ObjectiveThis study aims to compare the modeling effects of submaxillary gland antigen and salivary gland antigen in the establishment of Sjögren syndrome (SS) mouse models, and to characterize the phenotypic and immunological features of these models in comparison with spontaneous SS-prone non-obese diabetic (NOD)/LtJ mice. MethodsAdult C57BL/6J mice (equal numbers of males and females) were immunized with submaxillary gland antigen or salivary gland antigen, respectively, combined with Freund's adjuvant to induce SS models. Mice immunized with phosphate-buffered saline (PBS) combined with Freund's adjuvant served as the control group. Immunization was induced via multiple subcutaneous injections in the back with antigen combined with Freund's complete adjuvant (FCA) on Days 1 and 7. A booster immunization was administered via multiple subcutaneous injections in the back with antigen combined with Freund's incomplete adjuvant (FIA) on Day 14. Female NOD/LtJ mice were used as the spontaneous SS model group, with ICR mice as the corresponding control strain for comparative analysis. Body weight, water intake, and salivary flow rate of mice were dynamically monitored for 4 weeks. At the end of the experiment, tissue and serum samples were collected, the weights of submaxillary glands, thymus, and spleen were measured, and organ indices (organ-to-body weight ratios) were calculated. Pathological morphological analysis of the submaxillary gland and spleen was performed with hematoxylin and eosin (HE) staining. Serum interleukin-17 (IL-17) level was detected using enzyme-linked immunosorbent assay (ELISA). Real-time quantitative polymerase chain reaction was used to detect the mRNA expression levels of SS type A (SSA) and SS type B (SSB) in submaxillary gland tissues. ResultsFemale mice in the submaxillary gland antigen group exhibited significantly increased water intake (P<0.05) and reduced salivary flow rate (P<0.05) compared with the female control group. No statistically significant differences were observed in the submaxillary gland index, thymus index and spleen index (P>0.05). Focal lymphocytic infiltration was observed in the submaxillary glands, and the splenic marginal zone was enlarged. Serum IL-17 levels were significantly increased (P<0.05). There was no significant difference in submaxillary gland SSA/SSB expression levels (P>0.05). Compared with the female control group, female mice in the salivary gland antigen group showed no statistically significant differences in water intake, salivary flow rate, submaxillary gland index, and spleen index (P>0.05), whereas the thymus index was significantly reduced (P<0.01). Mild inflammatory cell infiltration and glandular atrophy were observed in the submaxillary glands, and the splenic white pulp and marginal zone were slightly enlarged. Serum IL-17 levels and submaxillary gland SSB mRNA expression levels were significantly increased (P<0.01), whereas no significant change was observed in submaxillary gland SSA expression levels (P>0.05). Compared with the male control group, mild submaxillary gland atrophy was observed in male mice in the submaxillary gland antigen group, whereas no obvious changes were found in other modeling-related indicators (P>0.05). Compared with the ICR control group, NOD/LtJ model mice exhibited elevated water intake (P<0.05), significantly reduced salivary flow rate (P<0.01), no significant differences in the submaxillary gland index or spleen index (P>0.05), but a significantly increased thymus index (P<0.05). Marked focal infiltration was observed in the submaxillary glands, the splenic marginal zone was obviously enlarged, and serum IL-17 concentrations as well as submaxillary gland SSA/SSB expression levels were significantly increased (P<0.05). ConclusionSubmaxillary gland antigen and salivary gland antigen can induce SS-related features in female C57BL/6J mice. The SS-related phenotype is more pronounced in the submaxillary gland antigen group than in the salivary gland antigen group, but weaker than that in spontaneously SS-prone female NOD/LtJ mice. Immunization of male C57BL/6J mice with submaxillary or salivary gland antigens fails to induce an obvious SS phenotype.

