ObjectiveTo investigate the protective effect and mechanism of Wendan Ningxin granules （WNG） on susceptibility to atrial fibrillation （AF） in mice with inflammatory injury. Methods100 C57BL/6 mice were divided into a blank control group， a model group， a low-dose WNG group （2.34 g·kg^-1·d^-1）， a high-dose WNG group （4.68 g·kg^-1·d^-1）， and an amiodarone positive control group （0.091 g·kg^-1·d^-1）， with 20 mice in each group. Except for the blank control group， mice in other groups received intraperitoneal injections of lipopolysaccharide （LPS） to establish an inflammatory injury model. Treatment groups received continuous intragastric administration of their respective interventions for four weeks. During the fourth week， the treatment groups received LPS injections concurrently with their treatments. The blank control and model groups received distilled water （10 mL·kg^-1·d^-1） by gavage， with a gavage volume of 10 mL·kg^-1 for all groups， once daily. Hematoxylin-eosin （HE） staining and Sirius red staining were used to observe atrial tissue morphology and fibrosis degree. Immunohistochemistry was used to assess the expression of α-smooth muscle actin （α-SMA） in mouse atrial tissue. Electrophysiological detection was performed using a multi-channel electrophysiology mapping system to measure AF inducibility， AF duration， and atrial effective refractory period （AERP）. High-resolution optical mapping was used to measure action potential duration （APD） dispersion， conduction heterogeneity index， and calcium transient （CaT） dispersion. Real-time quantitative polymerase chain reaction （Real-time PCR） was used to detect mRNA expression of proteins related to diastolic calcium leakage in mouse atria： Ca²⁺/calmodulin-dependent protein kinase Ⅱ（CaMKⅡ）， ryanodine receptor 2（RyR2）， sarco/endoplasmic reticulum Ca²⁺-ATPase （SERCA）， and sodium-calcium exchanger （NCX）. Western blot analysis was performed to detect the expression of CaMKII， RyR2， SERCA， and NCX proteins in myocardial tissue from each group. Enzyme-linked immunosorbent assay （ELISA） was used to measure serum levels of inflammatory factors interleukin-1β （IL-1β） and tumor necrosis factor-α （TNF-α）. ResultsPathological staining results showed that compared with the blank control group， the model group exhibited disrupted atrial tissue structure， inflammatory cell infiltration， atrial fibrosis， and diffuse infiltration of numerous brown α-SMA positive cells in the atrial interstitium （P<0.01）. AF could be induced by electrical stimulation with a longer duration. AERP was shortened， while APD dispersion， conduction heterogeneity index， and CaT dispersion were increased （P<0.01）. The expression of proteins associated with diastolic calcium leakage， including CaMKⅡ， RyR2， and NCX1， showed elevated mRNA and protein levels， whereas SERCA2a mRNA and protein expression decreased （P<0.05）. Serum levels of inflammatory factors IL-1β and TNF-α were elevated （P<0.01）. Compared with the model group， intervention with WNG alleviated cardiac structural damage， reduced inflammatory cell infiltration， improved atrial fibrosis， and reduced the diffuse infiltration of α-SMA positive cells （P<0.01）. AF inducibility and AF duration upon electrical stimulation were significantly reduced （P<0.05）， AERP was prolonged （P<0.05）， mRNA and protein expression of CaMKⅡ， RyR2， and NCX1-proteins associated with diastolic calcium leakage-were reduced， whilst mRNA and protein expression of SERCA2a increased （P<0.05）， and serum levels of IL-1β and TNF-α were decreased （P<0.01）. ConclusionBoth low‑ and high‑dose WNG can effectively reduce susceptibility to inflammation-related AF. The mechanism by which WNG reduce AF susceptibility may be related to regulating proteins involved in sarcoplasmic reticulum diastolic calcium leak， thereby improving cardiac electrical remodeling， and alleviating inflammation-induced myocardial fibrosis， thus improving cardiac structural remodeling.

