Homo- or heterodimeric compounds that affect dimeric protein function through interaction between monomeric moieties and protein subunits can serve as valuable sources of potent and selective drug candidates. Here, we screened an in-house dimeric natural product collection, and panepocyclinol A (PecA) emerged as a selective and potent STAT3 inhibitor with profound anti-tumor efficacy. Through cross-linking C712/C718 residues in separate STAT3 monomers with two distinct Michael receptors, PecA inhibits STAT3 DNA binding affinity and transcription activity. Molecular dynamics simulation reveals the key conformation changes of STAT3 dimers upon the di-covalent binding with PecA that abolishes its DNA interactions. Furthermore, PecA exhibits high efficacy against anaplastic large T cell lymphoma in vitro and in vivo, especially those with constitutively activated STAT3 or STAT3^Y640F. In summary, our study describes a distinct and effective di-covalent modification for the dimeric compound PecA to disrupt STAT3 function.

Pelvic organ prolapse (POP), whose etiology is influenced by genetic and clinical risk factors, considerably impacts women's quality of life. However, the genetic underpinnings in non-European populations and comprehensive risk models integrating genetic and clinical factors remain underexplored. This study constructed the first polygenic risk score (PRS) for POP in the Chinese population by utilizing 20 disease-associated variants from the largest existing genome-wide association study. We analyzed a discovery cohort of 576 cases and 623 controls and a validation cohort of 264 cases and 200 controls. Results showed that the case group exhibited a significantly higher PRS than the control group. Moreover, the odds ratio of the top 10% risk group was 2.6 times higher than that of the bottom 10%. A high PRS was significantly correlated with POP occurrence in women older than 50 years old and in those with one or no childbirths. As far as we know, the integrated prediction model, which combined PRS and clinical risk factors, demonstrated better predictive accuracy than other existing PRS models. This combined risk assessment model serves as a robust tool for POP risk prediction and stratification, thereby offering insights into individualized preventive measures and treatment strategies in future clinical practice.
Humans ; Female ; Pelvic Organ Prolapse/epidemiology* ; Middle Aged ; Risk Assessment/methods* ; China/epidemiology* ; Multifactorial Inheritance ; Aged ; Risk Factors ; Genome-Wide Association Study ; Genetic Predisposition to Disease ; Case-Control Studies ; Adult ; Polymorphism, Single Nucleotide ; Genetic Risk Score ; East Asian People

OBJECTIVE: To investigate the relationship between the trajectories of serum potassium changes after intensive care unit (ICU) admission and 30-day death risk in patients with sepsis. METHODS: A retrospective cohort study was conducted, including adult patients with sepsis admitted to the comprehensive ICU, medical intensive care unit (MICU) and emergency intensive care unit (EICU) of Guizhou Medical University Affiliated Hospital from January 2020 to January 2024. The patients who had a minimum of 5 days' hospitalisation in the ICU and who had at least 7 consecutive days of the serum potassium measurements were classified into five trajectories groups according to group-based trajectory modelling (GBTM) using SAS software. This was based on tendency changes in serum potassium levels in patients after admission to the ICU, which was categorized as follows: slowly increased from a low level group, slowly increased from a medium level of normal range group, slowly decreased from a medium level of normal range group, slowly decreased from a high level group, and slowly increased from a high level of normal range group. The patient's gender, age, medical history, and white blood cell count (WBC), platelet count (PLT), procalcitonin (PCT), activated partial thromboplastin time (APTT), prothrombin time (PT), blood sodium, and serum creatinine (SCr) at the time of admission to the ICU were collected. At the same time, the patient's worst sequential organ failure assessment (SOFA) score within 24 hours of admission to the ICU, length of ICU stay, and 30-day outcome were record. The differences in clinical data among different groups of patients were compared. The 30-day cumulative survival rates of the various serum potassium trajectories were plotted using Kaplan-Meier survival curves, the groups were then compared using the Log-Rank test. A multivariate Cox proportional risk regression analysis was developed to evaluate the independent effect of serum potassium trajectory on 30-day death risk. RESULTS: Finally, 342 ICU sepsis patients were enrolled, of which 42 patients in the slowly increased from a low level group (12.28%), 127 patients in the slowly increased from a medium level of normal range group (37.14%), 118 patients in the slowly decreased from a medium level of normal range group (34.50%), 28 patients in the slowly decreased from a high level group (8.19%), and 27 patients in the slowly increased from a high level of normal range group (7.89%). Except for age and APTT differences, there were no statistically significant differences in other clinical characteristics among the patients in the different serum potassium trajectories groups. Kaplan-Meier survival curves showed that there was statistically significant difference in the 30-day cumulative survival rate among the patients in the different serum potassium trajectories groups (Log-Rank test: χ² = 14.696, P = 0.005), with the lowest in the slowly increased from a high level of normal range group (39.3%). Multivariate Cox proportional risk regression analysis showed that the patients with the serum potassium trajectory of slowly increased from a high level of normal range had the highest 30-day death risk [hazard ratio (HR) = 2.341, 95% confidence interval (95%CI) was 1.049-5.226, P = 0.038]. This association persisted after adjustment for variables such as gender, age, medical history, SOFA score, WBC, PLT, PCT, APTT, PT, blood sodium, and SCr (HR = 3.058, 95%CI was 1.249-7.488, P = 0.014). CONCLUSION Compared with the patients whose serum potassium fluctuated within the normal range, the sepsis patients in the ICU with a serum potassium trajectory that slowly increased from a high level of normal range had a significantly higher 30-day death risk.
Humans ; Retrospective Studies ; Intensive Care Units ; Sepsis/blood* ; Potassium/blood* ; Male ; Female ; Middle Aged ; Aged ; Risk Factors ; Hospital Mortality ; Prognosis

