Aim To predict and verify the potential mechanism of the compatibility of"ginseng-astragalus-pueraria"in protecting islet morphology and improving insulin resistance by using network pharmacology.Methods The active ingredients and targets of the horn medicine were obtained from three platforms:TC-MSP,TCMIP,and BATMAN.The targets of type 2 dia-betes mellitus(T2DM)were obtained from three plat-forms:TTD,OMIM,and disgeNET.The PPI network was constructed by using the STRING database and Cy-toscape 3.9.1;GO and KEGG analysis were per-formed;POCASA 1.1 was used to predict protein binding sites,and AutoDock Vina1.1.2 was used for docking and experimental verification.Results"Gin-seng-astragalus-pueraria"screened out 2 021 targets,of which 152 were closely related to T2DM,and 10 key genes and the AGE-RAGE signaling pathway were i-dentified.Molecular docking showed that quercetin had good binding to RAGE,INS,and PI3K.Experi-ments showed that the horn drug increased insulin binding rate and secretion index and reduced serum in-sulin level and insulin resistance index.These data benefited from"ginseng-astragalus-pueraria"reducing the expression of AGE-RAGE,activating PI3K-Akt,in-hibiting NF-κB,and reducing the expression of IL-6,IL-1β and TNF-α.Conclusion The study suggests that"ginseng-astragalus-pueraria"regulates the AGE-RAGE/PI3K-Akt/NF-κB signaling pathway,repairs damaged islet morphology,and improves insulin resist-ance.

Objective:To evaluate the relationship between sevoflurane preconditioning-induced reduction of cognitive impairment and hippocampal necroptosis after cardiopulmonary bypass (CPB) in rats.Methods:Sixty SPF healthy male Sprague-Dawley rats, aged 6 months, weighing 400-450 g, were divided into 4 groups ( n=15 each) using the random number table method: control group (group C), sevoflurane group (Sev group), CPB group and CPB+ sevoflurane preconditioning group (CPB+ Sev group). The rats were exposed to 0.4% sevoflurane for 2 h in CPB+ Sev group and Sev group. The CPB model was established at 30 min after the end of sevoflurane preconditioning in CPB+ Sev group. The open field test was performed to assess the autonomic movement ability on the 2nd day after CPB. The Morris water maze test was used to assess the cognitive function on the 3rd day after CPB. The hippocampal tissues were removed after the end of the Morris water maze test for determination of the necroptosis rate and cytosolic calcium concentration of hippocampal neuron ([Ca 2+ ] i) (by flow cytometry) and the expression of phosphorylated receptor-interacting protein kinase 1 (p-RIPK1), phosphorylated RIPK3 and phosphorylated mixed-lineage kinase-like domain (p-MLKL) (by Western blot) and for microscopic examination of the ultrastructure of hippocampal neurons (by transmission electron microscopy). Results:There was no statistically significant difference in the parameters of the open field test among the four groups ( P>0.05). Compared with group C, the escape latency was significantly prolonged, the number of crossing the original platform was decreased, the time of staying at the original platform quadrant was shortened, the hippocampal necroptosis rate and [Ca 2+ ] i were increased, the expression of p-RIPK1, p-RIPK3 and p-MLKL was up-regulated ( P<0.05), the organelles of hippocampal neurons swelled, lysosomes broke, and some chromatin in nuclei dissoluted in CPB group. Compared with CPB group, the escape latency was significantly shortened, the number of crossing the original platform was increased, the time of staying at the original platform quadrant was prolonged, the hippocampal necroptosis rate and [Ca 2+ ] i were decreased, the expression of p-RIPK1, p-RIPK3 and p-MLKL was down-regulated ( P<0.05), and the damage to the ultrastructure of hippocampal neurons was sinificantly reduced in CPB+ Sev group ( P<0.05). Conclusions:The mechanism by which sevoflurane preconditioning attenuates cognitive impairment may be related to the inhibition of calcium overload-mediated hippocampal necroptosis in a rat model of CPB.