Background Co-exposure to noise and microwave radiation occurs frequently. The central nervous system has been identified as a sensitive target organ for both noise and microwave exposure individually, and the underlying mechanisms remain poorly understood. The specific biological effects resulting from co-exposure to these two factors have yet to be fully elucidated. Objective To clarify the effects of co-exposure to noise and microwave on neurobehavior and hippocampal tissue structure, and to explore the underlying mechanism through the assessment of serum cytokines. Methods C57BL/6N mice were selected and randomly assigned to a blank control group, a noise group, a microwave group, and a combined noise & microwave exposure group. To establish the exposure models, the noise group was subjected to broadband noise at 100 dB for 2 h, while the microwave group received radiation at a central frequency of 9.375 GHz with an average power density of 12 mW·cm⁻² and a specific absorption rate of 2.58 W·kg⁻¹ for 15 min. Open field and tail suspension tests assessed anxiety-like emotional behaviour; novel object recognition and Y-maze tests evaluated cognitive function. Histological changes in hippocampal tissue were examined using haematoxylin and eosin (HE) staining, and Nissl staining under light microscopy. Serum cytokine levels were measured using radioimmunoassay and enzyme-linked immunosorbent assay (ELISA). Results After 3 d of exposure, the noise, microwave, and combined exposure groups showed significant reductions in exploration frequency, duration, and distance within the central zone of the open field test compared to the control group (P < 0.01); the combined exposure group exhibited increased ratios of peripheral-to-central exploration time and distance (P < 0.05). After 7 d of exposure, compared with the control group, the noise group maintained a decrease in central zone exploration time (P < 0.01), while the combined exposure group showed persistent decline across all central zone metrics (P < 0.05) and elevated peripheral-to-central ratios (P < 0.05); compared to the microwave group, the combined exposure group showed significant less time in the central zone (P < 0.05) and higher peripheral-to-central ratios (P < 0.05). Regarding behaviour and cognition, compared with the control group, the combined exposure group showed increased immobility time in the tail suspension test after 3 d of exposure (P < 0.01). At this interval, all exposure groups demonstrated reduced frequency and duration of novel object recognition (P < 0.05), with the combined exposure group showing a marked decrease in novel arm exploration time (P < 0.01). After 7 d of exposure, compared with the control group, the noise group showed reduced novel object recognition frequency (P < 0.05), and both the noise and microwave groups exhibited decreased novel arm exploration time (P < 0.05). Pathological alterations including an increased number of hyperchromatic nuclei and depleted Nissl bodies were observed in the CA3 and DG regions across all exposure groups with the most severe lesions observed in the combined exposure group. Serum levels of central nervous system-specific protein β (S-100β), glial fibrillary acidic protein (GFAP), and corticosterone (CORT) were significantly elevated in all exposure groups compared with the control group (P < 0.05). Aquaporin-4 (AQP4) levels increased in the combined exposure group (P < 0.05), while CXC chemokine ligand 10 (CXCL10) levels rose in both the noise and combined groups compared with the control group (P < 0.05). Specifically, S-100β and CXCL10 levels in the combined exposure group were higher than those in the microwave group (P < 0.05); moreover, levels of S-100β, GFAP, CORT, AQP4, and CXCL10 in the combined exposure group were significantly higher than those in the noise group (P < 0.05). Conclusion Combined exposure to noise and microwave radiation induces pathological changes in the hippocampus of mice, increases levels of serum stress hormones and neuro-specific biomarkers. These impairments are more severe than those observed following single-factor exposure. The underlaying mechanism may be related to systemic stress response, neuronal damage, astrocyte activation, and changes in blood-brain barrier permeability, leading to emotional behavioral abnormalities and cognitive decline.

