Various therapeuti modailities have been engineered for lung cancer treatment, but their clinic application is severely impeded by the poor therapy efficiency and immunosuppressive microenvironment. Herein, we fabricated a library of small molecule redox-labile nanoparticles (NPs) (i.e., diPTX-2C NPs, diPTX-2S NPs, and diPTX-2Se NPs) by the self-assembly of dimer paclitaxel (PTX) prodrug, and then utilized these NPs with the traditional Chinese medicine (TCM) Qi-Yu-San-Long-Fang (Q) for effective chemoimmunotherapy on Lewis lung carcinoma (LLC)-bearing mice models. Under the high concentration of glutathione (GSH) and H₂O₂, diPTX-2Se NPs could specifically release PTX in cancer cells and exert a higher selectivity and toxicity than normal cells. In LLC tumor-bearing mice, oral administration of Q not only effectively downregulated programmed death ligand-1 (PD-L1) expression, but also remodeled the immunosuppressive tumor immune microenvironment via the increase of CD4⁺ T and CD8⁺ T cell proportion and the repolarization of M2 into M1 macrophages in tumor tissues, collectively achieving superior synergistic treatment outcomes in combination with intravenous PTX prodrug NPs. Besides, we found that the combination regimen also demonstrated excellent chemoimmunotherapeutic performances on low-dose small established tumor and high-dose large established tumor models. This study may shed light on the potent utilization of Chinese and Western-integrative strategy for efficient tumor chemoimmunotherapy.

In order to understand the difference and expression of genes in CEK cells before and af-ter baicalin interferes with IBV,further reveal and analyze the mechanism of baicalin interfering IBV replication in CEK cells in vitro.After IBV infected CEK cells for 2 h,9.75 mg/L baicalin liq-uid was added to interfere with CEK cells,which was recorded as the baicalin(H-IBV)group,and three replicate wells were set in the control group and the IBV(IBV)infection group.After 36 h culture,cell samples were collected and subject to transcriptome for sequencing.The results showed that there were 102 differentially expressed genes in H-IBV group compared with IBV in-fection group,among which 48 genes weresignificantly up-regulated and 54 genes were significantly down-regulated.Through functional annotation in GO and KEGG databases,it was found that dif-ferentially expressed genes were mainly annotated in biological processes such as cellular proces-ses,biological regulation,metabolism,and secondary pathways such as viral infectious diseases,signal transduction and interaction.Retinol metabolism pathway,phospholipid transfer to mem-brane,IL-27 mediated signaling pathway,MDA5/RIG-I and Toll-like receptor signaling pathway were significantly enriched in CEK cells,and the production of type Ⅰ interferon and interferon al-pha and the process of antiviral infection were also positively regulated.There were more differen-tial genes enriched in nucleic acid catalysis,immune system,and reaction,and interbiological reac-tion.Through the STRING network interaction map,it was found that most immune-related genes could form a 36-node interaction network centered on IRF7,TLR3 and STAT1.Therefore,com-pared with IBV group,the differentially expressed genes after baicalin treatment were mainly an-notated and enriched in the biological process,and the immune system and response were en-hanced,mainly through the positive regulation of IRF7 in the MDA5/RIG-I receptor signaling pathway and the inhibition of TLR3 signal transduction in the Toll-like receptor signaling path-way.Positive regulation of IL-27 mediated pathway and regulation of JAK-STAT signaling path-way were supplemented by activation of the expression of IRF7,TLR3,STAT1 and other related genes,and interaction with corresponding downstream proteins to promote the expression of IFN-α and regulatory cytokines,coupled with negative regulation of viral(defense)response and viral processes.Thus,baicalin interferes with IBV replication in CEK cells.