Background: s/Aims: Non-invasive models stratifying clinically significant portal hypertension (CSPH) are limited. Herein, we developed a new non-invasive model for predicting CSPH in patients with compensated cirrhosis and investigated whether carvedilol can prevent hepatic decompensation in patients with high-risk CSPH stratified using the new model. Methods: Non-invasive risk factors of CSPH were identified via systematic review and meta-analysis of studies involving patients with hepatic venous pressure gradient (HVPG). A new non-invasive model was validated for various performance aspects in three cohorts, i.e., a multicenter HVPG cohort, a follow-up cohort, and a carvediloltreating cohort. Results: In the meta-analysis with six studies (n=819), liver stiffness measurement and platelet count were identified as independent risk factors for CSPH and were used to develop the new “CSPH risk” model. In the HVPG cohort (n=151), the new model accurately predicted CSPH with cutoff values of 0 and –0.68 for ruling in and out CSPH, respectively. In the follow-up cohort (n=1,102), the cumulative incidences of decompensation events significantly differed using the cutoff values of <–0.68 (low-risk), –0.68 to 0 (medium-risk), and >0 (high-risk). In the carvediloltreated cohort, patients with high-risk CSPH treated with carvedilol (n=81) had lower rates of decompensation events than non-selective beta-blockers untreated patients with high-risk CSPH (n=613 before propensity score matching [PSM], n=162 after PSM). Conclusions Treatment with carvedilol significantly reduces the risk of hepatic decompensation in patients with high-risk CSPH stratified by the new model.

Background: s/Aims: Non-invasive models stratifying clinically significant portal hypertension (CSPH) are limited. Herein, we developed a new non-invasive model for predicting CSPH in patients with compensated cirrhosis and investigated whether carvedilol can prevent hepatic decompensation in patients with high-risk CSPH stratified using the new model. Methods: Non-invasive risk factors of CSPH were identified via systematic review and meta-analysis of studies involving patients with hepatic venous pressure gradient (HVPG). A new non-invasive model was validated for various performance aspects in three cohorts, i.e., a multicenter HVPG cohort, a follow-up cohort, and a carvediloltreating cohort. Results: In the meta-analysis with six studies (n=819), liver stiffness measurement and platelet count were identified as independent risk factors for CSPH and were used to develop the new “CSPH risk” model. In the HVPG cohort (n=151), the new model accurately predicted CSPH with cutoff values of 0 and –0.68 for ruling in and out CSPH, respectively. In the follow-up cohort (n=1,102), the cumulative incidences of decompensation events significantly differed using the cutoff values of <–0.68 (low-risk), –0.68 to 0 (medium-risk), and >0 (high-risk). In the carvediloltreated cohort, patients with high-risk CSPH treated with carvedilol (n=81) had lower rates of decompensation events than non-selective beta-blockers untreated patients with high-risk CSPH (n=613 before propensity score matching [PSM], n=162 after PSM). Conclusions Treatment with carvedilol significantly reduces the risk of hepatic decompensation in patients with high-risk CSPH stratified by the new model.

Background: s/Aims: Non-invasive models stratifying clinically significant portal hypertension (CSPH) are limited. Herein, we developed a new non-invasive model for predicting CSPH in patients with compensated cirrhosis and investigated whether carvedilol can prevent hepatic decompensation in patients with high-risk CSPH stratified using the new model. Methods: Non-invasive risk factors of CSPH were identified via systematic review and meta-analysis of studies involving patients with hepatic venous pressure gradient (HVPG). A new non-invasive model was validated for various performance aspects in three cohorts, i.e., a multicenter HVPG cohort, a follow-up cohort, and a carvediloltreating cohort. Results: In the meta-analysis with six studies (n=819), liver stiffness measurement and platelet count were identified as independent risk factors for CSPH and were used to develop the new “CSPH risk” model. In the HVPG cohort (n=151), the new model accurately predicted CSPH with cutoff values of 0 and –0.68 for ruling in and out CSPH, respectively. In the follow-up cohort (n=1,102), the cumulative incidences of decompensation events significantly differed using the cutoff values of <–0.68 (low-risk), –0.68 to 0 (medium-risk), and >0 (high-risk). In the carvediloltreated cohort, patients with high-risk CSPH treated with carvedilol (n=81) had lower rates of decompensation events than non-selective beta-blockers untreated patients with high-risk CSPH (n=613 before propensity score matching [PSM], n=162 after PSM). Conclusions Treatment with carvedilol significantly reduces the risk of hepatic decompensation in patients with high-risk CSPH stratified by the new model.