OBJECTIVE To investigate the ameliorative effect and mechanism of short-acting exenatide on diabetic cognitive dysfunction. METHODS Spontaneously diabetic db / db mice were randomly divided into model group （normal saline） and exenatide group （50 μg/kg）， with db / m mice as the normal control group （normal saline）， with 8 mice in each group. Mice in each group were subcutaneously injected with corresponding drugs or normal saline twice daily for 8 consecutive weeks. Body weight and fasting blood glucose were measured at a fixed time every week. Cognitive function was evaluated by Morris water maze test. The levels of oxidative st ress indicators [malondialdehyde （MDA）， superoxide dismutase （SOD）， glutathione （GSH） ] ， cyclic adenosine monophosphate （cAMP） and protein kinase A （PKA） were detected in hippocampus tissue of mice. The hippocampal neuronal HT22 cells of mice were divided into control group （25 mmol/L glucose）， high glucose group （125 mmol/L glucose）， high glucose+exenatide group （125 mmol/L glucose+20 nmol/L exenatide）， high glucose+exenatide+H89 （PKA inhibitor） group （125 mmol/L glucose+20 nmol/L exenatide+10 μmol/L H89）， and high glucose+H89 group （125 mmol/L glucose+10 μmol/L H89）. After 48 h of intervention with corresponding solutions/culture medium， the levels of oxidative stress indicators， cAMP and PKA， the activities of mitochondrial respiratory enzymes Ⅱ and Ⅳ， and the phosphorylation level of dynamin-related protein 1 （Drp1） were measured. RESULTS Animal experiments showed that compared with the normal control group， the model group exhibited significantly increased body weight， fasting blood glucose and MDA level in the hippocampus （ P ＜0.05）， as well as significantly prolonged escape latency （ P ＜0.05）； swimming speed significantly slowed down， the time spent in the target quadrant， the number of platform crossings， and the levels of SOD， GSH， cAMP and PKA in the hippocampus were significantly decreased （ P ＜0.05）. Compared with model group， all the above indicators （except for swimming speed） in the exenatide group were significantly reversed （ P ＜0.05）. Cell experiments showed that compared with high glucose group， the high glucose+exenatide group had significantly decreased MDA level （ P ＜0.05）， and significantly increased levels of SOD， GSH， cAMP and PKA， the activities of mitochondrial respiratory enzymes Ⅱ and Ⅳ， and phosphorylation level of Drp1 （ P ＜0.05）. Compared with high glucose+exenatide group， the above indicators in the high glucose+exenatide+H89 group were significantly reversed （ P ＜0.05）. CONCLUSIONS Short-acting exenatide can activate the cAMP/PKA pathway， promote Drp1 phosphorylation， and increase the activities of mitochondrial respiratory enzymes， thereby maintaining mitochondrial stability， reducing oxidative stress injury， and ultimately improving diabetic cognitive dysfunction.

ObjectiveTo investigate the role of interleukin （IL）-17A in acute inhalational pneumonia induced by the highly drug-resistant and hypervirulent Staphylococcus aureus strain USA300-R in mice. MethodsAn acute inhalational pneumonia model was established in mice using an aerosolized pulmonary delivery technique. RNA sequencing （RNA-seq） and enzyme-linked immunosorbent assay （ELISA） were employed to examine the expression dynamics of Il17a mRNA and IL-17A protein， respectively， in the lungs of infected mice. Il17a knockout （Il17a^-/-） mice were generated using CRISPR/Cas9 gene editing technology. The survival rate， body weight， bacterial load in lung tissue， and histopathological changes were compared between Il17a^-/- and wild-type （WT） mice following inhalational infection with USA300-R. Results12 hours after USA300-R infection， compared to pre-infection， the expression level of Il17a mRNA in lung tissue and the level of IL-17A protein in bronchoalveolar lavage fluid （BALF） increased by approximately 50-fold （P<0.01） and 6-fold （P<0.001）， respectively. Compared to WT mice， Il17a^-/- mice exhibited approximately 10-fold higher bacterial loads in lung tissue at both 12 and 24 hours post-infection （P<0.001， P<0.05）. However， they showed significantly attenuated lung histopathological injury， reduced alveolar wall thickening， markedly decreased neutrophil infiltration， and an approximately 50% improvement in survival rate （P<0.05）. ConclusionIn acute Staphylococcus aureus USA300-R inhalational pneumonia， IL-17A contributes to bacterial clearance by recruiting neutrophils； however， excessive neutrophil infiltration exacerbates pulmonary inflammation and injury， reduces survival rates， and represents a potential therapeutic target.

