Objective To investigate whether exposure pathways influence the distribution pattern and toxicity of polystyrene nanoplastics(PSNPs)in hepatic cells.Methods Male C57BL/6J wild-type healthy mice aged 6 to 8 weeks old and weighed 18 to 22 g were administered with PSNPs via gavage or tail vein injection.Then,we tracked PSNPs distribution in the major organs of mice via an in vivo imaging system(IVIS).After that,we analyzed the cellular accumulation patterns in hepatic cell subpopulations(hepatocytes and Kupffer cells)using immunofluorescence and transmission electron microscopy(TEM).300 nm PSNPs were administered via gastric gavage or tail vein injection,and 70 nm PSNPs were injected via the portal vein.The cellular localization of PSNPs in the liver was analyzed using immunofluorescence.Subsequently,using AML-12 cells,a normal mouse liver cell line,as the parenchymal hepatocyte model,the uptake of PSNPs in AML-12 cells was analyzed by confocal laser scanning microscope(CLSM).Flow cytometry was performed to observe and quantify PSNPs uptake,and to analyze the underlying endocytosis mechanisms.IVIS was used to analyze PSNPs uptake features in vivo.Finally,using mouse macrophage line RAW264.7 as a Kupffer cell model and AML-12 cells as a parenchymal hepatocyte model,the cell-type-specific toxic effects induced by 100 μg/ml PSNPs were examined through transcriptomics and metabolomics analyses.Results IVIS revealed predominant hepatic accumulation of PSNPs regardless of exposure pathways via intragastric gavage or tail vein injection.Immunofluorescence/TEM demonstrated exposure pathway-dependent cellular distribution:intragastric PSNPs were localized mainly in hepatocytes,while intravenous PSNPs were accumulated in Kupffer cells.Changes in particle size(300 nm vs.70 nm)did not alter the cellular distribution pattern,while 70 nm PSNPs injected via the portal vein accumulated in Kupffer cells,which suggested that the cell-type-specific distribution of PSNPs in the liver was independent of PSNPs size and might be related to the transport of PSNPs in the gastrointestinal tract.Flow cytometry showed that PSNPs uptake by AML-12 was time-dependent and that the underlying endocytosis mechanism involved pathways mediated by clathrin(P<0.000 1),macropinocytosis(P=0.002 6),and lipid rafts(P<0.000 1).Findings on PSNPs distribution in blood revealed that the uptake of PSNPs by hepatocytes exhibited a rate saturation phenomenon.Multi-omics analysis identified distinct toxicity patterns:PSNPs disrupted lipid metabolism and neurotransmitter homeostasis in AML-12 cells and induced inflammation and oxidative stress in Kupffer cells.Conclusion Exposure pathways mediate the hepatic cell-type-specific distribution of PSNPs,thereby altering the downstream toxicological consequences induced by exposure to PSNPs.

Objective To explore the correlation of changes in neutrophil gelatinase associated lipocalin(NGAL)and neutrophil to lymphocyte ratio(NLR)with risk of acute kidney injury(AKI)in elderly patients with coronary heart disease(CHD)after PCI.Methods A total of 150 elderly CHD patients admitted in our hospital from September 2020 to September 2024 were ret-rospectively included,and according to whether AKI occurred after PCI,they were divided into AKI group(46 cases)and non-AKI group(104 cases).NGAL and NLR were detected,and the relationship between their changes and risk of AKI after PCI was analyzed.Results The AKI group had significantly advanced age,higher serum creatinine(sCr)level,higher contrast agent dose,and elevated NGAL and NLR levels after PCI than the non-AKI group(P＜0.01).The NGAL and NLR were positively correlated with sCr level(r=0.272,r=0.370,P＜0.01).The NGAL,NLR,age and contrast agent dose were risk factors for AKI after PCI(P＜0.05,P＜0.01).ROC curve analysis revealed that the AUC value of NGAL and NLR in evaluating the risk of AKI after PCI was 0.844(95％CI:0.774-0.913,P=0.000)and 0.854(95％CI:0.779-0.929,P=0.000),respectively.Conclusion Elevated NGAL and NLR levels are related to the risk of AKI in elderly CHD patients after PCI,and they are helpful for early clinical identification.