The patient was a girl, aged 10 years, who was admitted due to fever for 5 days and pancytopenia in peripheral blood for 2 days. Bone marrow examination showed the presence of phagocytic activity, and peripheral blood tests showed pancytopenia, an increase in ferritin, a reduction in fibrinogen, increases in triglyceride and sCD25, and a reduction in natural killer cell activity, which led to the diagnosis of hemophagocytic lymphohistiocytosis (HLH). On the day of admission, the child developed convulsions and rapidly progressed to refractory status epilepticus, which was consistent with the manifestations of febrile infection-related epilepsy syndrome. HLH was controlled after active immunotherapy, with the sequela of refractory epilepsy, and her cognitive function was essentially within normal limits. This article reports the condition of febrile infection-related epilepsy syndrome caused by HLH for the first time in China, in order to improve the awareness of this disease among clinicians.
Humans ; Lymphohistiocytosis, Hemophagocytic/complications* ; Female ; Child ; Epilepsy/etiology* ; Fever/etiology* ; Epileptic Syndromes/etiology*

Liquiritigenin(LG)is a flavone of pharmacological importance,however,its application potential is severely limited due to its poor water solubility.LG could be disassociated slightly in water to form phenolate anion,therefore,better solubilization effect is expected by inclusion with cationic cyclodextrins(CCDs).In this work,four kinds of CCDs modified with amino groups at the primary face were synthesized,and their solid inclusion complexes with LG were successfully prepared by preparing their saturated solutions.The formation of the solid inclusion complexes was confirmed by scanning electron microscopy(SEM)and powder X-ray diffraction(PXRD),and their supramolecular binding behavior in solution was studied using multiple techniques.A 1∶1 inclusion stoichiometry of inclusion complexation was defined using Job plot by ultraviolet-visible(UV-vis)spectroscopy,and their binding stability constants(Ks)were determined as 2862.77,3494.70,6521.85 and 9599.48 L/mol using UV-vis spectroscopic titration,far more superior to that of nativeβ-CD(Ks=236.79 L/mol).This indicated that the amino side chains on CCDs could actively participate in the inclusion complexation through anion-cation interactions,significantly strengthening the host-guest binding between CCDs and LG.The inclusion modes were further elucidated based on proton and two-dimensional rotating-frame overhauser enhancement spectroscopy(2D-ROESY)nuclear magnetic resonance(NMR)experiments and molecular docking.Water solubility of LG was dramatically promoted up to 4.9 mg/mL,which was 70-fold higher than that of native LG.This study could draw inspiration for the binding and solubilization of phenols such as flavones by design of cationic macrocyclic molecules.

