This study investigated the mechanism by which kaempferol(KAE) affected intervertebral disc degeneration(IDD) through the p38 mitogen-activated protein kinase(p38 MAPK) signaling pathway. Rats were randomly divided into five groups: control group, model group, low-dose KAE group, medium-dose KAE group, and high-dose KAE group. An IDD model was established by needle puncture of the caudal intervertebral discs. Four weeks post-surgery, the rats were administered KAE via gavage for 8 consecutive weeks. Magnetic resonance imaging(MRI) was performed, and samples were collected. In vitro, an inflammation model of nucleus pulposus cells(NPCs) induced by tumor necrosis factor-alpha(TNF-α) was constructed. Anisomycin was used to activate the p38 MAPK signaling pathway. NPCs were divided into blank, model, KAE, agonist, and KAE + agonist groups. After 1 day of treatment, cell proliferation activity was assessed using the CCK-8. Protein expression levels were determined by Western blot, and mRNA expression was measured by real-time quantitative polymerase chain reaction. Cell apoptosis was detected by TUNEL staining, and immunofluorescence staining was used to detect type Ⅱ collagen and matrix metalloproteinase 3(MMP3). In vivo results indicated significant improvement in the degree of IDD in the treatment groups compared to the model group, with the medium-dose group showing more pronounced therapeutic effects than the low-and high-dose groups. In vitro results demonstrated that KAE treatment significantly enhanced NPC proliferation activity, down-regulated the expression levels of Bcl-2-associated X protein(Bax), interleukin-6(IL-6), interleukin-17A(IL-17A), MMP3, and a disintegrin and metalloproteinase with thrombospondin motifs 5, and inhibited the phosphorylation of p38 MAPK pathway-related proteins. Activation of the p38 MAPK signaling pathway by anisomycin reduced the therapeutic effects of KAE. The study concluded that KAE could improve the proliferation activity of degenerated NPCs, reduce inflammation levels, and slow the progression of IDD in rats, and the mechanism was likely related to the regulation of the p38 MAPK signaling pathway.
Animals ; p38 Mitogen-Activated Protein Kinases/genetics* ; Kaempferols/pharmacology* ; Intervertebral Disc Degeneration/genetics* ; Rats ; Rats, Sprague-Dawley ; Male ; Apoptosis/drug effects* ; Cell Proliferation/drug effects* ; Nucleus Pulposus/drug effects* ; Signal Transduction/drug effects* ; Humans ; MAP Kinase Signaling System/drug effects*

Objective To explore the predictive value of the model for end-stage liver disease (MELD) score, energy metabolism and serum thyroid hormone levels on the severity and prognosis of patients with liver failure and their correlation. Methods This study collected clinicopathological data from 60 liver failure patients, e.g., end-stage liver disease (MELD) score, energy metabolism, and serum thyroid hormone levels. The χ 2 test was performed to analyze the categorical variables, while the Mann-Whitney U test and independent sample t test were performed to assess the continuous variables between the two groups. Spearman correlation coefficient test was used to evaluate correlation of each index. The receiver operating characteristic (ROC) curve was used to analyze the optimal cut-off points of serum total triiodothyronine (TT3) and free triiodothyronine (FT3) levels in predicting prognosis of the patients. Results The rates of low TT3 and FT3 levels in liver failure patients were 78.2% and 69.1%, respectively, whereas the low TT3 rates were 95.2% and 67.6% and the low FT3 rates were 90.5% and 55.9% in survival and non-survival groups of patients, respectively (both P < 0.05). Moreover, the MELD score was significantly higher in the non-survival patients than in survival patients [26.0(21.0-29.0) vs 21.0 (19.0-24.0), Z =-3.396, P =0.001], while TT3 and FT3 levels were significantly lower in the non-survival patients than in the survival patients [0.69(0.62-0.73) vs 0.83(0.69-0.94) and 2.17(1.99-2.31) vs 2.54(2.12-2.86), respectively; Z =-2.884、-2.876, all P < 0.01]. The MELD score was negatively associated with serum TT3, FT3, and thyroid stimulating hormone (TSH) levels and the respiratory quotient (RQ) ( r =-0.487、-0.329、-0.422、-0.350, all P < 0.01), whereas the RQ was associated with serum TT3 and FT3 levels ( r =0.271、0.265, all P < 0.05). The optimal cutoff values in predicting the severity and survival of patients was 0.75 nmol/L and 2.37pmol/L with the sensitivity values of 67.6% and 64.7% and the specificity of 90.5% and 81.0%, respectively. Conclusion Abnormal thyroid hormone levels and low respiratory quotient could be used to predict the severity and prognosis of patients with liver failure.