Objective:To investigate the correlation and predictive value of fibrinogen-to-albumin ratio (FAR) and clinical outcomes after intravenous thrombolysis in patients with acute ischemic stroke.Methods:Patients with acute ischemic stroke received intravenous thrombolysis treatment at Fuyang People's Hospital from November 2019 to August 2022 were retrospectively included. Their clinical, imaging, and laboratory data were collected. After 3 months of onset, a modified Rankin Scale was used for clinical outcome evaluation and a score >2 were defined as poor outcome. Multivariate logistic regression analysis was used to determine the correlation between FAR and poor outcome. Receiver operating characteristic (ROC) curve was used to evaluate the predictive value of FAR on adverse outcomes after intravenous thrombolysis in patients with acute ischemic stroke. Results:A total of 162 patients were included. There were 114 patients (70.4%) in the good outcome group and 48 (29.6%) in the poor outcome group. Univariate analysis showed that the baseline National Institutes of Health Stroke Scale (NIHSS) score, fasting blood glucose, fibrinogen, and FAR in the poor outcome group were significantly higher than those in the good outcome group, while the serum albumin was significantly lower than that of the good outcome group (all P<0.05). Multivariate logistic regression analysis showed that the baseline NIHSS score (odds ratio [ OR] 1.176, 95% confidence interval [ CI] 1.082-1.227; P<0.001), fasting blood glucose ( OR 1.206, 95% CI 1.018-1.430; P=0.030), and FAR ( OR 1.448, 95% CI 1.449-1.824; P=0.002) were the independent risk factors for poor outcome. The ROC curve analysis showed that the area under the curve of FAR for predicting poor outcomes was 0.706 (95% CI 0.616-0.796). When the FAR cutoff value was 8.06, the sensitivity and specificity were 66.7% and 78.2%, respectively. Conclusion:There is a significant correlation between FAR and outcomes after intravenous thrombolysis therapy in patients with acute ischemic stroke. Higher FAR has certain predictive value for poor outcomes of patients.

OBJECTIVE: To investigate the effect of calmodulin (CaM) and its mutants on binding to voltage-gated Na channel isoleucine-glutamine domain (Na1.2 IQ). METHODS: The cDNA of Na1.2 IQ was constructed by PCR technique, CaM mutants CaM, CaM and CaM were constructed with Quickchange site-directed mutagenesis kit (QIAGEN). The binding of Na1.2 IQ to CaM and CaM mutants under calcium and calcium free conditions were detected by pull-down assay. RESULTS: Na1.2 IQ and CaM were bound to each other at different calcium concentrations, while GST alone did not bind to CaM. The binding affinity of CaM and Na1.2 IQ at [Ca]-free was greater than that at 100 nmol/L [Ca] ( < 0.05). In the absence of calcium, the binding amount of CaM wild-type to Na1.2 IQ was greater than that of its mutant, and the binding affinity of CaM to Na1.2 IQ was the weakest among the three mutants ( < 0.05). CONCLUSIONS The binding ability of CaM and CaM mutants to Na1.2 IQ is Ca-dependent. This study has revealed a new mechanism of Na1.2 regulated by CaM, which would be useful for the study of ion channel related diseases.
Calcium ; metabolism ; Calmodulin ; genetics ; metabolism ; Mutation ; NAV1.2 Voltage-Gated Sodium Channel ; metabolism ; Protein Binding ; genetics

