ObjectiveTo investigate the mechanism of action of Kaixinsan in the treatment of Alzheimer's disease （AD） based on network pharmacology， molecular docking， and animal experimental validation. MethodsThe Traditional Chinese Medicine Systems Pharmacology Database and Analysis Platform（TCMSP） and the Encyclopedia of Traditional Chinese Medicine（ETCM） databases were used to obtain the active ingredients and targets of Kaixinsan. GeneCards， Online Mendelian Inheritance in Man（OMIM）， TTD， PharmGKB， and DrugBank databases were used to obtain the relevant targets of AD. The intersection （common targets） of the active ingredient targets of Kaixinsan and the relevant targets of AD was taken， and the network interaction analysis of the common targets was carried out in the STRING database to construct a protein-protein interaction（PPI） network. The CytoNCA plugin within Cytoscape was used to screen out the core targets， and the Metascape platform was used to perform gene ontology（GO） functional enrichment analysis and Kyoto encyclopedia of genes and genomes（KEGG） pathway enrichment analysis. The “drug-active ingredient-target” interaction network was constructed with the help of Cytoscape 3.8.2， and AutoDock Vina was used for molecular docking. Scopolamine （SCOP） was utilized for modeling and injected intraperitoneally once daily. Thirty-two male C57/BL6 mice were randomly divided into blank control （CON） group （0.9% NaCl， n=8）， model （SCOP） group （3 mg·kg^-1·d^-1， n=8）， positive control group （3 mg·kg^-1·d^-1 of SCOP+3 mg·kg^-1·d^-1 of Donepezil， n=8）， and Kaixinsan group （3 mg·kg^-1·d^-1 of SCOP+6.5 g·kg^-1·d^-1 of Kaixinsan， n=8）. Mice in each group were administered with 0.9% NaCl， Kaixinsan， or Donepezil by gavage twice a day for 14 days. Morris water maze experiment was used to observe the learning memory ability of mice. Hematoxylin-eosin （HE） staining method was used to observe the pathological changes in the CA1 area of the mouse hippocampus. Enzyme linked immunosorbent assay（ELISA） was used to determine the serum acetylcholine （ACh） and acetylcholinesterase （AChE） contents of mice. Western blot method was used to detect the protein expression levels of signal transducer and activator of transcription 3（STAT3） and nuclear transcription factor（NF）-κB p65 in the hippocampus of mice. ResultsA total of 73 active ingredients of Kaixinsan were obtained， and 578 potential targets （common targets） of Kaixinsan for the treatment of AD were screened out. Key active ingredients included kaempferol， gijugliflozin， etc.. Potential core targets were STAT3， NF-κB p65， et al. GO functional enrichment analysis obtained 3 124 biological functions， 254 cellular building blocks， and 461 molecular functions. KEGG pathway enrichment obtained 248 pathways， mainly involving cancer-related pathways， TRP pathway， cyclic adenosine monophosphate（cAMP） pathway， and NF-κB pathway. Molecular docking showed that the binding of the key active ingredients to the target targets was more stable. Morris water maze experiment indicated that Kaixinsan could improve the learning memory ability of SCOP-induced mice. HE staining and ELISA results showed that Kaixinsan had an ameliorating effect on central nerve injury in mice. Western blot test indicated that Kaixinsan had a down-regulating effect on the levels of NF-κB p65 phosphorylation and STAT3 phosphorylation in the hippocampal tissue of mice in the SCOP model. ConclusionKaixinsan can improve the cognitive impairment function in SCOP model mice and may reduce hippocampal neuronal damage and thus play a therapeutic role in the treatment of AD by regulating NF-κB p65， STAT3， and other targets involved in the NF-κB signaling pathway.