ObjectiveTo explore the mechanism through which Banxia Baizhu Tianmatang ameliorates cognitive impairment in epileptic rats induced by lithium chloride-pilocarpine by regulating the neuroinflammatory reaction mediated by NOD-like receptor protein 3 （NLRP3） inflammasomes. MethodsSixty male SD rats were randomly allocated into blank， model， carbamazepine （0.125 g·kg^-1·d^-1）， Banxia Baizhu Tianmatang （1.04 g·kg^-1·d^-1）， and carbamazepine （0.125 g·kg^-1·d^-1） + Banxia Baizhu Tianmatang （1.04 g·kg^-1·d^-1） groups （n=12）. After the modeling of epilepsy， rats were administrated with corresponding agents by gavage for 12 weeks. At the 6th and 12th week of the intervention， the rats’ hyper-excited behavior was evaluated by the stylus experiment， and at the 12^th week of intervention， the cognitive function was evaluated by Barnes maze. At the same time， the seizure frequency and severity grade （Racine score） were recorded. The serum and hippocampus tissue samples were collected after anesthesia for the following tests. Nissl staining was used to evaluate the degree of neuronal damage in the hippocampal CA1 area. The content of malondialdehyde （MDA） in the hippocampus was determined by the thiobarbituric acid （TBA） method. Serum levels of tumor necrosis factor-α （TNF-α）， interleukin-1β （IL-1β）， and interleukin-18 （IL-18） were quantified by enzyme-linked immunosorbent assay （ELISA）. Immunohistochemical method was adopted to detect the expression of apoptosis-associated speck-like protein containing a card （ASC） in the hippocampus. Western blot was employed to quantitatively analyze the protein levels of NLRP3， cysteinyl aspartate-specific proteinase-1 （Caspase-1）， and brain-derived neurotrophic factor （BDNF） in the hippocampus. ResultsThe model group showed increased stylus scores at the 6th and 12^th week after modeling， a decreased Barnes maze strategy score at the 12^th week， a prolonged incubation period （P<0.05）， elevated serum levels of inflammatory factors （P<0.05）， decreased neurons with scattered arrangement and large gaps in the hippocampus， increased content of MDA in the hippocampus （P<0.05）， an increased positive expression of ASC， and up-regulated protein levels of Caspase-1， NLRP3， and BDNF （P<0.05）. Compared with the model group， the intervention with Banxia Baizhu Tianmatang for 12 weeks was accompanied by a decreased stylus score， epileptic seizures with a decreased score， a decreased number， and shortened duration， an increased Barnes maze strategy score， shortened escape latency （P<0.01）， declined serum levels of inflammatory factors （P<0.05）， regular morphology of hippocampal neurons， reduced MDA content in the hippocampus （P<0.05）， a decreased positive expression of ASC， and down-regulated protein levels of Caspase-1， NLRP3， and BDNF （P<0.05， P<0.01）. In addition， compared with the carbamazepine group， Banxia Baizhu Tianmatang + carbamazepine showed improved performance in controlling the seizure， improved the cognitive behavior score and morphology of hippocampal neurons， alleviated the oxidative stress products， lowered the levels of inflammatory factors， reduced the positive expression of ASC in the hippocampus， and down-regulated the expression of Caspase-1， NLRP3 and BDNF， with no significant differences. ConclusionBanxia Baizhu Tianmatang may reduce neuroinflammation， control epileptic seizures， and ameliorate cognitive impairment by inhibiting the expression of NLRP3 inflammasomes.

This paper aimed to investigate the therapeutic effect and mechanism of action of the Yiqi Fumai Formula(YQFM), a kind of traditional Chinese medicine(TCM), on mice with experimental heart failure based on the "heart-gut axis" theory. Based on the network pharmacology integrated with the group collaboration algorithm, the active ingredients were screened, a "component-target-disease" network was constructed, and the potential pathways regulated by the formula were predicted and analyzed. Next, the model of experimental heart failure was established by intraperitoneal injection of adriamycin at a single high dose(15 mg·kg~(-1)) in BALB/c mice. After intraperitoneal injection of YQFM(lyophilized) at 7.90, 15.80, and 31.55 mg·d~(-1) for 7 d, the protective effects of the formula on cardiac function were evaluated using indicators such as ultrasonic electrocardiography and myocardial injury markers. Combined with inflammatory factors in the cardiac and colorectal tissue, as well as targeted assays, the relevant indicators of potential pathways were verified. Meanwhile, 16S rDNA sequencing was performed on mouse fecal samples using the Illumina platform to detect changes in gut flora and analyze differential metabolic pathways. The results show that the administration of injectable YQFM(lyophilized) for 7 d significantly increased the left ventricular end-systolic internal diameter, fractional shortening, and ejection fraction of cardiac tissue of mice with experimental heart failure(P<0.05). Moreover, markers of myocardial injury were significantly decreased(P<0.05), indicating improved cardiac function, along with significantly suppressed inflammatory responses in cardiac and intestinal tissue(P<0.05). Additionally, the species of causative organisms was decreased, and the homeostasis of gut flora was improved, involving a modulatory effect on PI3K-Akt signaling pathway-related inflammation in cardiac and colorectal tissue. In conclusion, YQFM can affect the "heart-gut axis" immunity through the homeostasis of the gut flora, thereby exerting a therapeutic effect on heart failure. This finding provides a reference for the combination of TCM and western medicine to prevent and treat heart failure based on the "heart-gut axis" theory.