Objective: To analyze influencing factors for depressive symptoms in the elderly aged 65 years and older in 8 longevity areas in China. Methods: We recruited 2 180 participants aged 65 years and older in 8 longevity areas from Healthy Aging and Biomarkers Cohort Study, a sub-cohort of the Chinese Longitudinal Healthy Longevity Survey in 2017. Multivariate logistic regression analysis was performed to evaluate the relationships of socio-demographic characteristics, behavioral lifestyle, chronic disease prevalence, functional status, family and social support with depressive symptoms in the elderly. Results: The detection rate of depression symptoms was 15.0% in the elderly aged 65 years and older in 8 longevity areas of China, and the detection rate of depression symptoms was 11.5% in men and 18.5% in women. Multivariate logistic regression analysis results showed that the detection rate of depressive symptoms was lower in the elderly who had regular physical exercises (OR=0.44, 95%CI: 0.26-0.74), frequent fish intakes (OR=0.57, 95%CI: 0.39-0.83), recreational activities (OR=0.65, 95%CI: 0.44-0.96), social activities (OR=0.28, 95%CI: 0.11-0.73) and community services (OR=0.68, 95%CI: 0.50-0.93). The elderly who were lack of sleep (OR=2.04, 95%CI: 1.49-2.80), had visual impairment (OR=1.54, 95%CI: 1.08-2.18), had gastrointestinal ulcer (OR=2.97, 95%CI: 1.53-5.77), had arthritis (OR=2.63, 95%CI: 1.61-4.32), had higher family expenditure than income (OR=1.80, 95%CI: 1.17-2.78) and were in poor economic condition (OR=4.58, 95%CI: 2.48-8.47) had higher detection rate of depressive symptoms. Conclusion The status of doing physical exercise, fish intake in diet, social activity participation, sleep quality or vision, and the prevalence of gastrointestinal ulcers and arthritis were associated with the detection rate of depressive symptoms in the elderly.

Objective: To establish a prediction model for 6-year incidence risk of chronic kidney disease (CKD) in the elderly aged 65 years and older in China. Methods: In this prospective cohort study, we used the data of 3 742 participants collected during 2008/2009-2014 and during 2012-2017/2018 from Healthy Aging and Biomarkers Cohort Study, a sub-cohort of the Chinese Longitudinal Healthy Longevity Survey. Two follow up surveys for renal function were successfully conducted for 1 055 participants without CKD in baseline survey. Lasso method was used for the selection of risk factors. The risk prediction model of CKD was established by using Cox proportional hazards regression models and visualized through nomogram tool. Bootstrap method (1 000 resample) was used for internal validation, and the performance of the model was assessed by C-index and calibration curve. Results: The mean age of participants was (80.8±11.4) years. In 4 797 person years of follow up, CKD was found in 262 participants (24.8%). Age, BMI, sex, education level, marital status, having retirement pension or insurance, hypertension prevalence, blood uric acid, blood urea nitrogen and total cholesterol levels and estimated glomerular filtration rate in baseline survey were used in the model to predict the 6-year incidence risk of CKD in the elderly. The corrected C-index was 0.766, the calibration curve showed good consistence between predicted probability and observed probability in high risk group, but relatively poor consistence in low risk group. Conclusion The incidence risk prediction model of CKD established in this study has a good performance, and the nomogram can be used as visualization tool to predict the 6-year risk of CKD in the elderly aged 65 years and older in China.

AIM:Tostudywhe ther theangiotens in-(1-7)[Ang-(1-7)]/Mas receptor axis protects cardio-myocytes against high glucose (HG)-induced injury by inhibiting nuclear factor-κB (NF-κB) pathway.METHODS:The cell viability was measured by CCK-8 assay.The intracellular levels of reactive oxygen species ( ROS) were detected by DCFH-DA staining .The number of apoptotic cells was tested by Hoechst 33258 nuclear staining .Mitochondrial membrane potential ( MMP) was examined by JC-1 staining.The levels of NF-κB p65 subunit and cleaved caspase-3 protein were de-termined by Western blotting.RESULTS: Treatment of H9c2 cardiac cells with 35 mmol/L glucose (HG) for 30, 60, 90, 120 and 150 min significantly enhanced the levels of phosphorated ( p) NF-κB p65, peaking at 60 min.Co-treatment of the cells with 1 μmol/L Ang-(1-7) and HG for 60 min attenuated the up-regulation of p-NF-κB p65 induced by HG. Co-treatment of the cells with Ang-(1-7) at concentrations of 0.1~30μmol/L and HG for 24 h inhibited HG-induced cy-totoxicity, evidenced by an increase in cell viability .On the other hand, 1 μmol/L Ang-(1-7) ameliorated HG-induced apoptosis, oxidative stress and mitochondrial damage , indicated by decreases in the number of apoptotic cells , cleaved caspase-3 level, ROS generation and MMP loss .However, the above cardioprotective effects of Ang-(1-7) were markedly blocked by A-779, an antagonist of Ang-(1-7) receptor (Mas receptor).Similarly, co-treatment of H9c2 cardiac cells with 100 μmol/L PDTC ( an inhibitor of NF-κB) and HG for 24 h also obviously reduced the above injuries induced by HG.CONCLUSION:Ang-(1-7)/Mas receptor axis prevents the cardiomyocytes from the HG-induced injury by inhibiting NF-κB pathway .

