BACKGROUND:Transcranial magneto-acoustic-electrical stimulation is a novel non-invasive neural regulation technique that utilizes the induced electric field generated by the coupling effect of ultrasound and static magnetic field to regulate the discharge activity of the nervous system.However,the mechanism by which it affects synaptic plasticity in the brain is still not enough. OBJECTIVE:To explore the effect of transcranial magneto-acoustic-electrical stimulation intensity on synaptic plasticity of the prefrontal cortex neural network in mice. METHODS:(1)Animal experiment:Twenty-four C57 mice were equally and randomly divided into four groups:the control group receiving pseudo-stimulation,the 6.35 W/cm2 stimulation group receiving coupled stimulation of 0.3 T,6.35 W/cm2,the 17.36 W/cm2 stimulation group receiving coupled stimulation of 0.3 T,17.36 W/cm2,and the 56.25 W/cm2 stimulation group receiving coupled stimulation of 0.3 T,56.25 W/cm2.The local field potential signals and behavioral correctness were recorded during the execution of T-maze in mice.(2)Modeling and simulation experiments:A neural network model of the prefrontal cortex in mice stimulated by transcranial magneto-acoustic-electrical stimulation was constructed to compare the structural connectivity characteristics of the neural network under different stimulation intensities. RESULTS AND CONCLUSION:Transcranial magneto-acoustic-electrical stimulation could effectively shorten the behavior learning time,improve the working memory ability of mice(P＜0.05),and continue to stimulate the frontal lobe of mice after learning behavior.There was no significant difference in the accuracy of the T-maze behavioral experiment among the experimental groups(P＞0.1).Analysis of local field potential signals in the frontal lobe of mice revealed that transcranial magneto-acoustic-electrical stimulation promoted energy enhancement of β and γ rhythms.As the stimulation intensity increased,there was an asynchronous decrease in β and γ rhythms.Through β-γ phase amplitude coupling,it was found that stimuli could enhance the neural network's ability to adapt to new information and task requirements.Modeling and simulation experiments found that stimulation could enhance the discharge level of the neural network,increase the long-term synaptic weight level,and decrease the short-term synaptic weight level only when the stimulation intensity was high.To conclude,there is a complex nonlinear relationship between different stimulus intensities and the functional structure of neural networks.This neural regulation technique may provide new possibilities for the treatment of related neurological diseases such as synaptic dysfunction and neural network abnormalities.

Objective:To evaluate the prevalence, potential risk factors, and correlation between coronary and peripheral microvascular dysfunction in heart failure with non-reduced ejection fraction (nHFrEF) patients.Methods:This was a prospective registry study. nHFrEF patients admitted to Zhongshan Hospital affiliated with Fudan University from December 2021 to December 2023 were enrolled. According to coronary flow reserve (CFR) or reactive congestion index (RHI), enrolled patients were divided into coronary microvascular endothelial dysfunction (CMD) group (CFR<2.5) and no CMD group (CFR≥2.5) or peripheral microvascular endothelial dysfunction (MED) group (RHI<1.67) and no MED group (RHI≥1.67). Patients′ general information, laboratory and auxiliary examination data were collected. Univariate and multivariate logistic regression were used to analyze the influencing factors of CMD and MED in nHFrEF patients, and Spearman correlation analysis was used to evaluate the correlation between MED and CMD.Results:A total of 142 nHFrEF patients were enrolled, aged 69.0 (59.0, 74.0) years, with a male proportion of 66.9% (95/142). The grouping results were as follows: (1) According to CFR, there were 73 cases in the CMD group and 69 cases in the no CMD group; (2) According to RHI, there were 57 cases in the MED group and 85 cases in the no MED group. The prevalence of CMD and MED in this study was 51.4% (73/142) and 40.1% (57/142), respectively. Univariate logistic regression analysis showed that increased heart rate, chronic kidney disease, atrial fibrillation, elevated N-terminal pro-B type natriuretic peptide levels, and increased urinary albumin/creatinine ratio were risk factors for CMD, while increased RHI was a protective factor for CMD; Atrial fibrillation is a risk factor for MED, while increased CFR is a protective factor for MED. Incorporating clinically significant variables from univariate analysis into multivariate analysis, the results showed that increased heart rate and elevated RHI remained risk and protective factors for CMD, respectively; increased CFR remains a protective factor for MED. Spearman correlation analysis showed that CFR was negatively correlated with lg urinary albumin/creatinine ratio, lg cardiac troponin T, lg N-terminal pro-B type natriuretic peptide, and heart rate; RHI is positively correlated with CFR.Conclusions:The prevalence of CMD and MED in nHFrEF patients is high, and the two have a certain positive correlation. Increased heart rate and RHI are risk and protective factors for CMD, respectively, while increased CFR is a protective factor for MED. MED may be a potential therapeutic target for nHFrEF patients.