Animals ; Drugs, Chinese Herbal/administration & dosage* ; Heart Failure/microbiology* ; Mice ; Mice, Inbred BALB C ; Male ; Disease Models, Animal ; Gastrointestinal Microbiome/drug effects* ; Heart/physiopathology* ; Humans ; Signal Transduction/drug effects*

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Background: and Purpose This study aimed to investigate the association between residual inflammatory risk (RIR) and vulnerable plaques using high-resolution magnetic resonance imaging (HRMRI) in symptomatic intracranial atherosclerotic stenosis (ICAS). Methods: This retrospective study included 70%–99% symptomatic ICAS patients hospitalized from January 2016 to December 2022. Patients were classified into four groups based on high-sensitivity C-reactive protein (hs-CRP) and low-density lipoprotein cholesterol (LDL-C): residual cholesterol inflammatory risk (RCIR, hs-CRP ≥3 mg/L and LDL-C ≥2.6 mmol/L), RIR (hs-CRP ≥3 mg/L and LDL-C <2.6 mmol/L), residual cholesterol risk (RCR, hs-CRP <3 mg/L and LDL-C ≥2.6 mmol/L), and no residual risk (NRR, hs-CRP <3 mg/L and LDL-C <2.6 mmol/L). Vulnerable plaque features on HRMRI included positive remodeling, diffuse distribution, intraplaque hemorrhage, and strong enhancement. Results: Among 336 included patients, 21, 60, 58, and 197 were assigned to the RCIR, RIR, RCR, and NRR groups, respectively. Patients with RCIR (adjusted odds ratio [aOR], 3.606; 95% confidence interval [CI], 1.346–9.662; P=0.011) and RIR (aOR, 3.361; 95% CI, 1.774–6.368, P<0.001) had higher risks of strong enhancement than those with NRR. Additionally, patients with RCIR (aOR, 2.965; 95% CI, 1.060–8.297; P=0.038) were more likely to have intraplaque hemorrhage compared with those with NRR. In the sensitivity analysis, RCR (aOR, 2.595; 95% CI, 1.201–5.608; P=0.015) exhibited an additional correlation with an increased risk of intraplaque hemorrhage. Conclusion In patients with symptomatic ICAS, RIR is associated with a higher risk of intraplaque hemorrhage and strong enhancement, indicating an increased vulnerability to atherosclerotic plaques.

Background: and Purpose This study aimed to investigate the association between residual inflammatory risk (RIR) and vulnerable plaques using high-resolution magnetic resonance imaging (HRMRI) in symptomatic intracranial atherosclerotic stenosis (ICAS). Methods: This retrospective study included 70%–99% symptomatic ICAS patients hospitalized from January 2016 to December 2022. Patients were classified into four groups based on high-sensitivity C-reactive protein (hs-CRP) and low-density lipoprotein cholesterol (LDL-C): residual cholesterol inflammatory risk (RCIR, hs-CRP ≥3 mg/L and LDL-C ≥2.6 mmol/L), RIR (hs-CRP ≥3 mg/L and LDL-C <2.6 mmol/L), residual cholesterol risk (RCR, hs-CRP <3 mg/L and LDL-C ≥2.6 mmol/L), and no residual risk (NRR, hs-CRP <3 mg/L and LDL-C <2.6 mmol/L). Vulnerable plaque features on HRMRI included positive remodeling, diffuse distribution, intraplaque hemorrhage, and strong enhancement. Results: Among 336 included patients, 21, 60, 58, and 197 were assigned to the RCIR, RIR, RCR, and NRR groups, respectively. Patients with RCIR (adjusted odds ratio [aOR], 3.606; 95% confidence interval [CI], 1.346–9.662; P=0.011) and RIR (aOR, 3.361; 95% CI, 1.774–6.368, P<0.001) had higher risks of strong enhancement than those with NRR. Additionally, patients with RCIR (aOR, 2.965; 95% CI, 1.060–8.297; P=0.038) were more likely to have intraplaque hemorrhage compared with those with NRR. In the sensitivity analysis, RCR (aOR, 2.595; 95% CI, 1.201–5.608; P=0.015) exhibited an additional correlation with an increased risk of intraplaque hemorrhage. Conclusion In patients with symptomatic ICAS, RIR is associated with a higher risk of intraplaque hemorrhage and strong enhancement, indicating an increased vulnerability to atherosclerotic plaques.