Objective: To prove the validity and accuracy of the digitizer instead of the conventional electronics plug-in for radionuclide measurement. Methods:  Based on a large-area flow-gas multi-wire proportional counter for 2πα and 2πβ surface particle emission rate measurement, the DT5730 digital waveform sampler developed by CAEN was used for waveform signal acquisition, amplitude analysis, and data processing of the α-plane source 241Am and the β-plane source nuclides 14C, 36Cl, and 90Sr-90Y of different energies. Results: The deviations between the α and β surface particle emission rate results obtained after dead time and background corrections and the measurements obtained based on the plug-in calibrator were all within 0.6%, within the uncertainty range, under consistent experimental conditions such as electronics threshold and high pressure. Conclusion The digitizer is an effective alternative to conventional electronics plug-ins for α and β signal acquisition and processing and the accurate measurement of α and β emission rates.

Objective To evaluate the relationship between preoperative prognostic nutritional index(PNI),controlling nutritional status(CONUT)and Naples prognostic score(NPS)and the clinicopathological characteristics and prognosis of patients with radical resection of hepatocellular carcinoma.Methods The clinicopathological data of 122 patients with hepatocellular carcinoma who underwent radical resection in the first affiliated hospital of university of science and technology of China from January 2016 to December 2019 were retrospec-tively analyzed,and the relationship between preoperative PNI,CONUT and NPS and the clinicopathological characteristics and prognosis was analyzed.The survival curve was drawn by Kaplan-Meier method.Cox proportional-hazards regression model was used to analyze the influencing factors of the overall survival of hepatocellular carcinoma patients.The area under the receiver operating characteristic(ROC)curve(AUC)was used to compare the predictive value of each scoring system.Results Preoperative PNI was related to the tumor differentiation,microvascular invasion(MVI),cirrhosis and preoperative hemoglobin level(P<0.05).The preoperative CONUT was related to the tumor differentiation,cirrhosis and preoperative hemoglobin level(P<0.05).The preoperative NPS was related to the cirrhosis and preoperative hemoglobin level(P<0.05).The low PNI group,high CONUT group and high NPS group had longer postoperative hospital stay and higher postoperative complications rate compared with the high PNI group,low CONUT group and low NPS group,respectively,and the differences were statistically significant(P<0.05).Cox proportional-hazards regression model showed that preoperative PNI,CONUT and NPS were associated with the prognosis of patients with hepatocellular carcinoma(P<0.05);However,only preoperative NPS was the independent risk factor for prognosis of patients with hepatocellular carcinoma(P<0.05).The ROC curve results showed that the AUC of NPS was higher than those of PNI and CONUT.Conclusion preoperative PNI,CONUT and NPS are all related to the prognosis of hepatocellular carcinoma patients undergoing radical resection,and the predictive value of preoperative NPS is higher than preoperative PNI and CONUT.

Objective To correct the counting loss of ³⁷Ar below the activity threshold during the measurement of the absolute activity of the inert radioactive gas ³⁷Ar using the proportional counter filled with gas. Methods Monte Carlo simulation with Geant4 was performed to establish a proportional counter model and output the energy deposition spectrum of ³⁷Ar, which were used to simulate and analyze the causes and correction of counting loss. Results The photon detection efficiency was only 38.7% at 60 kPa. The counting loss was mainly caused by the wall effect produced by the photons, which could be reduced by increasing the gas pressure and corrected by extrapolation. The influence of wall effect at 100 kPa was 4.4%, and the deviation between simulation and experiment was < 0.6%. Conclusion A factor could be calculated by Geant4 simulation for the correction of counting loss, thus achieving the accurate measurement of ³⁷Ar activity by proportional counter.