ObjectiveTo observe the protective effect of Erchentang （ECT） on SiO₂-induced lung injury in rats and to explore its underlying mechanism. MethodsA rat model of lung injury was established by a single intratracheal instillation of 50 mg·mL^-1 SiO₂ suspension. Thirty male Sprague-Dawley （SD） rats were randomly assigned to five groups： control， model， low and high-dose （4.5 g·kg^-1·d^-1 and 9 g·kg^-1·d^-1， respectively） ECT， and dexamethasone （0.2 mg·kg^-1·d^-1）. All the groups were treated for 4 consecutive weeks. Histopathological alterations in the lung tissue were examined by hematoxylin and eosin （HE） staining. The levels of malondialdehyde （MDA）， superoxide dismutase （SOD）， and glutathione peroxidase （GSH-Px） in the lung tissue were measured through biochemical assays. The expression of key molecules in the nuclear factor erythroid 2-related factor 2 （Nrf2）/heme oxygenase-1 （HO-1） pathway was determined by Real-time fluorescence quantitative polymerase chain reaction （Real-time PCR）， Western blot， and immunofluorescence assay. The primary active components of ECT were identified by ultra-performance liquid chromatography-tandem mass spectrometry （UPLC-MS/MS）， and their binding affinity to Nrf2/HO-1 was assessed by molecular docking. Untargeted metabolomics of the lung tissue was performed based on UPLC-quadrupole time-of-flight mass spectrometry （UPLC-Q-TOF-MS）， and correlation analysis was performed to identify differential metabolites and parameters closely associated with the Nrf2/HO-1 pathway. ResultsCompared with the control group， the model group exhibited a reduction in body weight gain， an increase in lung index， increased MDA content， weakened SOD and GSH-Px activities in the lung tissue， down-regulated mRNA and protein levels of Nrf2 and protein levels of HO-1 and GPX4， and an up-regulated protein level of Keap1 （P<0.05， P<0.01）. Treatment with ECT attenuated the SiO₂-induced decline in body weight （P<0.05）， alleviated inflammatory cell infiltration and silicotic nodule formation in alveoli， and reduced the MDA content and enhanced the SOD and GSH-Px activities in the lung tissue （P<0.05， P<0.01）. UPLC-MS/MS and molecular docking revealed that core components of ECT， such as hesperidin and glycyrrhizic acid， displayed strong binding affinity to Nrf2/HO-1. Molecular biological experiments demonstrated that ECT promoted nuclear translocation of Nrf2， up-regulated the mRNA and protein levels of HO-1 and GPX4， and down-regulated Keap1 expression （P<0.05， P<0.01）. Metabolomic analysis indicated that ECT reversed the SiO₂-induced aberrant expression of metabolites， including linoleic acid and glutamine （P<0.05， P<0.01）. Correlation analysis showed that Nrf2 and HO-1 were positively correlated with SOD and GSH-Px （P<0.05， P<0.01）， but negatively correlated with glutamine and serine （P<0.05， P<0.01）. ConclusionECT may activate the Nrf2/HO-1 pathway through its core active components， thereby regulating oxidative stress and metabolic disorders to ameliorate SiO₂-induced lung injury in rats. This study provides experimental evidence for ECT in the prevention and treatment of occupational lung injury.

