ObjectiveTo examine the impact of Toll-like receptor 4 （TLR4）-mediated neutrophil extracellular traps （NETs） formation on isoproterenol （ISO）-induced heart failure （HF） in aged mice. MethodsThe mice were randomly divided into Control group， Model group， TAK-242 （TLR4 inhibitor） group， LPS （TLR4 agonist） group and LPS+DNaseⅠ （NETs inhibitor） group， with 8 mice in each group. The HF model was established by continuous infusion of ISO through an osmotic pump， and TAK-242， LPS， and LPS+DNaseⅠ interventions were administered during the last week of infusion for 7 consecutive days. ELISA was used to detect the N-terminal pro-B-type natriuretic peptide （NT-pro BNP）， cardiac troponin I （cTnI）， interleukin-1β （IL-1β）， interleukin-6 （IL-6）， tumor necrosis factor-α （TNF-α）， and serum and myocardial tissue myeloperoxidase-DNA （MPO-DNA） and neutrophil elastase-DNA （NE-DNA） levels. HE staining was used to observe the pathological changes of myocardial tissue. Masson staining was used to observe the deposition of collagen fibers in myocardial tissue. Immunofluorescence was used to observe the colocalization of Ly6G and MPO in myocardial tissue. The protein expressions of TLR4， MPO， NE and cit-H3 in myocardial tissue were detected by Western blot. ResultsCompared with the Control group， the end-diastolic interventricular septal thickness （IVSD）， left ventricular end-diastolic diameter （LVEDD） and left ventricular end-systolic diameter （LVESD） in the Mode group significantly increased （P<0.01）， fractional shortening （FS） and ejection fraction （EF） significantly decreased （P<0.01）， and the myocardial structure was significantly damaged. The myocardial collagen fiber precipitation， serum NT-pro BNP， cTnI， IL-1β， IL-6 and TNF-α contents， MPO-DNA and NE-DNA contents in serum and myocardial tissue significantly increased （P<0.01）. The co-localization of Ly6G and MPO and the expression of TLR4， MPO， NE and cit-H3 proteins in myocardial tissue significantly increased （P<0.01）. After TAK-242 intervention， the above indicators were significantly reversed， while the injury was further aggravated in LPS group. DNaseⅠ treatment could partially alleviate the deterioration of myocardial structure and function induced by LPS. ConclusionTLR4 and NETs are abnormally elevated in the myocardial tissue of aged HF mice. Treatment with the TLR4 inhibitor TAK-242 effectively suppresses NET formation， attenuates inflammatory responses， and enhances cardiac function in aged HF mice.

Objective To explore the effects and mechanism of Dahuang Tangluo Pills on intestinal inflammatory injury in type 2 diabetes mellitus(T2DM)rats based on TLR4/NF-κB signaling pathway.Methods Eight ZDF(fa/+)rats were used as the blank group,and 40 ZDF(fa/fa)rats were fed with high-fat diet and then randomly divided into model group,metformin group(0.18 g/kg metformin)and TCM high-,medium-and low-dosage groups(2.16,1.08,0.54 g/kg Dahuang Tangluo Pills),respectively.The medication groups were gavaged with corresponding dosages for 12 consecutive weeks.The body mass and fasting blood glucose(FBG)of rats before and after intervention were detected.After the intervention,an oral glucose tolerance test(OGTT)was performed,the serum glucose(GLU),glycosylated serum protein(GSP),triglycerides(TG),total cholesterol(TC),low-density lipoprotein cholesterol(LDL-C)and high-density lipoprotein cholesterol(HDL-C)contents were detected.ELISA was used to detect serum fasting insulin(FINS),free fatty acids(FFA)and tumor necrosis factor-α(TNF-α),interleukin(IL)-6,IL-22,lipopolysaccharide(LPS),secreted immunoglobulin A(SIgA)contents in colonic tissue.HE staining was used to observe the morphology of colonic tissue,and Western blot was used to detect the expressions of Toll like receptor 4(TLR4),nuclear factor-κB p65(NF-κB p65),p-NF-κB p65,NF-κB inhibitor α(IκBα),p-IκBα,myeloid differentiation factor 88(MyD88)and zona pellucida protein-1(ZO-1)in colonic tissue.Results Compared with the blank group,the body mass and FBG significantly increased in the model group(P<0.01),blood glucose significantly increased at all time points of OGTT(P<0.01),serum GLU,GSP,TG,TC,LDL-C,FINS,FFA and TNF-α,IL-6,IL-22,LPS contents in colonic tissue significantly increased,serum HDL-C and colonic tissue SIgA contents significantly decreased(P<0.01),with colonic tissue nuclear condensation,cytoplasmic dissolution,inflammatory cell infiltration.The protein expressions of TLR4,NF-κB p65,p-NF-κB p65,p-IκBα and MyD88 in colonic tissue significantly increased,while the protein expressions of IκBα and ZO-1 significantly decreased(P<0.01).Compared with the model group,the body mass and FBG significantly decreased in metformin group,TCM high-and medium-dosage groups(P<0.01),blood glucose decreased at different time points of OGTT,and serum GLU,GSP,TG,TC,LDL-C,FINS,FFA and TNF-α,IL-6,IL-22,LPS contents in colonic tissue significantly decreased,serum HDL-C and colonic tissue SIgA contents significantly increased(P<0.05,P<0.01),with significant improvement in colonic tissue structure and reduction in inflammatory cell infiltration.The protein expressions of TLR4,NF-κB p65,p-NF-κB p65,p-IκBα and MyD88 in colonic tissue significantly decreased,while the proteins expression of IκBα and ZO-1 significantly increased(P<0.05,P<0.01).Conclusion Dahuang Tangluo Pills may inhibit the activation of the TLR4/NF-κB signaling pathway,reduce the release of inflammatory factors,improve intestinal inflammatory injury,restore intestinal homeostasis,thereby improving glucose and lipid metabolism and exerting therapeutic effects on T2DM.