Objective To analyze the target,signal pathway and potential mechanism of Banxia Baizhu Tianma Decoction in the treatment of epilepsy based on network pharmacology,and to verify it by molecular docking technology and animal experiments.Methods The active ingredients and drug targets of Banxia Baizhu Tianma Decoction were screened by BATMAN and other databases.The targets of epilepsy-related diseases were obtained by GeneCards and other databases,and the intersection targets were taken.Constructing'drug-ingredient-target-disease'network and PPI network to screen the core targets.The core active ingredients were screened according to GO,KEGG functional enrichment analysis and'pathway-target-active ingredient'network.Molecular docking was used to verify the core targets and core active ingredients.In the animal experiment,the rat model of epilepsy was induced by lithium chloride-pilocarpine,and 40 Wistar rats were divided into normal control group,model control group,carbamazepine group and Banxia Baizhu Tianma Decoction group.The seizures were observed by behavior.Nissl staining was used to observe neuronal damage in hippocampus.Immunohistochemistry was used to detect the expression of BAX,BCL-2 and Caspase-3 protein.Results A total of 1072 targets of Banxia Baizhu Tianma Decoction were screened,1046 disease targets of epilepsy were screened,and 220 intersection targets of Banxia Baizhu Tianma Decoction in the treatment of epilepsy were screened.The core targets AKT1,ALB,ACTB,INS and TNF of PPI network were obtained.KEGG pathway mainly involves TNF signaling pathway,IL-17 signaling pathway,cAMP signaling pathway,pathways of neurodegeneration-multiple diseases,serotonergic synapse and Dopaminergic synapse.The core active ingredients with the highest correlation in the'pathway-target-active component'network were Betulin,Ephedrine,Ergotamine and Thymol.Results of molecular docking indicated that the core target had satisfactory affinity with those active ingredients.Animal experiments showed that Banxia Baizhu Tianma Decoction could effectively reduce epileptic seizures in rats,improve hippocampal neuronal damage in rats,significantly reduce the percentage of neuronal apoptosis,significantly down-regulate the expression of pro-apoptotic proteins BAX and Caspase-3,and up-regulate the expression of anti-apoptotic protein BCL-2.Conclusion Banxia Baizhu Tianma Decoction has the characteristics of multi-component,multi-target and multi-pathway in the treatment of epilepsy.Inhibiting neuronal apoptosis and reducing hippocampal neuronal damage may be one of the important mechanisms for its treatment of epilepsy.

Background: and Purpose This study aimed to investigate the association between residual inflammatory risk (RIR) and vulnerable plaques using high-resolution magnetic resonance imaging (HRMRI) in symptomatic intracranial atherosclerotic stenosis (ICAS). Methods: This retrospective study included 70%–99% symptomatic ICAS patients hospitalized from January 2016 to December 2022. Patients were classified into four groups based on high-sensitivity C-reactive protein (hs-CRP) and low-density lipoprotein cholesterol (LDL-C): residual cholesterol inflammatory risk (RCIR, hs-CRP ≥3 mg/L and LDL-C ≥2.6 mmol/L), RIR (hs-CRP ≥3 mg/L and LDL-C <2.6 mmol/L), residual cholesterol risk (RCR, hs-CRP <3 mg/L and LDL-C ≥2.6 mmol/L), and no residual risk (NRR, hs-CRP <3 mg/L and LDL-C <2.6 mmol/L). Vulnerable plaque features on HRMRI included positive remodeling, diffuse distribution, intraplaque hemorrhage, and strong enhancement. Results: Among 336 included patients, 21, 60, 58, and 197 were assigned to the RCIR, RIR, RCR, and NRR groups, respectively. Patients with RCIR (adjusted odds ratio [aOR], 3.606; 95% confidence interval [CI], 1.346–9.662; P=0.011) and RIR (aOR, 3.361; 95% CI, 1.774–6.368, P<0.001) had higher risks of strong enhancement than those with NRR. Additionally, patients with RCIR (aOR, 2.965; 95% CI, 1.060–8.297; P=0.038) were more likely to have intraplaque hemorrhage compared with those with NRR. In the sensitivity analysis, RCR (aOR, 2.595; 95% CI, 1.201–5.608; P=0.015) exhibited an additional correlation with an increased risk of intraplaque hemorrhage. Conclusion In patients with symptomatic ICAS, RIR is associated with a higher risk of intraplaque hemorrhage and strong enhancement, indicating an increased vulnerability to atherosclerotic plaques.