Objectives:To evaluate the imaging effects of the novel sympathetic nerve imaging agent 18F-FPMBBG in healthy volunteers and heart failure patients.Methods:Four healthy volunteers and four heart failure patients were selected to undergo 18F-FPMBBG positron emission tomography/computed tomography(PET/CT)dynamic imaging,the radioactivity distribution characteristics of 18F-FPMBBG in the heart and adjacent organs of the two groups were observed,and the uptake of 18F-FPMBBG by the left ventricular myocardium was compared in the two groups.Results:No adverse effects were observed in all subjects after intravenous injection of 18F-FPMBBG.In healthy volunteers,the heart uptake was rapid and stable,lung uptake was very low,and the blood pool and liver clearance were fast.The heart/liver uptake ratios at 30,60,and 90 minutes after injection were 2.33±0.81,3.29±0.90 and 3.80±1.07,respectively.The average standard uptake value(SUVmean)of 18F-FPMBBG in the heart failure group was significantly lower than that in the healthy volunteer group(P=0.003).The washout rate(WR)was significantly higher in the heart failure group([16.53±2.76]%vs.[3.88±4.51]%,P=0.003).Conclusions:18F-FPMBBG showed good imaging and diagnostic effects in the preliminary imaging of healthy subjects and heart failure patients,and it has the potential to become an ideal cardiac sympathetic nerve imaging agent.

Objective:To analyze the clinical and electrophysiological characteristics of patients with sensory neuronopathies (SNN), and to evaluate the significance of electrophysiological markers in the diagnosis and assessment of disease progression.Methods:A retrospective analysis was performed to evaluate the clinical manifestations, electrophysiological characteristics, and spinal cord magnetic resonance imaging (MRI) features of 8 cases diagnosed with SNN at the Third Central Hospital of Tianjin between 2015 and 2023. The neurophysiological examination mainly included limb nerve conduction study (NCS), same core needle electrode electromyography, somatosensory evoked potential (SEP), skin sympathetic reflex (SSR), and contact heat evoked potential (CHEP).Results:Among the 8 cases with SNN, 7 cases exhibited asymmetrical onset and a non-length-dependent pattern. All the 8 cases presented with severe deep sensory ataxia, accompanied by superficial sensory abnormalities and tendon areflexia. Paraneoplastic SNN were the most prevalent etiological subtype (4 cases), all of whom presented peripheral neuropathy as the initial symptom. Among these 4 cases, malignancies were identified in 3 cases and 3 cases presented with anti-Hu antibodies. Among the remaining 4 patients, 2 cases were autoimmune and the other 2 cases were idiopathic. NCS results of the 8 cases revealed decrease or absence of sensory nerve action potential (SNAP) amplitudes, with normal sensory conduction velocities. Six cases showed abnormal SEP, including 2 cases of central damage and 4 cases of peripheral damage, 5 cases had abnormal SSR, and 2 cases exhibited abnormal CHEP. Motor nerve conduction studies were normal in all 8 cases. Six patients underwent spinal MRI, and 4 exhibited abnormal signals in dorsal columns.Conclusions:The hallmark clinical manifestation of SNN is sensory ataxia, characterized by substantial impairment of superficial sensation, typically manifesting in a non-length-dependent distribution. Beyond the widespread and significant reduction in SNAP amplitudes, SNN may also exhibit additional electrophysiological impairments, such as those observed in SEP, SSR and CHEP.SEP combined with spinal cord MRI can improve the detection rate for damages in the central sensory conduction pathway.

