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We prepare high-filling two-component arrays of tens of fermionic ^{6}Li atoms in optical tweezers, with the atoms in the ground motional state of each tweezer. Using a stroboscopic technique, we configure the arrays in various two-dimensional geometries with negligible Floquet heating. A full spin- and density-resolved readout of individual sites allows us to postselect near-zero entropy initial states for fermionic quantum simulation. We prepare a correlated state in a two-by-two tunnel-coupled Hubbard plaquette, demonstrating all the building blocks for realizing a programmable fermionic quantum simulator.
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Objectives: The systemic immune-inflammation index (SII), a novel and systematic inflammatory biomarker that is associated with chronic kidney disease (CKD), has not received much attention. This study aimed to investigate the relationship between SII and CKD in the United States (U.S.) population. Methods: Our study ultimately included a nationally representative sample of 10,787 adults who participated in the 2007-2018 National Health and Nutrition Examination Survey. Weighted multivariate logistic regression was used to assess the correlation between SII and CKD, and a restricted cubic spline (RCS) model was subsequently used to explore the non-linear relationship between SII and CKD. Subgroup analyses were performed to further the effects of other covariates on the relationship between SII and CKD. Results: Following confounder adjustment, a higher SII was related to the incidence of CKD (OR =1.36; 95% CI, 1.07-1.73; p =0.01), as validated by multivariable logistic regression. The RCS curve revealed a non-linear positive correlation between SII/1000 and CKD incidence (p for non-linear =0.0206). Additionally, subgroup analysis confirmed a stronger correlation for male participants (OR =2.628; 95% CI, 1.829-3.776) than for female participants (OR =1.733; 95% CI, 1.379-2.178) (p for interaction =0.046). Conclusions: SII is positively associated with the incidence of CKD among U.S. adults, especially in males. However, further studies are needed to confirm our findings and explore the causal factors that can contribute to the prevention and treatment of CKD.
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Inflamación , Insuficiencia Renal Crónica , Adulto , Humanos , Femenino , Masculino , Encuestas Nutricionales , Inflamación/epidemiología , Insuficiencia Renal Crónica/epidemiologíaRESUMEN
Background: Periodontitis and benign prostatic hyperplasia (BPH) are all common chronic diseases with higher incidence in middle-aged and old men. Several studies have indicated a potential association between periodontitis and BPH, although the findings remain inconclusive. However, there is no mendelian randomization (MR) studies to assess this association. Methods: The 40 men who had received health check-ups were included in an epidemiological study. Genetic data of BPH (13118 cases and 72799 controls) and periodontitis (3046 cases and 195395 controls) from FinnGen project was used to perform two-sample MR analysis. The inverse-variance weighted (IVW) model was identified as the primary analytical method, with MR Egger, weighted median, simple mode, and weighted mode serving as additional approaches. Results: The epidemiological analysis demonstrated a lack of statistically significant differences in the prevalence of clinical BPH between severe periodontitis group and non-severe periodontitis group. Similarly, no statistically significant differences were found in the prevalence of severe periodontitis among individuals with clinical BPH compared to those without. Additionally, Among the five models utilized in MR analysis, including the IVW model, no evidence of a causal link between periodontitis and BPH was observed. Conclusion: The findings from our epidemiological investigation and MR analysis do not provide support for a causal relationship between periodontitis and BPH.
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Matrix Metalloproteinases (MMPs) have been demonstrated to be essential in facilitating the migration and metastasis of clear cell renal cell carcinoma (ccRCC). However, the ability of the MMP family to predict clinical outcomes and guide optimal therapeutic strategies for ccRCC patients remains incompletely understood. In this investigation, we initially conducted a thorough examination of the MMP family in pan-cancer. Notably, MMPs exhibited distinctive significance in ccRCC. Following this, we undertook an extensive analysis to evaluate the clinical value of MMPs and potential mechanisms by which MMPs contribute to the progression of ccRCC. A novel stratification method and prognostic model were developed based on MMPs in order to enhance the accuracy of prognosis prediction for ccRCC patients and facilitate personalized treatment. By conducting multi-omics analysis and transcriptional regulation analysis, it was hypothesized that SAA1 plays a crucial role in promoting ccRCC migration through MMPs. Subsequently, in vitro experiments confirmed that SAA1 regulates ccRCC cell migration via the ERK-AP1-MMPs axis. In conclusion, our study has explored the potential value of the MMP family as prognostic markers for ccRCC and as guides for medication regimens. Additionally, we have identified SAA1 as a crucial factor in the migration of ccRCC.
