Most cancers are currently incurable, partly due to abnormal post-translational modifications (PTMs). In this study, we initially used multiple myeloma (MM) as a working model and found that SUMOylation activating enzyme subunit 1 (SAE1) promotes the malignancy of MM. Through proteome microarray analysis, SAE1 was identified as a potential target for bioactive colcemid or its derivative colchicine. Elevated levels of SAE1 were associated with poor clinical survival and increased MM proliferation in vitro and in vivo. Additionally, SAE1 directly SUMOylated and upregulated the total protein expression of p27, leading to LLPS-mediated nuclear export of p27. Our study also demonstrated the involvement of SAE1 in other types of cancer cells, and provided the first monomer crystal structure of SAE1 and its key binding model with colchicine. Colchicine also showed promising results in the Patient-Derived Tumor Xenograft (PDX) model. Furthermore, a controlled clinical trial with 56 MM patients demonstrated the clinical efficacy of colchicine. Our findings reveal a novel mechanism by which tumor cells evade p27-induced cellular growth arrest through p27 SUMOylation-mediated nuclear export. SAE1 may serve as a promising therapeutic target, and colchicine may be a potential treatment option for multiple types of cancer in clinical settings.

OBJECTIVES: To study the mechanism mediating the protective effect of asiaticoside (AS) against myocardial ischemia-reperfusion injury (MIRI) in rats. METHODS: Fifty SD rats were randomized into sham-operated group, MIRI model group and AS treatment group. AS treatment was administered at low, moderate and high doses by daily gavage for 2 weeks before MIRI modeling (n=10). Serum levels of lactate dehydrogenase (LDH), creatine kinase isoenzyme (CK-MB), interleukin-18 (IL-18) and IL-1β, the volume of myocardial infarction and ischemia, and myocardial pathologies of the rats were determined or observed. The protein expression levels of NLRP3, ASC, caspase-1, GSDMD, GSDMD-N, IL-1β and IL-18 in the myocardial tissues were detected using Western blotting. The changes in the expression levels of these proteins were also detected in H9C2 cells with AS pretreatment prior to hypoxia-reoxygenation (H/R) injury. RESULTS: The rats models of MIRI exhibited significant myocardial infarction and ischemia with increased serum levels of LDH and CK-MB and myocardial expressions of NLRP3, ASC, caspase-1, GSDMD, GSDMD-N, IL-1β and IL-18. AS pretreatment effectively reduced myocardial infarction volume in the rat models and significantly reduced serum LDH and CK-MB levels and the protein levels in the myocardial tissue in a dose-dependent manner. In the H9C2 cell model of H/R injury, AS pretreatment significantly suppressed the elevation of the protein expressions of NLRP3, ASC, caspase-1, GSDMD, GSDMD-N, IL-1β and IL-18. Molecular docking studies showed that AS had a strong binding affinity with NLRP3. CONCLUSIONS Asiaticoside can alleviate MIRI in rats possibly by inhibiting NLRP3 inflammasome-mediated pyroptosis.
Animals ; Myocardial Reperfusion Injury/metabolism* ; NLR Family, Pyrin Domain-Containing 3 Protein/metabolism* ; Pyroptosis/drug effects* ; Rats, Sprague-Dawley ; Rats ; Inflammasomes/metabolism* ; Triterpenes/pharmacology* ; Interleukin-18/metabolism* ; Male ; Interleukin-1beta/metabolism* ; Caspase 1/metabolism*