Objectives:To evaluate the imaging effects of the novel sympathetic nerve imaging agent 18F-FPMBBG in healthy volunteers and heart failure patients.Methods:Four healthy volunteers and four heart failure patients were selected to undergo 18F-FPMBBG positron emission tomography/computed tomography(PET/CT)dynamic imaging,the radioactivity distribution characteristics of 18F-FPMBBG in the heart and adjacent organs of the two groups were observed,and the uptake of 18F-FPMBBG by the left ventricular myocardium was compared in the two groups.Results:No adverse effects were observed in all subjects after intravenous injection of 18F-FPMBBG.In healthy volunteers,the heart uptake was rapid and stable,lung uptake was very low,and the blood pool and liver clearance were fast.The heart/liver uptake ratios at 30,60,and 90 minutes after injection were 2.33±0.81,3.29±0.90 and 3.80±1.07,respectively.The average standard uptake value(SUVmean)of 18F-FPMBBG in the heart failure group was significantly lower than that in the healthy volunteer group(P=0.003).The washout rate(WR)was significantly higher in the heart failure group([16.53±2.76]%vs.[3.88±4.51]%,P=0.003).Conclusions:18F-FPMBBG showed good imaging and diagnostic effects in the preliminary imaging of healthy subjects and heart failure patients,and it has the potential to become an ideal cardiac sympathetic nerve imaging agent.

OBJECTIVE: To explore the protective effect of glycosaminoglycans (GAG) on vascular endothelium in patients with sepsis. METHODS: A prospective study was conducted on adult patients with sepsis admitted to the intensive care unit (ICU) of Hangzhou Normal University Affiliated Hospital from December 2022 to December 2023. Patients were randomly divided into conventional treatment group and GAG intervention group. Both groups were treated according to the 2021 Surviving Sepsis Campaign Guidelines. The GAG intervention group was additionally treated with GAG (2 mL of sulodexide intramuscular injection once daily for 7 days) on the basis of conventional treatment. Venous blood was collected from patients at 0, 6, 24, 48, 72 hours and 7 days after enrollment to detect serum vascular endothelial glycocalyx [heparan sulfate (HS) and syndecan-1 (SDC-1)], inflammatory markers [C-reactive protein (CRP), procalcitonin (PCT), tumor necrosis factor-α (TNF-α), interleukin-6 (IL-6)], and coagulation markers [prothrombin time (PT), activated partial thromboplastin time (APTT), antithrombin-III (AT-III), fibrinogen (Fib), D-Dimer], and to perform acute physiology and chronic health evaluation II (APACHE II), sequential organ failure assessment (SOFA), and International Society on Thrombosis and Haemostasis (ISTH) scores. The prognosis of patients (length of hospital stay, ICU and 28-day mortality) was observed. The receiver operator characteristic curve (ROC curve) was drawn to evaluate the value of HS in predicting the prognosis of sepsis patients, and the correlation between endothelial glycocalyx degradation products and various clinical indicators was analyzed. RESULTS: A total of 50 adult patients with sepsis meeting the inclusion criteria were enrolled, with 25 in the conventional treatment group and 25 in the GAG intervention group. In terms of degradation products of endothelial glycocalyx, compared to baseline, both groups showed an increasing trend in HS and SDC-1 levels post-treatment. However, the GAG intervention group exhibited significantly lower HS levels at 72 hours and 7 days, as well as lower SDC-1 levels at 6, 24, 48, 72 hours and 7 days compared to the conventional group. Among the surviving patients, the HS levels at 72 hours and SDC-1 levels at 6 hours of treatment in the GAG intervention group were significantly reduced compared to the conventional treatment group. In terms of severity score, compared with before treatment, the GAG intervention group showed a significant decrease in APACHE II, SOFA, and ISTH scores after 7 days of treatment. The SOFA scores of the GAG intervention group after 48 hours and 7 days of treatment were significantly lower than those of the conventional treatment group. In terms of inflammatory indicators, compared with before treatment, the GAG intervention group showed a significant decrease in IL-6 levels after 48 hours of treatment. With the prolongation of treatment time, the CRP levels of both groups of patients showed a significant downward trend, and at 7 days of treatment, the CRP level in the GAG intervention group was significantly lower than that in the conventional treatment group. In terms of coagulation function, with prolonged treatment time, PT and APTT of both groups of patients showed an increasing trend, while Fib showed a decreasing trend. The GAG intervention group showed a significant prolongation of PT after 72 hours of treatment compared to the conventional treatment group. In terms of prognosis, there were no statistically significant differences in ICU and 28-day mortality rates between the two groups. The GAG intervention group had significantly shorter hospital stays than the conventional treatment group. ROC curve analysis showed that HS, CRP, APTT, IL-6, APACHE II, SOFA, and ISTH scores were predictive factors for the prognosis of sepsis patients (all P < 0.05). Compared to a single indicator, the combined detection of multiple indicators has a higher value in predicting the prognosis of sepsis patients [area under the curve (AUC) = 0.911, 95% confidence interval (95%CI) was 0.817-1.000], with a sensitivity of 76.9% and a specificity of 91.9%. Correlation analysis showed that HS was significantly negatively correlated with Fib, PT, TNF-α, IL-6, and PCT (r values were -0.338, -0.396, -0.288, -0.319, and -0.340, all P < 0.05), while HS was significantly positively correlated with D-Dimer and CRP (r values were 0.347 and 0.354, both P < 0.05); SDC-1 was significantly negatively correlated with Fib, PT, APTT, TNF-α, IL-6, and ISTH scores (r values were -0.314, -0.294, -0.408, -0.353, -0.289, -0.287, all P < 0.05). CONCLUSIONS Early glycocalyx degradation can occur in sepsis patients. GAG have a protective effect on,the vascular endothelium, reducing the severity of sepsis and providing organ protection. HS, CRP, APTT, IL-6, APACHE II score, SOFA score, and ISTH score are independent predictive factors for the prognosis of sepsis patients. The combination of HS and the above indicators can significantly improve the accuracy of prediction.
Humans ; Sepsis/blood* ; Glycocalyx/drug effects* ; Glycosaminoglycans/pharmacology* ; Prospective Studies ; Endothelium, Vascular/metabolism* ; Syndecan-1/blood* ; Male ; Female ; C-Reactive Protein/metabolism* ; Interleukin-6/blood* ; Heparitin Sulfate/blood* ; Middle Aged ; Adult ; Tumor Necrosis Factor-alpha/blood* ; Procalcitonin/blood*