AIM:To investigate the roles of ATP-sensitive potassium ( KATP ) channels in high glucose-induced cardiac injury and the inhibitory effect of hydrogen sulfide ( H2 S) on the cardiomyocyte injury.METHODS:The expres-sion level of KATP channel protein was tested by Western blot.The cell viability was measured by CCK-8 assay.The number of apoptotic cells was observed by Hoechst 33258 nuclear staining.Mitochondrial membrane potential ( MMP) was exam-ined by JC-1 staining.RESULTS:After the H9c2 cells were treated with 35 mmol/L glucose ( high glucose, HG) for 1~24 h, the protein level of KATP channel was significantly reduced at 6 h, 9 h, 12 h and 24 h, reaching the minimum level at 12 h and 24 h.Pretreatment of the cells with 400μmol/L NaHS ( a donor of H2 S) prior to exposure to HG for 12 h con-siderably blocked the down-regulation of KATP channels induced by HG.Pretreatment of the cells with 100 μmol/L mito-chondrial KATP channel opener diazoxide, 50μmol/L non-selective KATP channel opener pinacidil or NaHS obviously inhibi-ted HG-induced injuries, leading to an increase in the cell viability, and decreases in the number of apoptotic cells and the MMP loss.Pretreatment with 100μmol/L mitochondrial KATP channel antagonist 5-hydroxydecanoic acid or 1 mmol/L non-selective KATP channel antagonist glibenclamide attenuated the above cardioprotective effects of NaHS.CONCLUSION:KATP channels mediate the inhibitory effect of H2 S on HG-induced cardiac injury.

OBJECTIVETo evaluate the feasibility, safety and diagnostic accuracy of pharmacologic stress of (99m)Technetium-MIBI single-photon emission computed tomography (SPECT) with intravenous adenosine triphosphate (ATP) in patients with suspected coronary artery disease.

METHODSThe study group included 263 patients who were suspected of having coronary artery disease. All patients underwent (99m)Tc-MIBI myocardial perfusion imaging with ATP infusion (0.16 mg/kg body weight per min for 5 min). 20 mCi of (99m)Tc-MIBI were injected 3 minutes after the start of ATP infusion. Myocardial SPECT images were obtained 60 minutes later. Then, two days later, 20 mCi of (99m)Tc-MIBI were administered at rest and myocardial SPECT was repeated. 51 patients also underwent coronary angiography within two weeks for evaluation of sensitivity and specificity of ATP-myocardial perfusion imaging in detection of coronary artery disease. The occurrence of cardiac and non-cardiac adverse effects was carefully monitored during and after intravenous ATP infusion.

RESULTSThe ATP infusion protocol was completed in all patients. Although 59% of the patients had various kinds of adverse effects, most of them were mild. No patient required aminophyline. The most severe adverse effect was second degree type II atria-ventricular block (4/263), but all events were transient. The sensitivity and specificity of ATP-myocardial perfusion imaging were 97% and 82%, respectively.

CONCLUSIONSIt is shown that (99m)Technetium-MIBI SPECT with intravenous ATP is a safe and feasible technique for detecting coronary artery disease in patients unable to perform the exercise test.

Adenosine Triphosphate ; adverse effects ; Adult ; Aged ; Aged, 80 and over ; Coronary Angiography ; Coronary Disease ; diagnosis ; Female ; Heart ; diagnostic imaging ; Humans ; Male ; Middle Aged ; Sensitivity and Specificity ; Technetium Tc 99m Sestamibi ; Tomography, Emission-Computed, Single-Photon