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Carcinoma de Células Renales , Movimiento Celular , Neoplasias Renales , Metaloproteinasas de la Matriz , Proteína Amiloide A Sérica , Carcinoma de Células Renales/genética , Carcinoma de Células Renales/patología , Carcinoma de Células Renales/metabolismo , Humanos , Movimiento Celular/genética , Neoplasias Renales/genética , Neoplasias Renales/patología , Neoplasias Renales/metabolismo , Metaloproteinasas de la Matriz/metabolismo , Metaloproteinasas de la Matriz/genética , Pronóstico , Línea Celular Tumoral , Proteína Amiloide A Sérica/metabolismo , Proteína Amiloide A Sérica/genética , Regulación Neoplásica de la Expresión Génica , Sistema de Señalización de MAP Quinasas , Femenino , Quinasas MAP Reguladas por Señal Extracelular/metabolismo , Masculino , Transducción de SeñalRESUMEN
Rationale: The heterogeneity of tumor cells within the glioblastoma (GBM) microenvironment presents a complex challenge in curbing GBM progression. Understanding the specific mechanisms of interaction between different GBM cell subclusters and non-tumor cells is crucial. Methods: In this study, we utilized a comprehensive approach integrating glioma single-cell and spatial transcriptomics. This allowed us to examine the molecular interactions and spatial localization within GBM, focusing on a specific tumor cell subcluster, GBM subcluster 6, and M2-type tumor-associated macrophages (M2 TAMs). Results: Our analysis revealed a significant correlation between a specific tumor cell subcluster, GBM cluster 6, and M2-type TAMs. Further in vitro and in vivo experiments demonstrated the specific regulatory role of the CEBPB transcriptional network in GBM subcluster 6, which governs its tumorigenicity, recruitment of M2 TAMs, and polarization. This regulation involves molecules such as MCP1 for macrophage recruitment and the SPP1-Integrin αvß1-Akt signaling pathway for M2 polarization. Conclusion: Our findings not only deepen our understanding of the formation of M2 TAMs, particularly highlighting the differential roles played by heterogeneous cells within GBM in this process, but also provided new insights for effectively controlling the malignant progression of GBM.
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Proteína beta Potenciadora de Unión a CCAAT , Glioblastoma , Microambiente Tumoral , Macrófagos Asociados a Tumores , Glioblastoma/patología , Glioblastoma/metabolismo , Glioblastoma/genética , Humanos , Proteína beta Potenciadora de Unión a CCAAT/metabolismo , Proteína beta Potenciadora de Unión a CCAAT/genética , Animales , Macrófagos Asociados a Tumores/metabolismo , Macrófagos Asociados a Tumores/inmunología , Ratones , Línea Celular Tumoral , Neoplasias Encefálicas/patología , Neoplasias Encefálicas/metabolismo , Neoplasias Encefálicas/genética , Regulación Neoplásica de la Expresión Génica , Transducción de Señal , Macrófagos/metabolismoRESUMEN
BACKGROUND: The six-transmembrane epithelial antigen of the prostate 3 (STEAP3) is a metalloreductase, which is essential for iron uptake. Existing literature has shown that STEAP3 may perform an important role in the onset and progression of tumors. Nonetheless, a complete pan-cancer investigation of the prognostic significance and immune properties of STEAP3 is currently unavailable. AIMS: As part of our investigation into the possible functions of STEAP3 in malignancies, we conducted a comprehensive analysis to examine the prognostic value and immune features of STEAP3 in human pan-cancer. METHODS AND RESULTS: R and Cytoscape programs were applied to analyze and visualize the data. The expression of STEAP3 in both cell lines and tissues was measured utilizing a variety of approaches. Using the shRNA knockdown technique, we tested the viability of the A498 and 786-O cell lines and validated their functions. Both CCK-8 and transwell assays were conducted to estimate cell proliferation and invasion. The expression of STEAP3 was substantially elevated and was shown to be linked to prognosis in the majority of malignancies, notably in clear cell renal cell carcinoma (ccRCC). In addition, the expression of STEAP3 was shown to have a strong correlation with immune infiltrates, which in turn triggered the recruitment and polarization of M2 macrophages in ccRCC. The protein STEAP3 shows promise as a predictor of responses to immune-checkpoint blockade (ICB) therapy. Positive links between STEAP3 and the epithelial-mesenchymal transition (EMT), the p53 pathway, and the immune-associated pathways were also found in the enrichment analysis. Our results illustrated that the STEAP3 expression level was substantially elevated in ccRCC tissues and suggested that it could stimulate EMT in ccRCC by downregulating CDH1. CONCLUSION: In a diverse range of cancers, STEAP3 might serve as a biomarker for determining the prognosis as well as a predictor of immunotherapy responsiveness. STEAP3 is a novel biological marker for determining prognosis, and it also performs a remarkable function in the promotion of tumor growth in ccRCC by enhancing invasion and EMT, as well as by triggering the recruitment and polarization of M2 macrophages.