Objective To systematically evaluate the efficacy and safety of proximal gastrectomy (PG) versus total gastrectomy (TG) for the treatment of Siewert type Ⅱ/Ⅲ adenocarcinoma of the esophagogastric junction (AEG). Methods PubMed, The Cochrane Library, Web of Science, EMbase, CNKI, Wanfang, and VIP databases were searched for literature comparing the efficacy and safety of PG and TG for the treatment of Siewert type Ⅱ/Ⅲ AEG. The search period was from database inception to March 2023. Meta-analysis was performed using Review Manager 5.4 software. Results A total of 23 articles were included, including 16 retrospective cohort studies, 5 prospective cohort studies, and 2 randomized controlled trials. The total sample size was 2 826 patients, with 1 389 patients undergoing PG and 1 437 patients undergoing TG. Meta-analysis results showed that compared with TG, PG had less intraoperative blood loss [MD=−19.85, 95%CI (−37.20, −2.51), P=0.02] and shorter postoperative hospital stay [MD=−1.23, 95%CI (−2.38, −0.08), P=0.04]. TG had a greater number of lymph nodes dissected [MD=−6.20, 95%CI (−7.68, −4.71), P<0.001] and a lower incidence of reflux esophagitis [MD=3.02, 95%CI (1.24, 7.34), P=0.01]. There were no statistically significant differences between the two surgical approaches in terms of operative time, postoperative survival rate (1-year, 3-year, 5-year), and postoperative overall complications (P>0.05). Conclusion PG has advantages in terms of intraoperative blood loss and postoperative hospital stay, while TG has advantages in terms of the number of lymph nodes dissected and the incidence of reflux esophagitis. There is no significant difference in long-term survival between the two surgical approaches.

ObjectiveTo investigate the relationship between mitochondrial DNA copy number (mtDNAcn) and cognitive dysfunction, and its mediating role between type 2 diabetes mellitus (T2DM) and cognitive dysfunction. MethodsA case-control study was conducted from May 2019 to April 2021 at the Shanghai Yangpu District Central Hospital, China. A total of 193 subjects were recruited and divided into two groups based on the Montreal Cognitive Assessment (MoCA): normal control (NC) group (n=95) and cognitive impairment group (n=98). The prevalence of T2DM was determined on the basis of medical history, while mtDNAcn in peripheral blood samples was quantified using realtime fluorescent quantitative polymerase chain reaction. ResultsUnivariate analyses revealed that the mean mtDNAcn in the cognitive impairment group was 0.76±0.37, significantly lower than that in the NC group (1.06±0.45) (P<0.05). Logistic regression analyses showed that higher mtDNAcn was associated with a reduced risk of cognitive impairment (OR=0.315, 95%CI: 0.125‒0.795). Additionaly, a statistically significant positive correlation was observed between mtDNAcn and the total MoCA score (r=0.381, P<0.01). Morever, T2DM history (OR=2.741, 95%CI: 1.002‒7.497) and elevated glycosylated hemoglobin (HbA1c) levels (OR=1.796, 95%CI: 1.190‒2.711) were identified as risk factors for cognitive impairment. Mediation analyses indicated that mtDNAcn served as a mediator between T2DM/HbA1c and the risk of cognitive impairment, with proportions of mediating effect of 9.04% and 9.18%, respectively. ConclusionPatients with mild and moderate cognitive impairment have significantly lower mtDNAcn than those with normal cognitive function. Reduced mtDNAcn is an influencing factor for cognitive dysfunction and may play a mediating role in the association between T2DM and mild to moderate cognitive impairment.