Objective:To explore the impact of metabolic syndrome in conjunction with hyperuricemia on the risk of new-onset cardiovascular disease.Methods:This study was a prospective cohort study. From June 2006 to October 2007, employees of Kailuan Group in Tangshan City, Hebei Province were selected as the research subjects. Participants were divided into four groups based on the presence or absence of metabolic syndrome and hyperuricemia. The groups include the normal group, pure hyperuricemia group, pure metabolic syndrome group, and the metabolic syndrome combined with hyperuricemia group. Four groups of participants were followed up, the primary endpoint was the occurrence of a first-ever cardiovascular disease event, including stroke and myocardial infarction. The cumulative incidence rates of cardiovascular disease in different groups during the continuous follow-up period were calculated using the Kaplan-Meier method, and the differences in cumulative incidence rates among groups were compared using the log-rank test. Multivariate Cox regression analysis was used to analyze the effect of hyperuricemia combined with metabolic syndrome on the risk of cardiovascular disease. The likelihood ratio test was used to analyze whether there was a multiplicative interaction and additive interaction between hyperuricemia and metabolic syndrome.Results:A total of 82 780 individuals were included, aged (51.5±12.6) years, and 68 622 (82.90%) were males, with a median follow-up of 14.97 years. Kaplan-Meier survival curve analysis showed that the cumulative incidence of cardiovascular disease was the highest in the metabolic syndrome combined with hyperuricemia group (log-rank P<0.001). Multivariate Cox regression analysis indicated that after adjusting for various confounding factors, the HR value and 95% CI of cardiovascular disease in the metabolic syndrome combined with hyperuricemia group were 1.24 (1.12-1.38) compared with the normal group, which were higher than those in the pure hyperuricemia group and the pure metabolic syndrome group alone. The effect of metabolic syndrome combined with hyperuricemia on the risk of cardiovascular disease demonstrated an additive effect (relative excess risk of interaction: 0.18(0.11-0.25), attributable proportion due to interaction: 0.14(0.09-0.19)). Conclusions:The combination of hyperuricemia and metabolic syndrome is an independent risk factor for cardiovascular disease. Compared to pure metabolic syndrome or hyperuricemia alone, the impact of metabolic syndrome combined with hyperuricemia on cardiovascular disease is more significant.

Objective:To analyze the electrocardiogram (ECG) data of congenital long QT syndrome (LQTS) patients, and to identify the ECG parameters for prediction of life-threatening arrhythmic events (LAEs).Methods:This cohort study enrolled patients diagnosed with congenital LQTS at the Department of Cardiology, Beijing Tsinghua Changgung Hospital from September 2014 to May 2023. Baseline clinical and ECG data were collected. Patients were followed with LAEs as the primary endpoint. Based on the occurrence of LAEs, patients were divided into two groups: the event group and the event-free group. Cox regression analysis was used to identify independent predictors of LAEs in LQTS patients.Results:A total of 293 patients diagnosed with congenital LQTS were included, aged 32.5 (19.0, 41.8) years, including 201 females (68.6%). Sixty-six patients experienced LAEs and 227 patients did not. Compared to the event-free group, the event group had a younger onset age (13.0 (5.5, 20.5) years vs. 26.0 (13.0, 35.0) years), a slower heart rate (69.0 (59.5, 76.5) beats/min vs. 77.0 (67.0, 88.0) beats/min), a higher proportion with family history of sudden cardiac death (30.3% vs. 14.5%), as well as longer QT intervals (500.0 (467.0, 594.0) ms vs. 428.0 (402.0, 470.0) ms) and QTc intervals (544.0 (502.5, 589.0) ms vs. 489.0 (480.0, 504.0) ms). Additionally, the event group had higher peak T-wave alternans value (65.0 (42.5, 85.3) μV vs. 44.0 (36.0, 54.0) μV), a higher proportion of patients with documented torsades de pointes (TdP) or ventricular fibrillation (VF) on 24-hour Holter monitoring (39.3% vs. 4.9%), and higher rates of pharmacological treatment (100.0% vs. 9.7%) and device therapy or left cardiac sympathetic denervation (45.5% vs. 2.2%) (all P<0.05). Multivariate Cox regression analysis identified that the heart rate<60 beats/min ( HR=2.0, 95% CI: 1.0-3.7) and QTc interval ≥500 ms ( HR=2.9, 95% CI: 1.5-5.6) on 12-lead ECG, as well as peak T-wave alternans value ≥55.5 μV ( HR=3.2, 95% CI: 1.3-7.8) and documented TdP or VF ( HR=2.0, 95% CI: 1.1-3.7) on 24-hour Holter monitoring were independent predictors of LAEs in LQTS patients (all P<0.05). Conclusion:Heart rate <60 beats/min and QTc interval ≥500 ms on 12-lead ECG, along with peak T-wave alternans value ≥55.5 μV and documented TdP or VF on 24-hour Holter monitoring, have been identified as independent predictors of LAEs in patients with LQTS. These ECG parameters may serve as valuable early indicators of sudden cardiac death in LQTS patients.