AIM:This study aims to investigate the molecular mechanism by which tubeimoside I(TBMS1)inhibits Snail expression in pancreatic cancer cells(PANC-1).METHODS:Human pancreatic cancer PANC-1 cells were cultured in vitro.The inhibitory effect of TBMS1 on PANC-1 cells was assessed using the MTT assay,and the data were analyzed based on the IC50 value of TBMS1.The impact of TBMS1 on the clonal formation ability of PANC-1 cells was evaluated through colony formation assays.The Transwell assay was employed to assess the effect of TBMS1 on the migrato-ry capability of PANC-1 cells.Apoptosis and cell cycle alterations in PANC-1 cells were analyzed using acridine orange staining and flow cytometry.The expression of Snail protein in pancreatic cancer and its relationship with survival of the patients were analyzed using the GEPIA database and Kaplan-Meier Plotter data.Immunofluorescence staining was con-ducted to investigate the effect of TBMS1 on Snail expression,while Western blot was used to evaluate the expression of poly(ADP-ribose)polymerase(PARP),E-cadherin and Snail in the cells.The ubiquitination of Snail protein was mea-sured using immunoprecipitation techniques.RESULTS:As the concentration of TBMS1 increased,the survival rate and number of clones formed by PANC-1 cells progressively decreased,leading to apoptosis,cleavage of PARP,and cell cycle arrest in the G1 phase.There was also a reduction in the proportion of cells in the S phase and a decrease in cell migration ability.The expression of Snail protein,a critical factor in cell migration,was inhibited,while E-cadherin protein levels were increased.Treatment with the proteasome inhibitor MG132 was able to reverse the suppression of Snail protein ex-pression caused by TBMS1.Immunoprecipitation results indicated that TBMS1 enhances the ubiquitination and subse-quent degradation of Snail protein.CONCLUSION:TBMS1 effectively inhibits the malignant progression of pancreatic cancer cells by promoting the ubiquitination and degradation of Snail protein in PANC-1 cells.

AIM:This study aims to investigate the molecular mechanism by which tubeimoside I(TBMS1)inhibits Snail expression in pancreatic cancer cells(PANC-1).METHODS:Human pancreatic cancer PANC-1 cells were cultured in vitro.The inhibitory effect of TBMS1 on PANC-1 cells was assessed using the MTT assay,and the data were analyzed based on the IC50 value of TBMS1.The impact of TBMS1 on the clonal formation ability of PANC-1 cells was evaluated through colony formation assays.The Transwell assay was employed to assess the effect of TBMS1 on the migrato-ry capability of PANC-1 cells.Apoptosis and cell cycle alterations in PANC-1 cells were analyzed using acridine orange staining and flow cytometry.The expression of Snail protein in pancreatic cancer and its relationship with survival of the patients were analyzed using the GEPIA database and Kaplan-Meier Plotter data.Immunofluorescence staining was con-ducted to investigate the effect of TBMS1 on Snail expression,while Western blot was used to evaluate the expression of poly(ADP-ribose)polymerase(PARP),E-cadherin and Snail in the cells.The ubiquitination of Snail protein was mea-sured using immunoprecipitation techniques.RESULTS:As the concentration of TBMS1 increased,the survival rate and number of clones formed by PANC-1 cells progressively decreased,leading to apoptosis,cleavage of PARP,and cell cycle arrest in the G1 phase.There was also a reduction in the proportion of cells in the S phase and a decrease in cell migration ability.The expression of Snail protein,a critical factor in cell migration,was inhibited,while E-cadherin protein levels were increased.Treatment with the proteasome inhibitor MG132 was able to reverse the suppression of Snail protein ex-pression caused by TBMS1.Immunoprecipitation results indicated that TBMS1 enhances the ubiquitination and subse-quent degradation of Snail protein.CONCLUSION:TBMS1 effectively inhibits the malignant progression of pancreatic cancer cells by promoting the ubiquitination and degradation of Snail protein in PANC-1 cells.