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Carcinoma de Células Renales , Neoplasias Renales , Masculino , Humanos , Carcinoma de Células Renales/genética , Carcinoma de Células Renales/patología , Neoplasias Renales/patología , Pronóstico , Próstata/patología , Proliferación Celular/genéticaRESUMEN
The characteristics of the tumour cells, as well as how tumour cells interact with their surroundings, affect the prognosis of cancer patients. The resident cells in the tumour microenvironment are mast cells (MCs), which are known for their functions in allergic responses, but their functions in the cancer milieu have been hotly contested. Several studies have revealed a link between MCs and the development of tumours. Mast cell proliferation in colorectal cancer (CRC) is correlated with angiogenesis, the number of lymph nodes to which the malignancy has spread, and patient prognosis. By releasing angiogenic factors (VEGF-A, CXCL 8, MMP-9, etc.) and lymphangiogenic factors (VEGF-C, VEGF-D, etc.) stored in granules, mast cells play a significant role in the development of CRC. On the other hand, MCs can actively encourage tumour development via pathways including the c-kit/SCF-dependent signaling cascade and histamine production. The impact of MC-derived mediators on tumour growth, the prognostic importance of MCs in patients with various stages of colorectal cancer, and crosstalk between MCs and CRC cells in the tumour microenvironment are discussed in this article. We acknowledge the need for a deeper comprehension of the function of MCs in CRC and the possibility that targeting MCs might be a useful therapeutic approach in the future.
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Neoplasias Colorrectales , Linfangiogénesis , Humanos , Mastocitos/metabolismo , Pronóstico , Transducción de Señal , Neoplasias Colorrectales/patología , Microambiente TumoralRESUMEN
pH is a crucial factor of microbial nitrification, which often combines with high-strength ammonium to influence nitrogen removal pathway in wastewater treatment. However, the detailed inhibitory mechanisms of pH stress are not sufficiently disclosed yet. In this study, the pH stress effect on nitrification was comprehensively studied by a set of experiments which identified the reactivity of nitrification processes and activity of nitrifiers, the time dependence of inhibition effect and the hybrid pH stress effect with ammonium. The results revealed two distinct inhibitory mechanisms dominating in alkaline and acid ranges. In alkaline range (pH > 8), pH stress causes physiological damages on microorganisms which is named as microbial inhibition. It has the features of less recoverability of nitrifiers, time-dependent inhibition effect and low pH-tolerance of nitrite oxidation bacteria. Free ammonia enhanced microbial inhibition and greatly promoted nitrite accumulation. A novel reactive inhibition mechanism dominated in acid range (pH < 7) was disclosed. It only impedes ammonia oxidation process (AOP) but not impair microbial activity obviously and the effect is time-independent. The mechanism was clarified from H+ transport because AOP involved H+ production. The H+ transport was impeded under acid stress owing to the decrease of pH gradient across cell membrane. The two mechanisms formed a panoramic view of pH stress effect on nitrification advancing the understanding of nitrifier adaptability and nitritation regulation in wastewater treatment processes.