Myocardial infarction (MI) is the leading cause of cardiovascular disease-related death worldwide. Nonetheless, existing therapeutic approaches for MI are hampered by issues such as reliance on pharmacological agents and suboptimal patient adherence. Caffeic acid (CA) is a bioactive polyphenolic compound with important anti-inflammatory, anti-bacterial and anti-oxidant functions. Still, its specific role and mechanism in treating cardiovascular disease remain to be further studied. In recent years, a large number of studies have shown that the kelch-like ECH-associated protein 1/nuclear factor erythroid 2 related factor 2 (Keap1/Nrf2) pathway is a key factor in the occurrence and development of cardiovascular diseases. In this study, H₂O₂-induced oxidative stress model of H9c2 cells and left anterior descending branch (LAD) conjunctival induced acute myocardial infarction reperfusion (AMI/R) model were used to evaluate the protective effect of CA on the heart. The interaction between CA and Keap1 was analyzed by CA-labeled fluorescence probe, target fishing, isothermal titration calorimetry (ITC), protein crystallography and surface plasmon resonance (SPR). Our results suggested that CA binds Keap1 and degrades Keap1 in a p62-dependent manner, further promoting nuclear transcription of Nrf2 and thus effectively reducing oxidative stress. In addition, based on the three-dimensional eutectic structure, it was confirmed that CA directly targets Keap1 protein by interacting with residues M550 and N532, inducing conformation changes in Keap1 protein. We also found that the CA analog chlorogenic acid (GCA) can bind Keap1. In conclusion, this study elucidates a novel molecular mechanism and structural basis for the protective effects of CA against oxidative damage via the Keap1-Nrf2 pathway.

OBJECTIVE To investigate the effects of catalpol on H2O2-induced osteoblast injury and its mechanism. METHODS The osteoblasts MC3T3-E1 were separated into control group， model group， empty group （transfected with empty plasmid）， catalpol group （100 μmol/L）， catalpol+forkhead box O3 （FoxO3） overexpression group （100 μmol/L catalpol+ transfected with FoxO3 overexpression plasmid）. After catalpol treatment and transfection， except for control group， other groups were induced with H2O2 to establish osteoblast oxidative stress model. The cell viability， apoptotic rate， alkaline phosphatase （ALP） activity， optical density （OD） value of calcium nodule， mean fluorescence intensity （MFI） of reactive oxygen species （ROS）， antioxidant enzyme activity [superoxide dismutase （SOD）， catalase （CAT）]， the levels of inflammatory factors [interleukin-6 （IL-6）， IL-1β]， and the expressions of FoxO3/Wnt/β-catenin signaling pathway-related proteins were detected in each group. RESULTS Compared with the control group， the cell viability， ALP activity， OD value of calcium nodule， activities of antioxidant enzyme， and the protein expressions of Wnt and β-catenin were decreased significantly in the model group， while apoptotic rate， MFI levels of ROS， inflammatory factor levels and the protein expression of FoxO3 were all increased significantly （P＜0.05）. Compared with the model group， above indicators of the empty group had no significant change （P＞0.05）， while those of catalpol group were reversed significantly （P＜0.05）. Compared with the catalpol group， the reversal effect of the changes in the above indicators was significantly weakened in the catalpol+FoxO3 overexpression group cells （P＜0.05）. CONCLUSIONS Catalpol can activate Wnt/β-catenin signaling pathway by down-regulating FoxO3， thereby inhibiting H2O2-induced MC3T3-E1 oxidative stress and inflammation reaction， enhancing cell viability and osteogenic differentiation activity， and alleviating apoptosis injury.