OBJECTIVE: Exposure to polycyclic aromatic hydrocarbons (PAHs) or metal(loid)s individually has been associated with neural tube defects (NTDs). However, the impacts of PAH and metal(loid) co-exposure and potential interaction effects on NTD risk remain unclear. We conducted a case-control study in China among population with a high prevalence of NTDs to investigate the combined effects of PAH and metal(loid) exposures on the risk of NTD. METHODS: Cases included 80 women who gave birth to offspring with NTDs, whereas controls were 50 women who delivered infants with no congenital malformations. We analyzed the levels of placental PAHs using gas chromatography and mass spectrometry, PAH-DNA adducts with ³²P-post-labeling method, and metal(loid)s with an inductively coupled plasma mass spectrometer. Unconditional logistic regression was employed to estimate the associations between individual exposures and NTDs. Least absolute shrinkage and selection operator (LASSO) penalized regression models were used to select a subset of exposures, while additive interaction models were used to identify interaction effects. RESULTS: In the single-exposure models, we found that eight PAHs, PAH-DNA adducts, and 28 metal(loid)s were associated with NTDs. Pyrene, selenium, molybdenum, cadmium, uranium, and rubidium were selected through LASSO regression and were statistically associated with NTDs in the multiple-exposure models. Women with high levels of pyrene and molybdenum or pyrene and selenium exhibited significantly increased risk of having offspring with NTDs, indicating that these combinations may have synergistic effects on the risk of NTDs. CONCLUSION Our findings suggest that individual PAHs and metal(loid)s, as well as their interactions, may be associated with the risk of NTDs, which warrants further investigation.
Humans ; Neural Tube Defects/chemically induced* ; Polycyclic Aromatic Hydrocarbons/adverse effects* ; Female ; Case-Control Studies ; China/epidemiology* ; Adult ; Pregnancy ; Environmental Pollutants ; Maternal Exposure/adverse effects* ; Metals/toxicity* ; Young Adult ; Risk Factors