Objective To investigate the role and mechanism of inflammatory marker C5a in regulating the polarization of M2 macro-phages as well as its clinical application value in the prognosis evaluation of lung cancer.Methods The phorbol 12-myristate 13-ace-tate(PMA)-pulsed human monocytic leukemia cell line THP-1 was stimulated with C5a for 0,6,12,24,and 48 h or 0,1,2,3,6,and 12 h,and then the expression levels of M2 markers CD163 and CD206 mRNA were determined by real-time fluorescence quantita-tive PCR(qRT-PCR).The expression level of general control non-repressed protein 5(GCN5)with histone acetyltransferase(HAT)activity was detected by Western blot.Co-immunoprecipitation(co-IP)was used to determine the acetylation of GATA binding protein 3(GATA3),a key transcription factor for macrophages,and its binding ability to GCN5 and E1A binding protein p300(Ep300/p300).After the macrophages pre-treated with GCN5 inhibitor butyrolactone 3(MB-3)were stimulated with C5a,the expression levels of CD163 and CD206,acetylation of GATA3,and its binding ability to GCN5 were determined by Western blot and co-IP.The clinical significance of the expression of C5a receptor 1(C5aR1)and GCN5 in lung cancer tissues in the prognosis of lung cancer patients was analyzed using the KM plotter database.Results C5a could significantly increase the expression levels of CD163 and CD206 mRNA,expression of GCN5,acetylation of GATA3,and its binding ability to GCN5 in PMA-induced adherent macrophages,but did not affect the binding of GATA3 to p300.Inhibiting the activity of GCN5 not only significantly reduced the acetylation of GATA3 and its binding ability to GCN5,but also down-regulated the expressions of CD163 and CD206.The overall survival rate of lung cancer patients with high expression of C5aR1 or GCN5 was significantly reduced.Conclusion C5a promotes the polarization of M2 macrophages by indu-cing GCN5 to acetylate GATA3.The expressions of C5aR1 and GCN5 in lung cancer tissues may have certain clinical application value for the prognosis of the patients.

Objective To introduce a modified technique of right ventricular outflow tract (RVOT) reconstruction using a handmade bicuspid pulmonary valve crafted from expanded polytetrafluoroethylene (ePTFE) and to summarize the early single-center experience. Methods Patients with complex congenital heart diseases (CHD) who underwent RVOT reconstruction with a handmade ePTFE bicuspid pulmonary valve due to pulmonary regurgitation at Guangdong Provincial People’s Hospital from April 2021 to February 2022 were selected. Postoperative artificial valve function and right heart function indicators were evaluated. Results A total of 17 patients were included, comprising 10 males and 7 females, with a mean age of (18.18±12.14) years and a mean body weight of (40.94±19.45) kg. Sixteen patients underwent reconstruction with a handmade valved conduit, with conduit sizes ranging from 18 to 24 mm. No patients required mechanical circulatory support, and no in-hospital deaths occurred. During a mean follow-up period of 12.89 months, only one patient developed valve dysfunction, and no related complications or adverse events were observed. The degree of pulmonary regurgitation was significantly improved post-RVOT reconstruction and during follow-up compared to preoperative levels (P<0.001). Postoperative right atrial diameter, right ventricular diameter, and tricuspid regurgitation area were all significantly reduced compared to preoperative values (P<0.05). Conclusion The use of a 0.1 mm ePTFE handmade bicuspid pulmonary valve for RVOT reconstruction in complex CHD is a feasible, effective, and safe technique.