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Compuestos de Amonio , Nitrificación , Amoníaco/metabolismo , Aguas Residuales , Compuestos de Amonio/química , Reactores Biológicos/microbiología , Concentración de Iones de Hidrógeno , Nitritos/química , Oxidación-Reducción , Nitrógeno/metabolismoRESUMEN
Renal lymphangiogenesis is a new field of international nephrology in recent years and plays an important role in the progression of chronic renal disease. CD137 was originally described as a surface molecule present on activated T and NK cells and detected on hypoxic endothelial cells and inflamed blood vessels, but its function on lymphatic endothelial cells remains unclear. We investigated the relationships among CD137, lymphangiogenesis and macrophages, which are involved in interstitial fibrosis. Similar to other chronic inflammatory diseases, we found lymphangiogenesis and expression of CD137 in the renal tissue of patients with IgA nephropathy. CD137-positive lymphatic vessels were involved in the development process of IgA nephropathy and positively correlated with serum creatinine, serum urea nitrogen, serum uric acid, and urinary 24 h total protein. The expression of these indicators was negatively correlated with eGFR, plasma albumin, and HB. In mouse models of UUO, we verified that CD137 expression was significantly elevated during lymphangiogenesis and that its ligand CD137L was released by macrophages after VEGF-C stimulation in the kidney. In vitro, recombinant CD137L significantly enhanced LEC proliferation, migration and tube formation, and these effects were inhibited by CD137 siRNA. Mechanistically, the CD137L interaction with CD137 induced the transition from LC3-I to LC3-II and the expression of Atg5, Atg7, Atg12 and p62 proteins by activating the PI3K/AKT/mTOR pathway to promote autophagy. Knockdown of Atg5 and Atg7 blocked CD137L-induced autophagy. Thus, we propose that CD137L secretion by macrophages interacts with CD137 on lymphatic endothelial cells to prompt lymphangiogenesis in the kidney, which further drives fibrogenic responses. Our findings suggest that inhibition of the CD137-CD137L pathway is a novel therapeutic approach for obstructive nephropathy.
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Glomerulonefritis por IGA , Linfangiogénesis , Ligando 4-1BB/metabolismo , Animales , Autofagia/genética , Células Endoteliales/metabolismo , Femenino , Fibrosis , Glomerulonefritis por IGA/metabolismo , Humanos , Linfangiogénesis/genética , Macrófagos/metabolismo , Masculino , Ratones , Fosfatidilinositol 3-Quinasas/metabolismo , Ácido Úrico/metabolismoRESUMEN
BACKGROUND: Glioma is the most common malignant intracranial tumor with high lethality. Despite surgery combined with chemoradiotherapy, the prognosis for patients with glioma remains poor. This is primarily due to acquired chemoradiotherapy resistance. Therefore, to improve the prognosis of glioma, further study into the mechanism of chemoradiotherapy resistance is needed. OBJECTIVE: This study aimed to (1) evaluate the prognosis of patients with glioma by using a prognostic risk score model constructed by chemoradiotherapy resistance genes, (2) provide new targets and directions for precise treatment of glioma, and (3) discuss the tumor heterogeneity of tumor cells. METHODS: According to therapy class and overall survival (OS), we identified 53 genes associated with glioma chemoradiotherapy resistance in The Cancer Genome Atlas Glioblastoma (TCGA GBM) database. Considering the important role of chemoradiotherapy resistance-related genes in the prognosis of glioma, we preliminarily screened and identified vital prognostic factors among these genes by using the Cox regression model of absolute contraction and selection operators in the TCGA GBM lower-grade glioma (TCGA GBMLGG) dataset. Next, the heterogeneity of the chemoradiotherapy resistance-associated genes in different glioma cells was revealed by single-cell sequencing in the GSE117891 cohort. RESULTS: A prognostic risk score model consisting of three genes (ARL4C, MSN, TNFAIP6) was constructed. The expression of this model was high in glioma neural progenitor cells (NPCs) and low in glioma oligodendrocytes. The OS rates were significantly lower in the high- vs. low-risk group. CONCLUSION: Our 3 gene risk score complements the current glioma diagnosis and provides a novel insight into chemoradiotherapy resistance mechanisms for the prognosis of patients with glioma.
