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.

ObjectiveThis study aimed to elucidate the specific molecular mechanism by which PAGE5 promotes breast cancer cell invasion and hepatic metastasis through regulating the PI3K/AKT signaling pathway and its downstream effector， matrix metalloproteinase 1 （MMP1）. MethodsBioinformatics analysis using the TCGA database was performed to evaluate PAGE5 expression in metastatic breast cancer tissues. The effects of PAGE5 on the proliferation， migration， and invasion capabilities of breast cancer cells were analyzed using CCK-8， EdU， Transwell， and wound healing assays. A splenic injection hepatic metastasis model in NOD-SCID mice was employed to validate the impact of PAGE5 on breast cancer liver metastasis. Transcriptome sequencing and KEGG enrichment analysis were conducted to identify potential signaling pathways regulated by PAGE5. Western blot was used to detect AKT phosphorylation levels. Quantitative real-time polymerase chain reaction （qPCR） was applied to screen and validate downstream target molecules of PAGE5. ResultsBioinformatic analysis revealed that PAGE5 expression was significantly upregulated in distant metastasis of breast cancer. Both in vitro and in vivo experiments confirmed that PAGE5 overexpression markedly enhanced the migration and invasion abilities of breast cancer cells and promoted the formation of liver metastatic lesions， whereas PAGE5 knockdown suppressed breast cancer liver metastasis （P＜0.000 1）. Transcriptome sequencing and KEGG enrichment analysis indicated that PAGE5 significantly activated the PI3K-AKT signaling pathway （P=0.028 5）. Western blot confirmed that PAGE5 upregulated p-AKT levels， which could be reversed by MK2206. The qPCR results confirmed that MMP1 is a key downstream effector of PAGE5， and its expression can be inhibited by MK2206 （P＜0.000 1）. ConclusionsThis study preliminarily demonstrates that PAGE5 can activate the PI3K/AKT signaling pathway and mediate the invasion and liver metastasis of breast cancer through MMP1.

ObjectiveThis study aimed to elucidate the specific molecular mechanism by which PAGE5 promotes breast cancer cell invasion and hepatic metastasis through regulating the PI3K/AKT signaling pathway and its downstream effector， matrix metalloproteinase 1 （MMP1）. MethodsBioinformatics analysis using the TCGA database was performed to evaluate PAGE5 expression in metastatic breast cancer tissues. The effects of PAGE5 on the proliferation， migration， and invasion capabilities of breast cancer cells were analyzed using CCK-8， EdU， Transwell， and wound healing assays. A splenic injection hepatic metastasis model in NOD-SCID mice was employed to validate the impact of PAGE5 on breast cancer liver metastasis. Transcriptome sequencing and KEGG enrichment analysis were conducted to identify potential signaling pathways regulated by PAGE5. Western blot was used to detect AKT phosphorylation levels. Quantitative real-time polymerase chain reaction （qPCR） was applied to screen and validate downstream target molecules of PAGE5. ResultsBioinformatic analysis revealed that PAGE5 expression was significantly upregulated in distant metastasis of breast cancer. Both in vitro and in vivo experiments confirmed that PAGE5 overexpression markedly enhanced the migration and invasion abilities of breast cancer cells and promoted the formation of liver metastatic lesions， whereas PAGE5 knockdown suppressed breast cancer liver metastasis （P＜0.000 1）. Transcriptome sequencing and KEGG enrichment analysis indicated that PAGE5 significantly activated the PI3K-AKT signaling pathway （P=0.028 5）. Western blot confirmed that PAGE5 upregulated p-AKT levels， which could be reversed by MK2206. The qPCR results confirmed that MMP1 is a key downstream effector of PAGE5， and its expression can be inhibited by MK2206 （P＜0.000 1）. ConclusionsThis study preliminarily demonstrates that PAGE5 can activate the PI3K/AKT signaling pathway and mediate the invasion and liver metastasis of breast cancer through MMP1.

It is considered that although meibomian gland dysfunction （MGD）-associated dry eye is mainly manifested by signs of dryness such as ocular dryness and burning sensation， it may also be accompanied by signs of dampness， including thick meibomian secretions， epigastric and abdominal fullness， and a greasy tongue coating， thus presenting a pattern characterized by the coexistence of dryness and dampness. Based on LIU Wansu's theory of "promoting the flow of dampness to moisten dryness"， this disease is understood from the perspectives of an imbalance between dryness and dampness in the middle jiao （焦） and abnormal distribution of body fluids. For dampness and turbidity constraint and stagnation， treatment should focus on diffusing the lung， fortifying the spleen， promoting the flow of dampness， and resolving turbidity， with modified Sanren Decoction （三仁汤） combined with Shenling Baizhu Powder （参苓白术散） commonly used. For steaming of dampness-heat， treatment should focus on clearing heat， draining dampness， and moistening dryness with sweet and cool medicinals， with modified Jinzhi Qingmu Formula （金栀清目方） combined with Shashen Maidong Decoction （沙参麦冬汤） commonly used. For dryness-toxin damaging the physical form， treatment should focus on nourishing yin and blood， unblocking the collaterals， and resolving toxins， with modified Qiju Dihuang Pill （杞菊地黄丸） combined with Taohong Siwu Decoction （桃红四物汤） commonly used.

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.

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.

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.

Objective:Exploring the association between Life's Crucial 9 (LC9) and the risk of thyroid dysfunction (TD), as well as its potential predictive capacity.Methods:A total of 247 600 TD-free participants from the UK Biobank were enrolled in the study. The LC9 score was divided into three CVH groups: low (0-), medium (50-), and high (80-100). Cox proportional hazards regression models were used to calculate the HRs and 95% CIs of the risk of TD with LC9 CVH status. Calculate Harrell's concordance index ( C-index), net reclassification improvement (NRI), and integrated discrimination improvement (IDI) to evaluate the predictive ability of the LC9 score and Life's Essential 8 (LE8) score. Results:During a median follow-up of 12.3 years, 5 515, 911, and 4 869 new cases of TD, hyperthyroidism, and hypothyroidism were documented, respectively. Participants with a high LE8 CVH group had 57.00% ( HR=0.43, 95% CI: 0.38-0.49), 55.00% ( HR=0.45, 95% CI: 0.34-0.60), and 58.00% ( HR=0.42, 95% CI: 0.37-0.47) lower risk of TD, hyperthyroidism, and hypothyroidism, respectively, than those with low CVH group. Compared with the LE8 score, the improvement in C-index for the LC9 score predicted TD risk was 0.004 (95% CI: 0.001-0.007), the NRI was 0.101 (95% CI: 0.021-0.103), and the IDI was 0.001 (95% CI: 0.000-0.001). Conclusions:The better CVH status, defined by LC9, was associated with a lower risk of TD. Compared to the LE8 score, the LC9 score demonstrated a significant enhancement in both risk discrimination and reclassification capability for TD risk.