Objective To investigate the consistency analysis between multimodal MRI in determining vaginal involvement and parametrial infiltration in cervical cancer patients and pathological examination.Methods Ninety-two patients with cervical cancer were regressively selected and who underwent preoperative multimodal MRI examination.Using pathological results as the gold standard,the receiver operating characteristic(ROC)curve was used to analyze the diagnostic efficacy of conventional MRI,diffusion weighted imaging(DWI)and dynamic contrast-enhanced magnetic resonance imaging(DCE-MRI)alone and in combination in predic-ting vaginal involvement and parametrial infiltration.Results(1)Vaginal involvement:the diagnostic sensitivity of conventional MRI was 65.96％,the specificity was 91.11％,and the area under the curve(AUC)was 0.775[95％confidence interval(CI)0.676-0.873].The sensitivity of DCE-MRI was 61.70％,the specificity was 95.56％,and the AUC was 0.797(95％CI 0.702-0.892).The sensitivity of DWI was 72.34％,the specificity was 88.89％,and the AUC was 0.817(95％CI 0.725-0.908).At the optimal cut-off point,the sensitivity of parallel combined detection was 97.87％,the specificity was 93.33％,and the AUC was 0.956(95％CI 0.907-0.918).(2)Parametrial infiltration:the diagnostic sensitivity of conventional MRI was 67.24％,the specificity was 91.18％,and the AUC was 0.783(95％CI 0.688-0.879).The sensitivity of DCE-MRI was 62.07％,the specificity was 94.12％,and the AUC was 0.781(95％CI 0.686-0.875).The sensitivity of DWI was 75.86％,the specificity was 97.06％,and the AUC was 0.865(95％CI 0.788-0.941).At the optimal cut-off point,the sensitivity of parallel combined detection was 98.28％,the specificity was 91.18％,and the AUC was 0.947(95％CI 0.888-1.000).Conclusion Combined multimodal MRI can improve the positive detection rate of vaginal involve-ment and parametrial infiltration in patients with cervical cancer,allowing for timely treatment adjustments,improved quality of life and longer survival.

Objective:To investigate the current situation and influence factors of prehospital thrombolysis treatment for ST segment elevation myocardial infarction (STEMI) in China, to analyze the main factors affecting prehospital thrombolysis implementation, and optimize the pre-hospital thrombolysis strategy for STEMI to reduce mortality.Methods:A multicenter cross-sectional survey was conducted. 21 cities from six major geographical regions in China were selected by using convenient sampling method. An anonymous online electronic questionnaire was used to investigate the current situation and influence factors of prehospital emergency physicians and grassroots physicians implementing prehospital thrombolysis treatment for STEMI patients. Chi-square test was used to analyze the differences in count data between groups, and multivariate logistic regression was used to analyze the factors affecting prehospital thrombolysis in STEMI.Results:A total of 5 163 prehospital emergency physicians and physicians from grassroots township health centers/community health service centers or village clinics participated in this survey. Among them, 3208 (62.13%) have never implemtent thrombolysis, and 1 955 (37.87%) have did it before. The results of the multivariate logistic regression analysis indicated that physicians with 5-10 years of experience ( OR=1.41, 95% CI: 1.18-1.69, P<0.01), 11-20 years of experience ( OR=1.25, 95% CI: 1.03-1.52, P=0.02), those working in village clinics ( OR=1.30, 95% CI: 1.05-1.61, P=0.02), those in pre-hospital emergency medical institutions/departments ( OR=3.19, 95% CI: 2.80-3.64, P<0.01), those whose units are equipped with remote ECG transmission capabilities ( OR=1.72, 95% CI: 1.50-1.96, P<0.01), or ECG AI-assisted diagnostic tools ( OR=1.31, 95% CI: 1.15-1.49, P<0.01), and those who believe that thrombolysis is highly effective and should be widely adopted ( OR=2.55, 95% CI: 2.09-3.12, P<0.01) or consider it somewhat effective but warranting caution ( OR=2.11, 95% CI: 1.73-2.59, P<0.001), were more likely to make pre-hospital thrombolysis decisions for STEMI patients. To improve the current situation of pre-hospital thrombolysis for STEMI, the top four measures prioritized by pre-hospital emergency and grassroots physicians were enhancing the rescue capabilities of primary care doctors (92.22%), strengthening guidance from higherlevel hospitals (84.99%), increasing support for information technology (83.37%), and improving public health education (74.75%). Conclusions:The implementation rate of prehospital thrombolysis for STEMI in China still needs to be improved. Optimizing the prehospital thrombolysis strategy for STEMI, strengthening the allocation of basic medical resources and information technology support, and improving the referral mechanism are conducive to the implementation of prehospital thrombolysis for STEMI.