Objective:To explore the assessment value of ultrasound scoring system combined with shear wave elastography(SWE)on curative effect of IgG4-related submandibular and lacrimal gland inflammation.Methods:This study was a prospective cohort study.A total of 103 patients with IgG4-related submandibular and/or lacrimal gland inflammation who admitted to the Department of Rheumatology and Immunology of Beijing Friendship Hospital,Capital Medical University from September 2022 to December 2024 were consecutively included.They were divided into an effective group(45 cases)and a non-effective group(58 cases)based on the curative effect.All patients were assessed by conventional ultrasound and SWE before and after treatment.Logistic regression analysis was used to determine the independent influencing factors of assessing the curative effect,and then,a receiver operating characteristic(ROC)curve and nomograms were drawn.Results:There were no statistically significant differences in gender and age between the effective group and the non-effective group(P>0.05).The difference between the submandibular and lacrimal gland score,change rate of score,difference of mean Young's modulus(Emean),Emean change rate,difference of maximum value of Young's modulus(Emax),and Emax change rate in the effective group were all higher than those in the non-effective group,and the differences were statistically significant(Z=-7.916,-7.680,-6.767,-6.722,-6.360,-5.957,P<0.05),respectively.The difference between the submandibular and lacrimal gland score(OR=2.90,P<0.001)and the Emax difference(OR=1.18,P<0.05)had diagnostic value for assessing the curative effectiveness.The area under curve(AUC)value,sensitivity,specificity and accuracy of the difference between submandibular and lacrimal gland score were respectively 0.945,88.9%,94.8%and 87.4%in assessing the curative effectiveness.The above indicators of Emax difference were respectively 0.866,86.7%,70.7%and 77.7%in assessing the curative effectiveness.The above indicators of the combination of them were respectively 0.976,93.3%,94.8%and 94.2%.Conclusion:The combination of the conventional ultrasound scoring system and SWE has higher diagnostic value in assessing the curative effect of IgG4-related submandibular and lacrimal gland inflammation.The combined application can significantly improve the accuracy and provide reliable imaging reference for clinical practice.

In recent years,the incidence of breast cancer among Chinese women has been increasing annually,with its poor prognosis and high mortality rates presenting major challenges in current breast cancer treatment.Breast cancer stem cells(BCSCs)are the key factors which leading to the occurrence,development,treatment resistance,and recurrence of breast cancer.A high proportion of BCSCs are also closely related to adverse outcome of breast cancer patients.However,traditional drugs are difficult to effectively eliminate BCSCs and may even increase their enrichment level.Therefore,developing therapeutic strategies specifically targeting BCSCs represents a critical breakthrough for improving treatment efficacy in breast cancer patients.Significant progresses have been made in this field,including the development of various inhibitors targeting BCSCs surface markers,key signaling pathways,and immune checkpoints,as well as advances in nano-drug delivery systems(NDDS)and the discovery of numerous novel targets,offering new directions for breast cancer treatment.This paper systematically reviews recent advances and existing challenges in BCSCs-targeted therapies,and outlines future directions,aiming to provide new insights for both clinical practice and scientific research in breast cancer treatment.

Automotive antifreeze, being colorless and odorless, can easily cause acute poisoning if ingested. Acute poisoning can lead to damage to the central nervous system, digestive system, and kidney function, and may even result in death. This article analyzes the clinical data, diagnostic and therapeutic processes, and outcomes of two patients admitted to the Department of Poisoning and Occupational Diseases, Emergency Medicine of Qilu Hospital, Shandong University, who suffered acute poisoning due to ingesting antifreeze. The findings aim to provide a reference for clinicians in the diagnosis and treatment of antifreeze poisoning.

This article analyzes the treatment process of a patient with respiratory failure caused by occupational acute acetonitrile poisoning. Due to operational errors, the patient's body was sprayed with a large amount of acetonitrile liquid, leading to the absorption of acetonitrile through the skin and resulting in acute poisoning. The clinical manifestations were nervous system and respiratory system damage, accompanied by severe lactic acidosis. After active comprehensive treatments such as tracheal intubation, mechanical ventilation, continuous renal replacement therapy (CRRT) , and glucocorticoids, the patient basically recovered. The treatment process of this patient indicates that early identification and correct first aid of acetonitrile poisoning are the keys to improving prognosis and can provide a reference for the handling of similar clinical cases.