BACKGROUND: Based on the China-VHD database, this study sought to develop and validate a Valvular Heart Disease- specific Age-adjusted Comorbidity Index (VHD-ACI) for predicting mortality risk in patients with VHD. METHODS & RESULTS: The China-VHD study was a nationwide, multi-centre multi-centre cohort study enrolling 13,917 patients with moderate or severe VHD across 46 medical centres in China between April-June 2018. After excluding cases with missing key variables, 11,459 patients were retained for final analysis. The primary endpoint was 2-year all-cause mortality, with 941 deaths (10.0%) observed during follow-up. The VHD-ACI was derived after identifying 13 independent mortality predictors: cardiomyopathy, myocardial infarction, chronic obstructive pulmonary disease, pulmonary artery hypertension, low body weight, anaemia, hypoalbuminaemia, renal insufficiency, moderate/severe hepatic dysfunction, heart failure, cancer, NYHA functional class and age. The index exhibited good discrimination (AUC, 0.79) and calibration (Brier score, 0.062) in the total cohort, outperforming both EuroSCORE II and ACCI (P < 0.001 for comparison). Internal validation through 100 bootstrap iterations yielded a C statistic of 0.694 (95% CI: 0.665-0.723) for 2-year mortality prediction. VHD-ACI scores, as a continuous variable (VHD-ACI score: adjusted HR (95% CI): 1.263 (1.245-1.282), P < 0.001) or categorized using thresholds determined by the Yoden index (VHD-ACI ≥ 9 vs. < 9, adjusted HR (95% CI): 6.216 (5.378-7.184), P < 0.001), were independently associated with mortality. The prognostic performance remained consistent across all VHD subtypes (aortic stenosis, aortic regurgitation, mitral stenosis, mitral regurgitation, tricuspid valve disease, mixed aortic/mitral valve disease and multiple VHD), and clinical subgroups stratified by therapeutic strategy, LVEF status (preserved vs. reduced), disease severity and etiology. CONCLUSION The VHD-ACI is a simple 13-comorbidity algorithm for the prediction of mortality in VHD patients and providing a simple and rapid tool for risk stratification.

[This corrects the article DOI: 10.1016/j.apsb.2022.05.019.].

Patients suffering from nerve injury often experience exacerbated pain responses and complain of memory deficits. The dorsal hippocampus (dHPC), a well-defined region responsible for learning and memory, displays maladaptive plasticity upon injury, which is assumed to underlie pain hypersensitivity and cognitive deficits. However, much attention has thus far been paid to intracellular mechanisms of plasticity rather than extracellular alterations that might trigger and facilitate intracellular changes. Emerging evidence has shown that nerve injury alters the microarchitecture of the extracellular matrix (ECM) and decreases ECM rigidity in the dHPC. Despite this, it remains elusive which element of the ECM in the dHPC is affected and how it contributes to neuropathic pain and comorbid cognitive deficits. Laminin, a key element of the ECM, consists of α-, β-, and γ-chains and has been implicated in several pathophysiological processes. Here, we showed that peripheral nerve injury downregulates laminin β1 (LAMB1) in the dHPC. Silencing of hippocampal LAMB1 exacerbates pain sensitivity and induces cognitive dysfunction. Further mechanistic analysis revealed that loss of hippocampal LAMB1 causes dysregulated Src/NR2A signaling cascades via interaction with integrin β1, leading to decreased Ca²⁺ levels in pyramidal neurons, which in turn orchestrates structural and functional plasticity and eventually results in exaggerated pain responses and cognitive deficits. In this study, we shed new light on the functional capability of hippocampal ECM LAMB1 in the modulation of neuropathic pain and comorbid cognitive deficits, and reveal a mechanism that conveys extracellular alterations to intracellular plasticity. Moreover, we identified hippocampal LAMB1/integrin β1 signaling as a potential therapeutic target for the treatment of neuropathic pain and related memory loss.
Animals ; Laminin/genetics* ; Hippocampus/metabolism* ; Neuralgia/metabolism* ; Cognitive Dysfunction/etiology* ; Male ; Peripheral Nerve Injuries/metabolism* ; Extracellular Matrix/metabolism* ; Integrin beta1/metabolism* ; Pyramidal Cells/metabolism* ; Signal Transduction

The prelimbic cortex (PL) plays a critical role in processing both the sensory and affective components of pain. However, the underlying molecular mechanisms remain poorly understood. In this study, we observed a reduction in hyperpolarization-activated cation current (I_h) in layer V pyramidal neurons of the contralateral PL in a mouse model of spared nerve injury (SNI). The expression of hyperpolarization-activated cyclic nucleotide-gated 2 (HCN2) channels was also decreased in the contralateral PL. Conversely, microinjection of fisetin, a partial agonist of HCN2, produced both analgesic and anxiolytic effects. Additionally, we found that cyclin-dependent kinase 5 (CDK5) was activated in the contralateral PL, where it formed a complex with HCN2 and phosphorylated its C-terminus. Knockdown of CDK5 restored HCN2 expression and alleviated both pain hypersensitivity and anxiety-like behaviors. Collectively, these results indicate that CDK5-mediated dysfunction of HCN2 in the PL underlies nerve injury-induced mechanical hypersensitivity and anxiety.
Animals ; Hyperpolarization-Activated Cyclic Nucleotide-Gated Channels/metabolism* ; Hyperalgesia/metabolism* ; Cyclin-Dependent Kinase 5/metabolism* ; Neuralgia/metabolism* ; Male ; Anxiety/metabolism* ; Mice ; Potassium Channels/metabolism* ; Mice, Inbred C57BL ; Disease Models, Animal ; Pyramidal Cells/metabolism*