Patients with severe trauma require an extremely timely treatment and transfusion plays an irreplaceable role in the emergency treatment of such patients. An increasing number of evidence-based medicinal evidences and clinical practices suggest that patients with severe traumatic bleeding benefit from early transfusion of low-titer group O whole blood or hemostatic resuscitation with red blood cells, plasma and platelet of a balanced ratio. However, the current domestic mode of blood supply cannot fully meet the requirements of timely and effective blood transfusion for emergency treatment of patients with severe trauma in clinical practice. In order to solve the key problems in blood supply and blood transfusion strategies for emergency treatment of severe trauma, Branch of Clinical Transfusion Medicine of Chinese Medical Association, Group for Trauma Emergency Care and Multiple Injuries of Trauma Branch of Chinese Medical Association, Young Scholar Group of Disaster Medicine Branch of Chinese Medical Association organized domestic experts of blood transfusion medicine and trauma treatment to jointly formulate Chinese expert consensus on blood support mode and blood transfusion strategies for emergency treatment of severe trauma patients ( version 2024). Based on the evidence-based medical evidence and Delphi method of expert consultation and voting, 10 recommendations were put forward from two aspects of blood support mode and transfusion strategies, aiming to provide a reference for transfusion resuscitation in the emergency treatment of severe trauma and further improve the success rate of treatment of patients with severe trauma.

Evaluating the consistency of herb injectable formulations could improve their product quality and clinical safety, particularly concerning the composition and content levels of trace ingredients. Panax notoginseng Saponins Injection (PNSI), widely used in China for treating acute cardiovascular diseases, contains low-abundance (10%-25%) and trace saponins in addition to its five main constituents (notoginsenoside R₁, ginsenoside Rg₁, ginsenoside Re, ginsenoside Rb₁, and ginsenoside Rd). This study aimed to establish a robust analytical method and assess the variability in trace saponin levels within PNSI from different vendors and formulation types. To achieve this, a liquid chromatography-triple quadrupole mass spectrometry (LC-MS/MS) method employing multiple ions monitoring (MIM) was developed. A "post-column valve switching" strategy was implemented to eliminate highly abundant peaks (NR₁, Rg₁, and Re) at 26 min. A total of 51 saponins in PNSI were quantified or relatively quantified using 18 saponin standards, with digoxin as the internal standard. This study evaluated 119 batches of PNSI from seven vendors, revealing significant variability in trace saponin levels among different vendors and formulation types. These findings highlight the importance of consistent content in low-abundance and trace saponins to ensure product control and clinical safety. Standardization of these ingredients is crucial for maintaining the quality and effectiveness of PNSI in treating acute cardiovascular diseases.
Ginsenosides ; Saponins ; Chemometrics ; Panax notoginseng ; Cardiovascular Diseases ; Chromatography, Liquid ; Tandem Mass Spectrometry