AIM: To investigate and clarify the intervention mechanism of trigonelline(TRG)in preventing ferroptosis in ARPE-19 cells based on the Nrf2/HO-1/GPX4 pathway.METHODS: The ARPE-19 cells were cultured and subsequently treated with varying concentrations of trigonelline to ascertain the most effective concentration for modulating the cells. Then the cells were categorized into distinct groups, including normal control(NC)group, high glucose(HG)group, Fer-1 group, TRG group based on the determined concentration. Samples from each group were then gathered to assess relevant indicators. The intracellular levels of glutathione(GSH), malondialdehyde(MDA), and Ferrion were quantified in accordance with the protocols provided by the GSH, MDA, and Ferrion detection kits. Flow cytometry was employed to measure the ROS levels within each group. Additionally, Western blot analysis was conducted to examine the expression of nuclear factor erythroid 2-related factor 2(Nrf2), heme oxygenase-1(HO-1), glutathione peroxidase(GPX4), and acyl-CoA synthetase long-chain family member 4(ACSL4)across the different groups.RESULTS: The preconditioning intervention with 40 μg/mL TRG effectively mitigated the decline in cell activity induced by high glucose levels. The levels of reactive oxygen species(ROS)and MDA in the HG group were markedly elevated compared to the NC group; and the TRG group exhibited significantly reduced levels of ROS and MDA compared to those of the HG group, with the antioxidant stress index GSH showing opposite trends to those of ROS and MDA across all the groups. Whereas the Fer-1 and TRG groups showed decreased expression levels of ACSL4 protein and iron ions, and the expression levels of Nrf2, HO-1 and GPX4 in the Fer-1 and TRG groups were increased.CONCLUSION: TRG protects ARPE-19 cells from the detrimental effects of high glucose by targeting the Nrf2/HO-1/GPX4 signaling pathway to counter ferroptosis.

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.

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.

Probiotics have shown excellent application prospects in preventing and treating many diseases. However, their sensitivity to the harsh environment in vivo always leads to a massive loss of viability and insufficient therapeutic effect. Fortunately, modified probiotics have emerged and provide multiple possibilities for their use in various diseases. Modification not only endows probiotics with extra capacity to resist severe environments but also gives them exogenous characteristics, such as prolonged retention time and improved therapeutic effects. Modified probiotics could combine with other therapies, which has opened up new avenues to enhance the efficacy of probiotic-based therapy. In this review, we have summarized the current physicochemical and biological modification strategies of probiotics. In addition, the progress of research on probiotic-based combination therapy has also been extensively reviewed, which contributes to the enhanced delivery of probiotics or other active constituents and provides new ideas for disease treatment, bioimaging, and diagnosis.

Tongue squamous cell carcinoma (TSCC) is a prevalent malignancy that afflicts the head and neck area and presents a high incidence of metastasis and invasion. Accurate diagnosis and effective treatment are essential for enhancing the quality of life and the survival rates of TSCC patients. The current treatment modalities for TSCC frequently suffer from a lack of specificity and efficacy. Nanoparticles with diagnostic and photothermal therapeutic properties may offer a new approach for the targeted therapy of TSCC. However, inadequate accumulation of photosensitizers at the tumor site diminishes the efficacy of photothermal therapy (PTT). This study modified gold nanodots (AuNDs) with the TSCC-targeting peptide HN-1 to improve the selectivity and therapeutic effects of PTT. The Au-HN-1 nanosystem effectively targeted the TSCC cells and was rapidly delivered to the tumor tissues compared to the AuNDs. The enhanced accumulation of photosensitizing agents at tumor sites achieved significant PTT effects in a mouse model of TSCC. Moreover, owing to its stable long-term fluorescence and high X-ray attenuation coefficient, the Au-HN-1 nanosystem can be used for fluorescence and computed tomography imaging of TSCC, rendering it useful for early tumor detection and accurate delineation of surgical margins. In conclusion, Au-HN-1 represents a promising nanomedicine for imaging-based diagnosis and targeted PTT of TSCC.
Tongue Neoplasms/diagnostic imaging* ; Carcinoma, Squamous Cell/diagnostic imaging* ; Animals ; Gold/chemistry* ; Mice ; Photothermal Therapy/methods* ; Tomography, X-Ray Computed ; Photosensitizing Agents ; Metal Nanoparticles ; Humans ; Cell Line, Tumor