OBJECTIVE: To investigate the therapeutic effects of Banxia Xiexin Decoction (BXD), a herbal medicine formula, on inflammation and the imbalance of the gut microbiota in a rat model of colorectal cancer (CRC) induced by azoxymethane (AOM) /dextran sulfate sodium (DSS). METHODS: A total of 75 male C57BL/6 mice were randomly divided into five groups: normal control group (NC), model group (MODEL), low-dose BXD treatment group (L-BXD), high-dose BXD treatment (H-BXD) group and MS treatment group (MS). BXD and MS were used in CRC mice at the doses of 3.915 g/kg, 15.66 g/kg, 0.6 g/kg for 3 weeks consecutively. Histopathological changes in the colon were observed using hematoxylin-eosin (HE) staining. The content of inflammatory factors in serum was detected by an enzyme-linked immunosorbent assay (ELISA), and the expression of mRNA and protein of genes related to immunity, apoptosis, inflammation, and inflammatory factors was evaluated. Changes in the intestinal flora of mouse fecal were determined based on high-throughput sequencing of the 16S rRNA microbial gene. RESULTS: Compared to the model group, the low-dose BXD and high-dose BXD groups decreased the number of colon tumors, reversed weight loss, and shortened colon length of mice. The pathological examination showed that BXD alleviated the malignancy of intestinal tumors. It also suppressed signal transducer and activator of transcription 3 (STAT3), matrix metalloproteinase-9 (MMP-9), and transforming growth factor beta 1 (TGF-β1) expression, while increasing the expression of the tight junction protein ZO-1 in colon tissues. Additionally, the levels of key pathway proteins involved in inflammation (phosphorylated-STAT3, Bcl-2, COX-2) and cell cycle regulatory molecules (c-Myc and PCNA) were reduced. According to 16S rRNA sequence analysis, BXD enhanced the relative abundance of potentially beneficial bacteria, while that of cancer-related bacteria decreased. CONCLUSION BXD plays a preventive role in developing colorectal cancer; its mechanisms are related to the inhibition of inflammation and tumor proliferation, as well as maintenance of intestinal homeostasis.

Objective To analyze the distribution of traditional Chinese medicine(TCM)syndromes in maintenance hemodialysis(MHD)patients and to evaluate the clinical efficacy of Jianpi Yishen Paidu Therapy(mainly with the actions of strengthening spleen,tonifying kidney,and removing toxins)across different syndrome types.Methods A total of 173 patients with stage 5 chronic kidney disease(CKD)undergoing MHD at Guangzhou Hospital of Integrated Traditional and Western Medicine between October 2019 and October 2024 were enrolled.Statistical analysis was performed on TCM syndrome distribution.Patients were categorized into three groups based on whether they received Jianpi Yishen Paidu Therapy for 2 weeks and their syndrome differentiation:spleen-kidney qi deficiency syndrome group(n=25),spleen-kidney yang deficiency syndrome group(n=39),and control group(n=109).Baseline data and laboratory parameters were collected to assess therapeutic efficacy of Jianpi Yishen Paidu Therapy.Results(1)Among deficiency patterns,spleen-kidney qi deficiency and spleen-kidney yang deficiency syndromes predominated;among excess syndromes,dampness-turbidity and blood stasis syndromes were most common.(2)Adjunctive Jianpi Yishen Paidu therapy enhanced treatment efficacy by decreasing serum creatinine(Scr),blood urea nitrogen(BUN),and cystatin C(Cys-C)levels while increasing hemoglobin(Hb)and serum albumin(ALB)(P＜0.05).Regarding calcium-phosphorus metabolism,the spleen-kidney qi deficiency group showed reduced serum phosphorus(P+)(P＜0.05),while both treatment groups(spleen-kidney qi/yang deficiency)exhibited elevated serum calcium(Ca2+)(P＜0.05)but with no intergroup difference in parathyroid hormone(PTH)(P＞0.05).No significant differences were observed in lipid profiles[total cholesterol(TC),triglycerides(TG),low-density lipoprotein cholesterol(LDL-C),high-density lipoprotein cholesterol(HDL-C)]among the three groups(P＞0.05).Dialysis vintage was significantly shortened in both treatment groups versus controls(P＜0.05).Conclusion MHD patients primarily exhibit spleen-kidney qi/yang deficiency syndromes(deficiency in the origin syndrome)and dampness-turbidity/blood stasis syndromes(excess in the superficiality syndrome).Syndrome differentiation-based intervention with Jianpi Yishen Paidu Therapy effectively delays renal function decline,improves calcium-phosphorus metabolism,and elevates Hb and ALB levels in MHD patients.