Objective To explore the correlation of changes in neutrophil gelatinase associated lipocalin(NGAL)and neutrophil to lymphocyte ratio(NLR)with risk of acute kidney injury(AKI)in elderly patients with coronary heart disease(CHD)after PCI.Methods A total of 150 elderly CHD patients admitted in our hospital from September 2020 to September 2024 were ret-rospectively included,and according to whether AKI occurred after PCI,they were divided into AKI group(46 cases)and non-AKI group(104 cases).NGAL and NLR were detected,and the relationship between their changes and risk of AKI after PCI was analyzed.Results The AKI group had significantly advanced age,higher serum creatinine(sCr)level,higher contrast agent dose,and elevated NGAL and NLR levels after PCI than the non-AKI group(P＜0.01).The NGAL and NLR were positively correlated with sCr level(r=0.272,r=0.370,P＜0.01).The NGAL,NLR,age and contrast agent dose were risk factors for AKI after PCI(P＜0.05,P＜0.01).ROC curve analysis revealed that the AUC value of NGAL and NLR in evaluating the risk of AKI after PCI was 0.844(95％CI:0.774-0.913,P=0.000)and 0.854(95％CI:0.779-0.929,P=0.000),respectively.Conclusion Elevated NGAL and NLR levels are related to the risk of AKI in elderly CHD patients after PCI,and they are helpful for early clinical identification.

Objective To investigate the effect of renal denervation on cardiac function and sympa-thetic nerve remodeling in spontaneously hypertensive rats(SHR).Methods Sixteen SPF male SHRs were randomly and equally divided into renal denervation(RDN)group and sham operation group,and 8 SPF Wistar-Kyoto(WKY)rats served as the normotensive control group.Blood pressure and heart rate of each group were non-invasively recorded every two weeks.In 8 weeks after the RDN procedure,mean arterial pressure was recorded after carotid artery catheterization,and heart rate variability,including low-frequency power(LF),high-frequency power(HF),and LF/HF ratio,was detected with electrocardiography.Cardiac function was assessed using echocar-diography(ECG),with indicators such as left ventricular ejection fraction(LVEF),left ventricu-lar fractional shortening(LVFS),left ventricular end-diastolic diameter(LVEDD),and left ven-tricular end-systolic diameter(LVESD).HE staining was used to assess myocardial injury,while immunohistochemical staining was employed to detect myocardial tyrosine hydroxylase(TH)density.RT-PCR was performed to measure the mRNA expression of IL-1β and TNF-α.Results The SBP before surgery,as well as at 2,4,6,and 8 weeks post-surgery,and the mean arterial pressure(MAP)were significantly higher in the sham operation and RDN groups than the control group,while,the MAP in the RDN group at 2,4,6,and 8 weeks post-surgery was significantly lower than that in the sham operation group(P＜0.05).Compared with the control group,the sham operation group showed significant increases in LVEDD,LVESD,heart weight-to-body weight ratio,myocardial TH,LF and LF/HF ratio,and myocardial IL-1β and TNF-α expression,while HF,LVEF,and LVFS were significantly reduced(P＜0.05,P＜0.01).Compared with the sham operation group,the RDN group showed significant increases in LVEF[(83.32±2.34)％vs(75.33±2.46)％,P＜0.05],LVFS[(45.57±2.42)％vs(38.42±1.64)％,P＜0.05],and HF(66.73±2.33 vs 60.23±1.54,P＜0.01).Meanwhile,LVESD[(3.56±0.34)mm vs(4.33±0.36)mm,P＜0.05],LVEDD[(6.43±0.38)mm vs(7.23±0.42)mm,P＜0.05],heart weight-to-body weight ratio(3.52±0.16 vs 3.82±0.22,P＜0.05),myocardial TH(0.15±0.01 vs 0.19±0.02,P＜0.05),LF[(15.55±1.08)％vs(19.91±1.79)％,P＜0.01]and LF/HF ratio(0.23±0.01 vs 0.33±0.03,P＜0.01),and the mRNA levels of myocardial IL-1β(2.47±0.15 vs 3.12±0.18,P＜0.05)and TNF-a(3.15±0.21 vs 3.79±0.17,P＜0.05)were significantly reduced.Conclusion RDN can reduce blood pressure in SHR,improve cardiac structure and function,and inhibit cardi-ac sympathetic nerve remodeling,which may be through alleviating neuroinflammation.