Increasing evidence showed that histone deacetylase 6 (HDAC6) dysfunction is directly associated with the onset and progression of various diseases, especially cancers, making the development of HDAC6-targeted anti-tumor agents a research hotspot. In this study, artificial intelligence (AI) technology and molecular simulation strategies were fully integrated to construct an efficient and precise drug screening pipeline, which combined Voting strategy based on compound-protein interaction (CPI) prediction models, cascade molecular docking, and molecular dynamic (MD) simulations. The biological potential of the screened compounds was further evaluated through enzymatic and cellular activity assays. Among the identified compounds, Cmpd.18 exhibited more potent HDAC6 enzyme inhibitory activity (IC₅₀ = 5.41 nM) than that of tubastatin A (TubA) (IC₅₀ = 15.11 nM), along with a favorable subtype selectivity profile (selectivity index ≈ 117.23 for HDAC1), which was further verified by the Western blot analysis. Additionally, Cmpd.18 induced G2/M phase arrest and promoted apoptosis in HCT-116 cells, exerting desirable antiproliferative activity (IC₅₀ = 2.59 μM). Furthermore, based on long-term MD simulation trajectory, the key residues facilitating Cmpd.18's binding were identified by decomposition free energy analysis, thereby elucidating its binding mechanism. Moreover, the representative conformation analysis also indicated that Cmpd.18 could stably bind to the active pocket in an effective conformation, thus demonstrating the potential for in-depth research of the 2-(2-phenoxyethyl)pyridazin-3(2H)-one scaffold.

Prostate cancer (PCa) is the most common urological malignancy in men worldwide, and its incidence is increasing annually. Radiotherapy is one of the main treatment methods for PCa. However, some patients still have recurrence, local progression, and even distant metastasis after receiving radical radiotherapy. As an emerging tumor treatment strategy, immunotherapy has made great progress in the treatment of various solid tumors. Owing to the inherent immune escape mechanism of PCa, the efficacy of immunotherapy is unsatisfactory. Therefore, new combined strategies must be explored to improve the efficacy of immunotherapy for PCa. With the in-depth study of the tumor immune microenvironment, the immunomodulatory effect of radiotherapy has gradually attracted attention. Researchers found that the immunomodulatory effect of radiotherapy depends on the dose. Low-dose radiotherapy can enhance tumor immunogenicity by remodeling the tumor microenvironment, whereas high-dose radiotherapy can further activate the innate immune signaling pathway by directly inducing the immunogenic necrosis of tumor cells. Therefore, the synergistic strategy of radiotherapy and immunotherapy has become a research hotspot. This work aims to review the regulatory effect of radiotherapy on PCa antitumor immunity, clarify the latest progress and potential clinical value of radiotherapy combined with immunotherapy, and provide a theoretical basis and new research directions for optimizing the combination immunotherapy strategies for prostate cancer.

Gastric cancer with peritoneal metastasis (GCPM) is a common and lethal manifestation of advanced gastric cancer, with a median survival of only 5-11 months. This consensus was developed by 30 experts from Asia (China, Japan, Korea, and Singapore) using the Delphi method and the GRADE evidence grading system. A total of 29 statements were formulated, covering the diagnosis and assessment of GCPM, indications for laparoscopic exploration and NIPS (normothermic intraperitoneal and systemic treatment), treatment regimens, prevention and management of complications, criteria for conversion surgery, and postoperative intraperitoneal therapy. The consensus aims to standardize clinical practice and improve the prognosis of patients with GCPM.

ObjectiveTo evaluate the quality of Lygodium japonicum (Thunb.) Sw. (L. japonicum, Hai Jin Sha) by comparing its components without stewed (W) and stewed (S) using ultra-high-performance liquid chromatography (UHPLC) and chemometric analysis. Additionally, network pharmacology was employed to investigate the possible mechanisms of action of L. japonicum in the urinary calculi (UC) treatment.MethodsA fingerprinting method was established to identify components through UHPLC-tandem mass spectrometry. Chemometric techniques were used to compare the L. japonicum extraction methods. Furthermore, various network pharmacological approaches were used to identify and analyze the potential targets of the identified components in relation to UC.ResultsThe W and S extracts were distributed into two distinct clusters. Significant differences in the levels of protocatechuic aldehyde, caffeic acid, and p-coumaric acid were observed between S and W. Network pharmacology analysis revealed that the primary targets of L. japonicum in the UC treatment were serum albumin and epidermal growth factor receptors, with potential active components including protocatechuic acid and caffeic acid.ConclusionThis study comprehensively examined the therapeutic components of L. japonicum before and after boiling, shedding light on its potential mechanisms of action in UC treatment. These findings offer valuable insights into the development and utilization of L. japonicum resources.