Objective: To analyze the mediating effects of self-efficacy and self-management behaviors on the relationship between depression symptoms and glycemic control among elderly patients with type 2 diabetes mellitus (T2DM), so as to provide references for optimizing health management of elderly T2DM patients. Methods: T2DM patients aged ≥60 years from 8 community health service centers in Nanjing City were selected using a convenience sampling method. Basic information such as gender and age was collected through questionnaires. Depressive symptoms, self-efficacy, and self-management behaviors were assessed using the Patient Health Questionnaire, the Diabetes Self-Efficacy Scale, and the Diabetes Self-Management Behavior Scale, respectively. Glycated hemoglobin (HbA1c) was measured to evaluate glycemic control. A mediating effect model was constructed to analyze the mediating effects of self-efficacy and self-management behaviors on the relationship between depressive symptoms and glycemic control. Results: A total of 567 elderly T2DM patients were included, with a median age of 70.00 (interquartile range, 7.50) years. There were 248 males (43.74%) and 319 females (56.26%). The median scores of self-efficacy, self-management behaviors, depressive symptoms, and HbA1c were 3.89 (interquartile range, 0.78), 4.45 (interquartile range, 1.55), 4.00 (interquartile range, 6.00), and 6.80% (interquartile range, 1.40%), respectively. The mediating effect analysis showed that depressive symptoms indirectly affected glycemic control among elderly T2DM patients through the independent mediating effects of self-efficacy (β=0.028, 95%CI: 0.016-0.043) and self-management behaviors (β=0.009, 95%CI: 0.003-0.016), as well as the chain mediating effect of both (β=0.025, 95%CI: 0.017-0.035). The mediating effects of self-efficacy and self-management behaviors accounted for 36.66% and 11.35% of the total effect, respectively, while the chain mediating effect accounted for 32.15% of the total effect. Conclusion Self-efficacy and self-management behaviors play mediating roles in the relationship between depressive symptoms and glycemic control among elderly T2DM patients.

BACKGROUND: Asthma is a common chronic inflammatory airway disease and intermittent hypoxia is increasingly recognized as a factor that may impact disease progression. The present study investigated whether intermittent hypoxia (IH) could aggravate asthma by promoting hypoxia-inducible factor-1α (HIF-1α)/nucleotide-binding oligomerization domain (NOD)-like receptor pyrin domain-containing protein 3 (NLRP3)/interleukin (IL)-1β-dependent pyroptosis and the inflammatory response and further elucidated the underlying molecular mechanisms involved. METHODS: A total of 49 patients diagnosed with severe bronchial asthma and diagnosed by polysomnography were enrolled at Tongji Hospital, Tongji Medical College of Huazhong University of Science and Technology, between January 2022 and December 2022, and their general data and induced sputum were collected. BEAS-2B cells were treated with IL-13 and subjected to IH. An ovalbumin (OVA)-treated mouse model was also used to assess the effects of chronic intermittent hypoxia (CIH) on asthma. Pyroptosis, the inflammatory response, and related signalling pathways were assessed in vivo and in vitro . RESULTS: In this study, as the apnoea and hypopnea index (AHI) increased, the proportion of patients with uncontrolled asthma increased. The proportions of neutrophils and the levels of IL-6, IL-8, HIF-1α and NLRP3 in induced sputum were related to the AHI. NLRP3-mediated pyroptosis, which could be mediated by the HIF-1α signalling pathway, was activated in IL-13 plus IH-treated BEAS-2B cells and in the lungs of OVA/CIH mice. HIF-1α downregulation significantly reduced lung pyroptosis and ameliorated neutrophil inflammation by modulating the NLRP3/IL-1β pathway both in vitro and in vivo . Similarly, pretreatment with LW6, an inhibitor of HIF-1α, effectively blocked the generation of inflammatory cytokines in neutrophils. In addition, administration of the NLRP3 activator nigericin obviously increased lung neutrophil inflammation. CONCLUSIONS Obstructive sleep apnoea-hypopnea syndrome (OSAHS) is a risk factor for asthma exacerbation. IH aggravates neutrophil inflammation in asthma via NLRP3/IL-1β-dependent pyroptosis mediated by the HIF-1α signalling pathway, which should be considered a potential therapeutic target for the treatment of asthma with OSAHS.
NLR Family, Pyrin Domain-Containing 3 Protein/metabolism* ; Humans ; Asthma/metabolism* ; Animals ; Pyroptosis/physiology* ; Hypoxia-Inducible Factor 1, alpha Subunit/metabolism* ; Mice ; Signal Transduction/physiology* ; Male ; Hypoxia/metabolism* ; Female ; Interleukin-1beta/metabolism* ; Adult ; Inflammation/metabolism* ; Middle Aged ; Mice, Inbred C57BL