Background Heavy metals may play an important role in environmental risk factors associated disorders of activities of daily living (ADL) in older adults. Objective To investigate the associations between plasma levels of six heavy metals (zinc, arsenic, cadmium, lead, manganese, and copper) and ADL disorders in older adults. Methods A cross-sectional survey was conducted from 2018 to 2019 among 1412 rural elderly people in Gongcheng Yao Autonomous County, Guangxi Zhuang Autonomous Region. The plasma metal concentrations were detected by inductively coupled plasma mass spectrometry (ICP-MS), and subsequently classified into three groups (T1-T3) based on tertiles, with the T1 group as the reference. The samples were assessed for ADL disorders using the ADL scale. Logistic regression and restricted cubic spline model (RCS) were used to estimate the odds ratio (OR) and 95% confidence interval (CI) to assess the associations between heavy metals and the prevalence of reporting ADL disorders. Results The mean age of the study population was (68.52 ± 5.92) years, 825 (58.4%) female and 587 (41.6%) male. Of these, 372 (26.34%) subjects reported ADL disorders, and most of them were female (74.30%). The results of logistic regression showed that the participants in the cadmium T2 group (0.15-0.25 µg·L⁻¹) had a higher risk of ADL disorders compared to the T1 group (≤0.15 μg·L⁻¹) (OR=1.552, 95%CI: 1.086, 2.134). After stratification by sex, the relative risk of ADL disorders was lower in the plasma copper T3 group (>1019.58 µg·L⁻¹) compared to the T1 group (≤868.12 μg·L⁻¹) in men (OR=0.481, 95%CI: 0.232, 0.998). The relative risk of ADL disorders was higher in the plasma cadmium T2 group (0.15-0.25 µg·L⁻¹) compared to the T1 group (≤0.15 μg·L⁻¹) in women (OR=1.758, 95%CI: 1.182, 2.616). The RCS results showed that the risk of ADL disorders in men was nonlinearly associated with copper (P_nonlinear=0.011, P_overall<0.05). Conclusion High levels of cadmium are positively associated with the risk of reporting ADL disorders, while high levels of copper are negatively associated with the risk of reporting ADL disorders in men.

Objective:To investigate the effect of tocilizumab (TCZ) on ventricular arrhythmias (VAs) after myocardial infarction (MI) in Sprague-Dawley rats and explore its potential mechanism.Methods:The random number table method was used to divide 32 adult male Sprague-Dawley rats into 4 groups: Sham group, TCZ group, MI group and MI+TCZ group, with 8 rats in each group. The MI model was established by ligation of the left anterior descending branch of the coronary artery in the MI and MI+TCZ groups, and only sutured without ligation in the Sham and TCZ groups. TCZ was injected into the left superior cervical ganglion (SCG) of rats in the TCZ and MI+TCZ groups after successful modeling or sham operation, and the same amount of normal saline was injected in the Sham and MI groups. 24 h after successful modeling, ECG of rats in each group was recorded, heart rate variability (HRV, including low frequency power (LF), high frequency power (HF), LF/HF ratio), QT interval, QTc interval were calculated, and left ventricular effective refractory period (ERP) and VA inducibility were measured. Myocardial infarct size and tissue changes were observed with triphenyl tetrazolium chloride staining and HE staining. Real-time PCR analysis was used to detect the messager RNA (mRNA) expression of interleukin-6 (IL-6) and signal transducer and activator of transcription (STAT) 3 in SCG and potassium voltage-gated channel subfamily D member 2 (Kcnd2) in myocardial infarction periphery. The expression of c-fos in SCG was detected by immunofluorescence staining.Results:Compared with Sham group and MI+TCZ group, rats in MI group had higher LF and LF/HF ratio, longer QT interval and QTc interval, more VAs induced, lower HF and shorter ERP ( P all<0.05). Triphenyl tetrazolium chloride staining and HE staining showed that rats in the Sham and TCZ groups had normal myocardial tissue structure, those in the MI group had severe myocardial injury, and those in the MI+TCZ group had less myocardial injury than those in the MI group. Real-ime PCR analysis showed that compared with Sham group and MI+TCZ group, mRNA expression levels of IL-6 and STAT3 in SCG of rats in MI group were higher, and mRNA expression level of myocardial Kcnd2 was lower ( P all<0.05). Immunofluorescence staining showed that the content of c-fos in SCG of rats in MI group was higher than that of Sham group and MI+TCZ group ( P all<0.05). Conclusions:TCZ may reduce neural activity of the SCG after MI by inhibiting the IL-6/STAT3 signaling pathway, thereby alleviating myocardial injury and inhibiting VAs.