Objective:To assess the clinical features and effectiveness of antiviral therapy in newborns with sensorineural hearing loss (SNHL) caused by congenital congenital cytomegalovirus (cCMV) infection, and to speculate the risk factors for poor hearing outcomes.Methods:A multicenter prospective cohort study wasconducted, enrolling 176 newborns diagnosed with cCMV at four research centers in Zhejiang Province from March 1, 2021, to April 30, 2024. Clinical characteristics at birth were recorded and hearing was followed up. The children were divided into groups based on their condition at birth, specifically into asymptomatic, mild symptom, and moderate to severe symptom groups. Additionally, they were divided into SNHL and normal hearing groups based on the results of air conduction brainstem audiometry at birth. And they were also divided into treatment and untreated groups according to antiviral treatment. Mann Whitney U test, and chi square test were used for inter group comparison to analyze the differences in clinical features between different disease groups, and to analyze the effects of clinical features, antiviral therapy, and other factors on hearing improvement. Logistic regression analysis was employed to identify the risk factors influencing hearing outcomes. Results:Among the cohort of 176 children diagnosed infection with cCMV, 90 cases were male and 86 cases were female. Of these, 79 cases were asymptomatic, 12 cases classified as mild cCMV and 85 cases as moderate to severe cCMV. Fifty cases belonged to SNHL group, with different degrees of severity, including 30 cases of mild, 9 cases of moderate, 5 cases of severe, and 6 cases of extremely severe SNHL. Among the 121 cases in the normal hearing group, 2 cases (1.7%) exhibited late-onset hearing loss despite having normal hearing at birth. Among 81 cases (46.0%) who completed the hearing follow-up, 71 cases (87.7%) had good hearing outcomes and 10 cases (12.3%) had poor hearing outcomes. Among the 81 children, 29 cases (35.8%) had SNHL at birth. During follow-up, the hearing threshold improved in 19 cases (65.5%), remained stable in 7 cases (24.1%) and progressed in 3 cases (10.3%). A total of 26 cases in the treatment group and 55 cases in the untreated group completed the hearing follow-up assessment. The rate of hearing improvement in the treatment group was found to be higher compared to the untreated group (13 cases (50.0%) vs. 6 cases (10.9%), χ2=15.00, P<0.01), with individuals in the treatment group having a 4.58 times greater likelihood of experiencing hearing improvement ( RR=4.58,95% CI 1.96-10.70, P<0.05). However, no statistically significant difference was observed in hearing outcomes between the antiviral treatment group and the untreated group ( RR=0.90, 95% CI 0.57-1.41, P=0.517). Multivariate analysis further confirmed SNHL ( OR=11.58, 95% CI 2.10-63.93, P=0.005) and preterm birth ( OR=4.98, 95% CI 1.06-23.41, P=0.042) as independent risk factors for poor hearing outcomes. Conclusions:SNHL resulting from cCMV infection presents symptoms at birth and can be improved by antiviral therapy. Poor hearing outcomes are associated with SNHL and prematurity.

Background::Liver cancer remains the sixth most commonly diagnosed cancer and the third leading cause of cancer-related deaths worldwide, causing a heavy burden globally. An updated assessment of the global epidemiology of the liver cancer burden that addresses geographical disparities is necessary to better understand and promote healthcare delivery.Methods::Data were extracted from the GLOBOCAN 2022 database, including the number, crude, and age-standardized rates of incidence and mortality at the global, country, continent, and human development index (HDI) regional levels. Age-standardized rates (incidence and mortality) per 100,000 person-years were adjusted based on the Segi-Doll World standard population. The mortality-to-incidence ratios (MIR) for each region and country were calculated. The HDI and gross national income (GNI) for 2022 were obtained, and a Pearson correlation analysis was conducted with the incidence, mortality, and MIR.Results::In 2022, approximately 866,136 new liver cancer cases and 758,725 related deaths were recorded worldwide, with a global MIR of 0.86. Males had a disproportionately higher burden than females across all levels, and the highest burden was observed in the elderly population. Geographically, the regions with the highest incidence rates included Micronesia, Eastern Asia, and Northern Africa, and the regions with the highest mortality rates included Northern Africa, Southeastern Asia, Eastern Asia, and Micronesia. Notably, Mongolia had a strikingly high burden compared to other countries. The highest MIR was observed in North America and the lowest in Africa. Negative associations of HDI and GNI with liver cancer mortality and MIR were identified, irrespective of sex.Conclusions::The current liver cancer burden underscores the presence of remarkable geographic heterogeneity, which is particularly evident across countries with varying HDI levels, highlighting the urgent need to prioritize health accessibility and availability to achieve health inequities.