Objectives: To investigated the safety and efficacy of treating patients with acute non-ST-segment elevation myocardial infarction (NSTEMI) and elevated levels of N-terminal pro-hormone B-type natriuretic peptide (NT-proBNP) with levosimendan within 24 hours of first medical contact (FMC). Methods: This multicenter, open-label, block-randomized controlled trial (NCT03189901) investigated the safety and efficacy of levosimendan as an early management strategy of acute heart failure (EMS-AHF) for patients with NSTEMI and high NT-proBNP levels. This study included 255 patients with NSTEMI and elevated NT-proBNP levels, including 142 males and 113 females with a median age of 65 (58-70) years, and were admitted in the emergency or outpatient departments at 14 medical centers in China between October 2017 and October 2021. The patients were randomly divided into a levosimendan group (n=129) and a control group (n=126). The primary outcome measure was NT-proBNP levels on day 3 of treatment and changes in the NT-proBNP levels from baseline on day 5 after randomization. The secondary outcome measures included the proportion of patients with more than 30% reduction in NT-proBNP levels from baseline, major adverse cardiovascular events (MACE) during hospitalization and at 6 months after hospitalization, safety during the treatment, and health economics indices. The measurement data parameters between groups were compared using the t-test or the non-parametric test. The count data parameters were compared between groups using the χ² test. Results: On day 3, the NT-proBNP levels in the levosimendan group were lower than the control group but were statistically insignificant [866 (455, 1 960) vs. 1 118 (459, 2 417) ng/L, Z=-1.25,P=0.21]. However, on day 5, changes in the NT-proBNP levels from baseline in the levosimendan group were significantly higher than the control group [67.6% (33.8%,82.5%)vs.54.8% (7.3%,77.9%), Z=-2.14, P=0.03]. There were no significant differences in the proportion of patients with more than 30% reduction in the NT-proBNP levels on day 5 between the levosimendan and the control groups [77.5% (100/129) vs. 69.0% (87/126), χ²=2.34, P=0.13]. Furthermore, incidences of MACE did not show any significant differences between the two groups during hospitalization [4.7% (6/129) vs. 7.1% (9/126), χ²=0.72, P=0.40] and at 6 months [14.7% (19/129) vs. 12.7% (16/126), χ²=0.22, P=0.64]. Four cardiac deaths were reported in the control group during hospitalization [0 (0/129) vs. 3.2% (4/126), P=0.06]. However, 6-month survival rates were comparable between the two groups (log-rank test, P=0.18). Moreover, adverse events or serious adverse events such as shock, ventricular fibrillation, and ventricular tachycardia were not reported in both the groups during levosimendan treatment (days 0-1). The total cost of hospitalization [34 591.00(15 527.46,59 324.80) vs. 37 144.65(16 066.90,63 919.00)yuan, Z=-0.26, P=0.80] and the total length of hospitalization [9 (8, 12) vs. 10 (7, 13) days, Z=0.72, P=0.72] were lower for patients in the levosimendan group compared to those in the control group, but did not show statistically significant differences. Conclusions: Early administration of levosimendan reduced NT-proBNP levels in NSTEMI patients with elevated NT-proBNP and did not increase the total cost and length of hospitalization, but did not significantly improve MACE during hospitalization or at 6 months.
Male ; Female ; Humans ; Aged ; Natriuretic Peptide, Brain ; Simendan/therapeutic use* ; Non-ST Elevated Myocardial Infarction ; Heart Failure/drug therapy* ; Peptide Fragments ; Arrhythmias, Cardiac ; Biomarkers ; Prognosis

Ulcerative colitis(UC) is a recurrent, intractable inflammatory bowel disease. Coptidis Rhizoma and Bovis Calculus, serving as heat-clearing and toxin-removing drugs, have long been used in the treatment of UC. Berberine(BBR) and ursodeoxycholic acid(UDCA), the main active components of Coptidis Rhizoma and Bovis Calculus, respectively, were employed to obtain UDCA-BBR supramolecular nanoparticles by stimulated co-decocting process for enhancing the therapeutic effect on UC. As revealed by the characterization of supramolecular nanoparticles by field emission scanning electron microscopy(FE-SEM) and dynamic light scattering(DLS), the supramolecular nanoparticles were tetrahedral nanoparticles with an average particle size of 180 nm. The molecular structure was described by ultraviolet spectroscopy, fluorescence spectroscopy, infrared spectroscopy, high-resolution mass spectrometry, and hydrogen-nuclear magnetic resonance(H-NMR) spectroscopy. The results showed that the formation of the supramolecular nano-particle was attributed to the mutual electrostatic attraction and hydrophobic interaction between BBR and UDCA. Additionally, supramolecular nanoparticles were also characterized by sustained release and pH sensitivity. The acute UC model was induced by dextran sulfate sodium(DSS) in mice. It was found that supramolecular nanoparticles could effectively improve body mass reduction and colon shortening in mice with UC(P<0.001) and decrease disease activity index(DAI)(P<0.01). There were statistically significant differences between the supramolecular nanoparticles group and the mechanical mixture group(P<0.001, P<0.05). Enzyme-linked immunosorbent assay(ELISA) was used to detect the serum levels of tumor necrosis factor-α(TNF-α) and interleukin-6(IL-6), and the results showed that supramolecular nanoparticles could reduce serum TNF-α and IL-6 levels(P<0.001) and exhibited an obvious difference with the mechanical mixture group(P<0.01, P<0.05). Flow cytometry indicated that supramolecular nanoparticles could reduce the recruitment of neutrophils in the lamina propria of the colon(P<0.05), which was significantly different from the mechanical mixture group(P<0.05). These findings suggested that as compared with the mechanical mixture, the supramolecular nanoparticles could effectively improve the symptoms of acute UC in mice. The study provides a new research idea for the poor absorption of small molecules and the unsatisfactory therapeutic effect of traditional Chinese medicine and lays a foundation for the research on the nano-drug delivery system of traditional Chinese medicine.
Animals ; Mice ; Colitis, Ulcerative/drug therapy* ; Ursodeoxycholic Acid/adverse effects* ; Berberine/pharmacology* ; Interleukin-6 ; Tumor Necrosis Factor-alpha/pharmacology* ; Drugs, Chinese Herbal/pharmacology* ; Colon ; Nanoparticles ; Dextran Sulfate/adverse effects* ; Disease Models, Animal ; Colitis/chemically induced*