Objective To investigate the effect of renal denervation on cardiac function and sympa-thetic nerve remodeling in spontaneously hypertensive rats(SHR).Methods Sixteen SPF male SHRs were randomly and equally divided into renal denervation(RDN)group and sham operation group,and 8 SPF Wistar-Kyoto(WKY)rats served as the normotensive control group.Blood pressure and heart rate of each group were non-invasively recorded every two weeks.In 8 weeks after the RDN procedure,mean arterial pressure was recorded after carotid artery catheterization,and heart rate variability,including low-frequency power(LF),high-frequency power(HF),and LF/HF ratio,was detected with electrocardiography.Cardiac function was assessed using echocar-diography(ECG),with indicators such as left ventricular ejection fraction(LVEF),left ventricu-lar fractional shortening(LVFS),left ventricular end-diastolic diameter(LVEDD),and left ven-tricular end-systolic diameter(LVESD).HE staining was used to assess myocardial injury,while immunohistochemical staining was employed to detect myocardial tyrosine hydroxylase(TH)density.RT-PCR was performed to measure the mRNA expression of IL-1β and TNF-α.Results The SBP before surgery,as well as at 2,4,6,and 8 weeks post-surgery,and the mean arterial pressure(MAP)were significantly higher in the sham operation and RDN groups than the control group,while,the MAP in the RDN group at 2,4,6,and 8 weeks post-surgery was significantly lower than that in the sham operation group(P＜0.05).Compared with the control group,the sham operation group showed significant increases in LVEDD,LVESD,heart weight-to-body weight ratio,myocardial TH,LF and LF/HF ratio,and myocardial IL-1β and TNF-α expression,while HF,LVEF,and LVFS were significantly reduced(P＜0.05,P＜0.01).Compared with the sham operation group,the RDN group showed significant increases in LVEF[(83.32±2.34)％vs(75.33±2.46)％,P＜0.05],LVFS[(45.57±2.42)％vs(38.42±1.64)％,P＜0.05],and HF(66.73±2.33 vs 60.23±1.54,P＜0.01).Meanwhile,LVESD[(3.56±0.34)mm vs(4.33±0.36)mm,P＜0.05],LVEDD[(6.43±0.38)mm vs(7.23±0.42)mm,P＜0.05],heart weight-to-body weight ratio(3.52±0.16 vs 3.82±0.22,P＜0.05),myocardial TH(0.15±0.01 vs 0.19±0.02,P＜0.05),LF[(15.55±1.08)％vs(19.91±1.79)％,P＜0.01]and LF/HF ratio(0.23±0.01 vs 0.33±0.03,P＜0.01),and the mRNA levels of myocardial IL-1β(2.47±0.15 vs 3.12±0.18,P＜0.05)and TNF-a(3.15±0.21 vs 3.79±0.17,P＜0.05)were significantly reduced.Conclusion RDN can reduce blood pressure in SHR,improve cardiac structure and function,and inhibit cardi-ac sympathetic nerve remodeling,which may be through alleviating neuroinflammation.

Objective:To investigate the current funding landscape of medical artificial intelligence (AI) projects in National Natural Science Foundation of China (NSFC) from 2015 to 2019.Methods:From 2015 to 2019, AI-related projects in NSFC Medical Science Department were collected. Comprehensive analysis was performed in the projects information including year, title, supporting institution, fund type, research findings, etc.Results:NSFC has funded a total of 278 projects related to artificial intelligence, with the total funding amount of 139 million yuan. The number of projects and the funding amount were increasing year by year. Among these, 90% (249/278) were general programs and young scientist funds; 53% (148/278) of the projects were regionally distributed in Beijing, Shanghai and Guangdong; 66% (184/278) of the projects were imaging-related researches; the projects mainly focused on diseases with high incidence in China, including neoplastic diseases, cardiovascular and nervous system diseases.Conclusion:The AI-related projects funded by NSFC are characterized by rapid growth in number and fund amounts, wide coverage of disciplines, and diverse types of research diseases. However, the unbalanced distribution of regions, research fields, and supporting institutions demands more attention in future.