Objective:To measure the skin thickness in patients with erysipelas by high-frequency ultrasonography (HF-USG), and to compare the clinical efficacy of systemic antibiotics alone versus their combination with glucocorticoids in the treatment of erysipelas.Methods:Hospitalized patients with erysipelas were enrolled from Zhongda Hospital, Southeast University from January to December in 2021, and randomly divided into the study group and control group according to the order of visits. The study group was treated with systemic cefathiamidine for 7 days followed by oral methylprednisolone at a dose of 0.4 mg·kg -1·d -1, while the control group was treated with cefathiamidine alone. Before and after the treatment for 10 days, the thicknesses of the epidermis-dermis layers and subcutaneous tissues were measured by HF-USG at the sites of the most severe skin lesions on the affected limbs and at the corresponding sites on the healthy limbs, and white blood cell (WBC) counts, neutrophil (NEU) counts, as well as C-reaction protein (CRP) levels were determined. The t test and non-parametric test were used to compare the efficacy between two groups. Results:A total of 23 patients with erysipelas were enrolled. Among the 12 patients in the study group, 8 were males and 4 were females, and their age was 71.4 ± 11.4 years. Among the 11 patients in the control group, 7 were males and 4 were females, and their age was 67.4 ± 11.1 years. Before treatment, the thicknesses of the epidermis-dermis layers (0.33 ± 0.12 cm) and subcutaneous tissues (1.08 ± 0.49 cm) in the study group were not significantly different from those in the control group (0.25 ± 0.09 cm, 0.98 ± 0.46 cm; t = -1.83, -0.49, P = 0.081, 0.626, respectively). After the 10-day treatment, the thicknesses of the epidermis-dermis layers and subcutaneous tissues of the skin lesions on the affected limbs significantly decreased in both groups compared with those before treatment (both P < 0.05), and the decrease in the thicknesses of subcutaneous tissues was significantly stronger in the study group (0.32 ± 0.33 cm) than in the control group (0.10 ± 0.07 cm; t = 2.20, P = 0.039). Before treatment, the WBC counts ([11.16 ± 4.42] × 10 9/L), NEU counts ([8.26 ± 4.16] × 10 9/L) and CRP levels (median [ Q1, Q3]: 72.20 [19.28, 140.50] mg/L) in the study group were not significantly different from those in the control group ([10.10 ± 4.53] × 10 9/L, [7.21 ± 3.00] × 10 9/L, 34.40 [8.00, 74.20] mg/L, respectively; t or Z = 0.60, 0.71, -0.85, P = 0.578, 0.496, 0.196, respectively). After the 10-day treatment, the WBC counts, NEU counts, and CRP levels significantly decreased in both groups compared with those before treatment (all P < 0.05) . Conclusion:The combined treatment with systemic antibiotics and glucocorticoids could effectively alleviate skin inflammation, and more rapidly reduce the thicknesses of inflamed subcutaneous tissues in patients with erysipelas compared with systemic antibiotics alone.

Objective To analyze the epidemic characteristics and causes of post-exposure immunization failure of rabies in Hubei Province from 2015 to 2021, and to provide evidence for the prevention and control of rabies in Hubei Province. Methods The investigation data of rabies cases in Hubei Province from 2015 to 2021 were collected, and descriptive epidemiological methods were used for data analysis. Results A total of 127 cases of rabies were reported in Hubei Province from 2015 to 2021, with an average annual incidence of 0.31/million, showing a downward trend. The male to female ratio was 1.70:1. Farmers accounted for 82.67% of the total cases, and the 50-79 years old group accounted for 75.59%. The incidence was mainly concentrated in Xiangyang, Shiyan, Yichang and Jingmen, accounting for 77.17%. Most of the cases were concentrated in summer and autumn. Exposure of grade Ⅱand Ⅲ accounted for 24.79% and 75.21%, respectively. Hands, lower limbs below knee, head, arms and lower limbs above knee accounted for 46.15%, 25.21%, 9.40%, 8.55% and 7.69% of the exposed parts, respectively. Dogs, cats and wild animals accounted for 95.73%, 3.42% and 0.85% of the exposed animals, respectively. Stray animals, domesticated animals, neighbors' animals and wild animals accounted for 41.88%, 37.61%, 19.66% and 0.85% of animal sources, respectively. Neither the neighbors’ animals nor domesticated animals were vaccinated against veterinary rabies virus. After exposure, 8.55% of patients went to medical institutions for standard treatment of wounds, 9.40% were vaccinated with human rabies vaccine, and 4.55% of patients with grade III exposure were injected with rabies virus immunoglobulin. The incubation period within 6 months, from 6 months to 1 year, and over 1 year accounted for 72.22%, 14.74%, and 12.04%, respectively. The exposure degree (Z=-1.98, P < 0.05), exposure site (χ²=10.91, P < 0.05) and wound treatment (χ²=15.73, P < 0.05) had statistically significant effects on the incubation period. Among the 11 cases of post-exposure immunization failure, all were grade Ⅲ exposure, 63.63% were exposed to the head and face, 81.81% were not fully vaccinated with human rabies virus vaccine, 63.63% were not immunized with immunoglobulin, and 27.27% were inappropriate wound treatment. Conclusion The key to rabies prevention and control is to standardize dog management, strengthen rabies education, standardize post-exposure wound treatment, timely vaccinate against rabies virus, and inject rabies virus immunoglobulin when necessary.