Platelets are reprogrammed by cancer via a process called education, which favors cancer development. The transcriptional profile of tumor-educated platelets (TEPs) is skewed and therefore practicable for cancer detection. This intercontinental, hospital-based, diagnostic study included 761 treatment-naïve inpatients with histologically confirmed adnexal masses and 167 healthy controls from nine medical centers (China, n = 3; Netherlands, n = 5; Poland, n = 1) between September 2016 and May 2019. The main outcomes were the performance of TEPs and their combination with CA125 in two Chinese (VC1 and VC2) and the European (VC3) validation cohorts collectively and independently. Exploratory outcome was the value of TEPs in public pan-cancer platelet transcriptome datasets. The AUCs for TEPs in the combined validation cohort, VC1, VC2, and VC3 were 0.918 (95% CI 0.889-0.948), 0.923 (0.855-0.990), 0.918 (0.872-0.963), and 0.887 (0.813-0.960), respectively. Combination of TEPs and CA125 demonstrated an AUC of 0.922 (0.889-0.955) in the combined validation cohort; 0.955 (0.912-0.997) in VC1; 0.939 (0.901-0.977) in VC2; 0.917 (0.824-1.000) in VC3. For subgroup analysis, TEPs exhibited an AUC of 0.858, 0.859, and 0.920 to detect early-stage, borderline, non-epithelial diseases and 0.899 to discriminate ovarian cancer from endometriosis. TEPs had robustness, compatibility, and universality for preoperative diagnosis of ovarian cancer since it withstood validations in populations of different ethnicities, heterogeneous histological subtypes, and early-stage ovarian cancer. However, these observations warrant prospective validations in a larger population before clinical utilities.
Humans ; Female ; Blood Platelets/pathology* ; Biomarkers, Tumor/genetics* ; Ovarian Neoplasms/pathology* ; China

Parkinson's disease (PD) is the most common neurodegenerative movement disease. It is featured by abnormal alpha-synuclein (α-syn) aggregation in dopaminergic neurons in the substantia nigra. Macroautophagy (autophagy) is an evolutionarily conserved cellular process for degradation of cellular contents, including protein aggregates, to maintain cellular homeostasis. Corynoxine B (Cory B), a natural alkaloid isolated from Uncaria rhynchophylla (Miq.) Jacks., has been reported to promote the clearance of α-syn in cell models by inducing autophagy. However, the molecular mechanism by which Cory B induces autophagy is not known, and the α-syn-lowering activity of Cory B has not been verified in animal models. Here, we report that Cory B enhanced the activity of Beclin 1/VPS34 complex and increased autophagy by promoting the interaction between Beclin 1 and HMGB1/2. Depletion of HMGB1/2 impaired Cory B-induced autophagy. We showed for the first time that, similar to HMGB1, HMGB2 is also required for autophagy and depletion of HMGB2 decreased autophagy levels and phosphatidylinositol 3-kinase III activity both under basal and stimulated conditions. By applying cellular thermal shift assay, surface plasmon resonance, and molecular docking, we confirmed that Cory B directly binds to HMGB1/2 near the C106 site. Furthermore, in vivo studies with a wild-type α-syn transgenic drosophila model of PD and an A53T α-syn transgenic mouse model of PD, Cory B enhanced autophagy, promoted α-syn clearance and improved behavioral abnormalities. Taken together, the results of this study reveal that Cory B enhances phosphatidylinositol 3-kinase III activity/autophagy by binding to HMGB1/2 and that this enhancement is neuroprotective against PD.