIONS: The lockdown exacerbated the burden of family caregivers when they cared for the hospitalised patients with cancer during the lockdown period. However, positive reframing of the lived experience facilitated their coping with the challenging situation. RELEVANCE TO CLINICAL PRACTICE: Findings from this study highlighted the potential proactive roles the healthcare providers could play in improving family caregivers' health and supporting them during and beyond the COVID-19 pandemic. REPORTING METHOD: The study adhered to relevant EQUATOR guidelines; the study was reported according to the COREQ checklist. PATIENT OR PUBLIC CONTRIBUTION: Family caregivers of patients with cancer were involved in data collection and member-checking of the transcripts and interpretations of their experiences.

Inflammation-the role of TRPA1 channel.

Recently, increasing numbers of studies have demonstrated that transient receptor potential ankyrin 1 (TRPA1) can be used as a potential target for the treatment of inflammatory diseases. TRPA1 is expressed in both neuronal and non-neuronal cells and is involved in diverse physiological activities, such as stabilizing of cell membrane potential, maintaining cellular humoral balance, and regulating intercellular signal transduction. TRPA1 is a multi-modal cell membrane receptor that can sense different stimuli, and generate action potential signals after activation via osmotic pressure, temperature, and inflammatory factors. In this study, we introduced the latest research progress on TRPA1 in inflammatory diseases from three different aspects. First, the inflammatory factors released after inflammation interacts with TRPA1 to promote inflammatory response; second, TRPA1 regulates the function of immune cells such as macrophages and T cells, In addition, it has anti-inflammatory and antioxidant effects in some inflammatory diseases. Third, we have summarized the application of antagonists and agonists targeting TRPA1 in the treatment of some inflammatory diseases.

Epigenetic Regulation of Neuroinflammation in Alzheimer's Disease.

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 ß (Aß) 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.

Safety and efficacy analysis of the off-label use of pipeline embolization devices for intracranial aneurysms: a propensity score matching study.

Background and objective: The safety and efficacy of on-label use of pipeline embolization devices (PEDs) are well established; however, there is much controversy over their off-label use. This study aimed to investigate the safety and efficacy of the off-label use of PEDs for treating intracranial aneurysms. Methods: This single-center study retrospectively included patients with digital subtraction angiography, computed tomographic angiography, or magnetic resonance angiography confirmed intracranial aneurysms treated with PEDs who were admitted to our institution between 1 January 2018 and 1 July 2022. Patients were divided into on- and off-label groups according to the Food and Drug Administration criteria published in 2021. Propensity score matching (PSM) was used to balance disparities in baseline information between the two groups. Safety outcomes included postoperative mortality and complication rates, whereas effectiveness outcomes included aneurysm occlusion rate (O'Kelly-Marotta grading system C + D grades), retreatment rate within 12 months, and postoperative functional score [modified Rankin scale (mRS) score]. The study was approved by the Ethics Committee of Scientific Research and Clinical Trial of the First Affiliated Hospital of Zhengzhou University (Ethics number: KY 2018-098-02). All patients provided informed consent. Results: A total of 242 patients with 261 aneurysms (160 on-label and 101 off-label aneurysms) were included in this study. PSM yielded 81 pairs of patients matched for baseline information. Postoperative hemorrhagic, ischemic, and procedure-related complication rates did not reach statistical significance. In addition, no statistically significant differences in the aneurysm occlusion rate, retreatment rate within 12 months, postoperative functional score (mRS score), or mRS score deterioration rate were observed between the two groups. A higher incidence of in-stent stenosis was observed in the off-label (4.9% vs. 21%, p = 0.002) group than in the on-label group; however, all patients were asymptomatic. Conclusion: Compared with on-label use, off-label use of PEDs for treating intracranial aneurysms did not increase the risk of complications, and the occlusion rates were comparable. Therefore, decisions regarding clinical management should not rely solely on on- or off-label indications.

Intrapersonal and interpersonal level factors influencing self-care practices among Hong Kong individuals with COVID-19-A qualitative study.