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Factores de Ribosilacion-ADP , Neoplasias Encefálicas , Moléculas de Adhesión Celular , Glioblastoma , Glioma , Proteínas de Microfilamentos , Factores de Ribosilacion-ADP/genética , Neoplasias Encefálicas/tratamiento farmacológico , Neoplasias Encefálicas/genética , Moléculas de Adhesión Celular/genética , Quimioradioterapia , Resistencia a Antineoplásicos , Regulación Neoplásica de la Expresión Génica , Glioblastoma/tratamiento farmacológico , Glioma/tratamiento farmacológico , Glioma/genética , Humanos , Proteínas de Microfilamentos/genética , Pronóstico , Tolerancia a Radiación , Células MadreRESUMEN
Grape seed proanthocyanidin extract (GSPE) has been reported to exhibit a variety of protective effects, such as antioxidant, anti-atherosclerosis and other pharmacological effects. As a member of the complement system, complement component 3 (C3) deposition in the glomerulus is recognized as an important causative mediator of various kidney diseases. In this study, we aimed to identify the effect of GSPE on C3 in the chronic kidney fibrosis and evaluate the possible mechanism. We observed that administration of GSPE relieves inflammation and chronic renal fibrosis in mouse models of UUO. GSPE inhibited C3 secreted by macrophages to relieve renal interstitial inflammation. In vitro, we found that C3 stimulated HMGB1 translocation form nucleus to cytoplasm and promote the expression of pro-inflammatory cytokines including TGF-ß1 in primary renal tubular epithelial cells (PTEC), which could be inhibited by GSPE. Meanwhile, GSPE could also decreased HMGB1-induced EMT of PTEC through suppresses the HMGB1/TLR4/p65/TGF-ß1 pathway. In addition, the myofibroblast activation was inhibited by GSPE via TGF-ß1/Smad2/3 signaling pathways in normal rat kidney fibroblast (NRK-49F) cells. Overall, these observations provide that GSPE alleviates renal fibrosis by inhibiting the C3/HMGB1/TGF-ß1 pathway and could thus lead to find the potential therapy for the suppression of renal fibrosis.
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Extracto de Semillas de Uva/farmacología , Riñón/efectos de los fármacos , Proantocianidinas/farmacología , Transducción de Señal/efectos de los fármacos , Animales , Células Cultivadas , Complemento C3/metabolismo , Modelos Animales de Enfermedad , Células Epiteliales/citología , Células Epiteliales/efectos de los fármacos , Células Epiteliales/metabolismo , Transición Epitelial-Mesenquimal/efectos de los fármacos , Fibrosis , Extracto de Semillas de Uva/uso terapéutico , Proteína HMGB1/metabolismo , Riñón/patología , Enfermedades Renales/metabolismo , Enfermedades Renales/patología , Enfermedades Renales/prevención & control , Túbulos Renales/citología , Masculino , Ratones , Ratones Endogámicos C57BL , Proantocianidinas/uso terapéutico , Ratas , Factor de Crecimiento Transformador beta1/metabolismoRESUMEN
N-acetylcysteine has been widely used as a nutritional supplement and drug in humans for its antioxidant properties. The complement activation fragment C5a is a strong proinflammatory molecule that mediates cell adhesion, chemotaxis, and the complex biological functions. However, the effect of NAC on the C5a, and the relationship of those two with cisplatin-induced acute kidney injury are unknown. In cisplatin induced AKI mouse model, mice with NAC administration had a marked improvement in renal function (BUN and Cr), decreased pathological damage, reduced inflammation, and alleviated renal oxidative stress. Furthermore, C5a and C5aR expression in the cisplatin-treated group was notably increased compared with the control group, and this increase could be significantly inhibited by NAC. In addition, neutrophils coexpressed distinctly with C5aR, and the number of infiltrating neutrophils (MPO+ly6G+) and inflammatory factors decreased with NAC treatment in the cisplatin-treated group. Overall, these data demonstrate that NAC could ameliorate cisplatin-induced nephrotoxicity in mice and the protective effects may be conducted by inhibiting the activation of kidney inflammation and the complement system.