Background: The unprecedented crisis during the fifth wave of the COVID-19 pandemic in Hong Kong placed a significant burden on the health care system. Therefore, the Hong Kong government advocated that individuals with no or mild COVID-19 symptoms should self-care at home. This study aimed to understand intrapersonal and interpersonal level factors that shaped self-care practices among home-quarantined individuals with COVID-19 during the peak of the pandemic. Methods: This study used convenience and snowball sampling whereby a total of 30 semi-structured telephone interviews were conducted between March and April 2022. Inductive content analysis was used to analyze the data. Results: Factors reported at the intrapersonal level included socioeconomic status and housing conditions, information and knowledge about COVID-19, long COVID, and psychological adjustments brought about by home quarantine. Factors identified at the interpersonal level included caregiving responsibilities, family relationships, and social support. Conclusions: Findings from this study identified a combination of intra and interpersonal level factors influenced an individual's self-care practices as a result of pandemic-induced quarantine. It was particularly concerning for those individuals in socially and economically deprived groups, where access to services was challenging. This study also raised awareness of the ineffectual and insufficient knowledge individuals held of self-medication and overall COVID-19 management. A key recommendation is developing family-based resilience programmes to support and empower vulnerable families to better cope with the realities of self-quarantine.

Neural-Networks-Based Prescribed Tracking for Nonaffine Switched Nonlinear Time-Delay Systems.

In this article, by using the neural-networks (NNs) separation and approximation technique, an adaptive scheme is presented to deliver the prescribed tracking performance for a class of unknown nonaffine switched nonlinear time-delay systems. The nonaffine terms are indifferentiable and the controllability condition is not required for each subsystem, which allows the considered tracking problem to not be efficiently solved by the traditional adaptive control algorithms. To solve the problem, NNs are utilized to separate and approximate the nonaffine functions, and then the dynamic surface control and convex combination method are utilized to construct a controller and a switching strategy. In addition, an adaptive law is considered for each subsystem to reduce the conservativeness. Under the designed controller and switching strategy, all the signals of the resulting closed-loop system are bounded, and the tracking performance is achieved with a prescribed level.

Spinal N-Cadherin/CREB Signaling Contributes to Chronic Alcohol Consumption-Enhanced Postsurgical Pain.

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.

Optogenetic Activation of Dopamine Receptor D1 and D2 Neurons in Anterior Cingulate Cortex Differentially Modulates Trigeminal Neuropathic Pain.

Anterior cingulate cortex (ACC) is a critical brain center for chronic pain processing. Dopamine signaling in the brain has been demonstrated to contribute to descending pain modulation. However, the role of ACC dopamine receptors in chronic neuropathic pain remains unclear. In this study, we investigated the effect of optogenetic activation of ACC dopamine receptors D1- and D2-expressing neurons on trigeminal neuropathic pain. Chronic constriction injury of infraorbital nerve (CCI-ION) was carried out to induce trigeminal neuropathic pain in mice. We conducted optogenetic stimulation to specifically activate D1- and D2-expressing neurons in the ACC. Western blotting and immunofluorescence staining were used to examine ACC D1 and D2 expression and localization. The von Frey and real-time place preference tests were performed to measure evoked mechanical pain and nonreflexive emotional pain behaviors, respectively. We observed that dopamine receptors D1 and D2 in the ACC are primarily expressed in excitatory neurons and that the D2 receptor is differentially regulated in the early and late phases of trigeminal neuropathic pain. Optogenetic activation of D1-expressing neurons in the ACC markedly exacerbates CCI-ION-induced trigeminal neuropathic pain in both early and late phases, but optogenetic activation of D2-expressing neurons in the ACC robustly ameliorates such pain in its late phase. Our results suggest that dopamine receptors D1 and D2 in the ACC play different roles in the modulation of trigeminal neuropathic pain.

Driving GABAergic neurons optogenetically improves learning, reduces amyloid load and enhances autophagy in a mouse model of Alzheimer's disease.

The changes of local field potentials (LFP, mainly gamma rhythm and theta rhythm) in the brain are closely related to learning and memory formation. Reduced gamma rhythm (20-50 Hz) and theta rhythm (4-10 Hz) has been observed in the progression of Alzheimer's disease (AD), but it is not clear whether it is related to cognition in AD. Here, we investigated behaviorally driven gamma rhythm and theta rhythm in APP/PS1 mice, and optogenetically stimulated GABAergic neurons in the brain to better understand the relationship between the changes of LFP, cognition, and cellular pathologies. Optogenetically driving GABAergic neurons rescued memory formation in a water maze task and normalized theta and gamma rhythm in the EEG. Furthermore, the optogenetic stimulation alleviated neuroinflammation and levels of amyloid-ß (Aß)1-42 fragments, and induced autophagy. GABA blockers also reversed the normalization of theta and gamma rhythms in the brain by optogenetic stimulation. The results demonstrate that stimulation of GABAergic interneurons not only rescues LFP rhythms and memory formation, but furthermore activates autophagy and reduces neuroinflammation, which have beneficial additional effects such as clearing amyloid. This is a proof of concept for a novel therapeutic approach to AD treatment.