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Acetilcisteína/farmacología , Lesión Renal Aguda/tratamiento farmacológico , Cisplatino/efectos adversos , Receptor de Anafilatoxina C5a/antagonistas & inhibidores , Animales , Apoptosis/efectos de los fármacos , Complemento C5a/metabolismo , Modelos Animales de Enfermedad , Inflamación , Riñón/efectos de los fármacos , Riñón/patología , Masculino , Ratones , Ratones Endogámicos C57BL , Neutrófilos , Estrés Oxidativo/efectos de los fármacos , Receptor de Anafilatoxina C5a/metabolismoRESUMEN
Complement synthesis in cells of origin is strongly linked to the pathogenesis and progression of renal disease. Multiple studies have examined local C3 synthesis in renal disease and elucidated the contribution of local cellular sources, but the contribution of infiltrating inflammatory cells remains unclear. We investigate the relationships among C3, macrophages and Th17 cells, which are involved in interstitial fibrosis. Here, we report that increased local C3 expression, mainly by monocyte/macrophages, was detected in renal biopsy specimens and was correlated with the severity of renal fibrosis (RF) and indexes of renal function. In mouse models of UUO (unilateral ureteral obstruction), we found that local C3 was constitutively expressed throughout the kidney in the interstitium, from which it was released by F4/80+macrophages. After the depletion of macrophages using clodronate, mice lacking macrophages exhibited reductions in C3 expression and renal tubulointerstitial fibrosis. Blocking C3 expression with a C3 and C3aR inhibitor provided similar protection against renal tubulointerstitial fibrosis. These protective effects were associated with reduced pro-inflammatory cytokines, renal recruitment of inflammatory cells, and the Th17 response. in vitro, recombinant C3a significantly enhanced T cell proliferation and IL-17A expression, which was mediated through phosphorylation of ERK, STAT3, and STAT5 and activation of NF-kB in T cells. More importantly, blockade of C3a by a C3aR inhibitor drastically suppressed IL-17A expression in C3a-stimulated T cells. We propose that local C3 secretion by macrophages leads to IL-17A-mediated inflammatory cell infiltration into the kidney, which further drives fibrogenic responses. Our findings suggest that inhibition of the C3a/C3aR pathway is a novel therapeutic approach for obstructive nephropathy.
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Complemento C3/inmunología , Interleucina-17/metabolismo , Enfermedades Renales/etiología , Enfermedades Renales/metabolismo , Macrófagos/inmunología , Macrófagos/metabolismo , Adolescente , Adulto , Biomarcadores , Biopsia , Complemento C3/biosíntesis , Citocinas/metabolismo , Femenino , Fibrosis , Técnica del Anticuerpo Fluorescente , Humanos , Inmunohistoquímica , Mediadores de Inflamación/metabolismo , Enfermedades Renales/patología , Masculino , Persona de Mediana Edad , Modelos Biológicos , Monocitos/inmunología , Monocitos/metabolismo , Adulto JovenRESUMEN
BACKGROUND: Shensong Yangxin (SSYX), a traditional Chinese herbal medicine, has long been used clinically to treat arrhythmias in China. However, the mechanism of SSYX on atrial fibrillation (AF) is unknown. In this study, we tested the hypothesis that the effect of SSYX on the progression of paroxysmal AF is correlated with the regulation of autonomic nerve activity. METHODS: Eighteen mongrel dogs were randomly divided into control group (n = 6), pacing group (n = 6), and pacing + SSYX group (n = 6). The control group was implanted with pacemakers without pacing; the pacing group was implanted with pacemakers with long-term intermittent atrial pacing; the pacing + SSYX group underwent long-term intermittent atrial pacing and SSYX oral administration. RESULTS: Compared to the pacing group, the parameters of heart rate variability were lower after 8 weeks in the pacing + SSYX group (low-frequency [LF] component: 20.85 ± 3.14 vs. 15.3 ± 1.89 ms 2 , P = 0.004; LF component/high-frequency component: 1.34 ± 0.33 vs. 0.77 ± 0.15, P < 0.001). The atrial effective refractory period (AERP) was shorter and the dispersion of the AERP was higher after 8 weeks in the pacing group, while the changes were suppressed by SSYX intake. The dogs in the pacing group had more episodes and longer durations of AF than that in the pacing + SSYX group. SSYX markedly inhibited the increase in sympathetic nerves and upregulation of tumor necrosis factor-alpha and interleukin-6 expression in the pacing + SSYX group. Furthermore, SSYX suppressed the decrease of acetylcholine and α7 nicotinic acetylcholine receptor protein induced by long-term intermittent atrial pacing. CONCLUSIONS: SSYX substantially prevents atrial electrical remodeling and the progression of AF. These effects of SSYX may have association with regulating the imbalance of autonomic nerve activity and the cholinergic anti-inflammatory pathway.