Objective:To investigate the dynamic changes of plasma high-mobility group box 1 (HMGB1) and its correlation with functional outcome and symptomatic intracranial hemorrhage (sICH) after endovascular treatment (EVT) in patients with acute large vessel occlusion stroke (ALVOS).Methods:Patients with ALVOS admitted to the Department of Neurology, Zengcheng District, Nanfang Hospital, Southern Medical University from June 2021 to April 2023 were included retrospectively. Plasma HMGB1 before EVT and at 6, 24, and 48 hours after procedure was detected, and the dynamic changes of plasma HMGB1 were compared and analyzed. The primary endpoint was the functional outcome evaluated using the modified Rankin Scale at 90 days of onset. A score of 0-2 was defined as good outcome and >2 was defined as poor outcome. The secondary endpoint was sICH, which was defined as the occurrence of hemorrhagic infarction after EVT and an increase of ≥4 in the National Institutes of Health Stroke Scale (NIHSS) score from baseline. Multivariate logistic regression analysis was used to evaluate the predictive value of HMGB1 for poor outcome and sICH. Results:A total of 73 patients with ALVOS received EVT were included. There were 54 males (74.0%), aged 62±12 years. The median time from onset to door was 90 minutes (interquartile range, 40-180 minutes), and the median time from onset to femoral artery puncture was 181 minutes (interquartile range, 140-280 minutes). Twenty-nine patients (39.7%) underwent bridging intravenous thrombolysis (IVT). At 90 days after onset, 37 patients (50.7%) had poor outcome, and 12 (16.4%) died during follow-up. Eleven patients (15.1%) developed sICH. After EVT, plasma HMGB1 showed a temporal increase, reaching its peak at 48 hours (median, 102.57 μg/L). Subgroup analysis showed that HMGB1 in the bridging IVT group at 6 hours ( P<0.05) and 24 hours ( P<0.05) after procedure were significantly higher than that at baseline. The non-bridging IVT group showed a significant increase at 6 hours after procedure ( P<0.05). There was no statistically significant difference in HMGB1 between the bridging IVT group and the non-bridging IVT group at the same time point. Multivariate logistic regression analysis showed that after adjusting for age, ischemic heart disease, triglycerides, uric acid, baseline NIHSS score, and sICH, the third quartile (adjusted odds ratio 7.087, 95% confidence interval 1.243-40.419; P=0.027) and fourth quartile (adjusted odds ratio 7.544, 95% confidence interval 1.260-45.172; P=0.027) of plasma HMGB1 were independent risk factors for poor outcome at 6 hours after procedure. The postoperative plasma HMGB1 in the sICH group was significantly higher than that in the non-sICH group ( P<0.05), but multivariate analysis showed no independent correlation between plasma HMGB1 and sICH. Conclusion:The elevation of plasma HMGB1 in patients with ALVOS at 6 hours after EVT is independently associated with poor outcome at 90 days after onset, but not with sICH.

The zebrafish model has attracted much attention due to its strong reproductive ability, short research cycle, and ease of maintenance. It has always been an important vertebrate model system, often used to carry out human disease research. Its motor behavior features have the advantages of being simpler, more intuitive, and quantifiable. In recent years, it has received widespread attention in the study of traditional Chinese medicine(TCM)for the treatment of sleep disorders, neurodegenerative diseases, fatigue, epilepsy, and other diseases. This paper reviews the characteristics of zebrafish motor behavior and its applications in the pharmacodynamic verification and mechanism research of TCM extracts, active ingredients, and TCM compounds, as well as in active ingredient screening and safety evaluation. The paper also analyzes its advantages and disadvantages, with the aim of improving the breadth and depth of zebrafish and its motor behavior applications in the field of TCM research.
Zebrafish/physiology* ; Medicine, Chinese Traditional ; Drugs, Chinese Herbal/therapeutic use* ; Disease Models, Animal ; Drug Evaluation, Preclinical/methods* ; Animals ; Sleep Wake Disorders/physiopathology* ; Epilepsy/physiopathology* ; Neurodegenerative Diseases/physiopathology* ; Fatigue/physiopathology* ; Behavior, Animal/physiology* ; Motor Activity/physiology*

Objective:To compare the efficacy of anrikefon and tegileridine for analgesia in patients with moderate-to-severe pain after abdominal surgery with general anesthesia.Methods:In this multicenter, randomized, double-blind, active-controlled clinical trial, 101 patients with moderate to severe pain (numeric pain rating scale [NRS] score ≥4 within 4 h after operation) after abdominal surgery with general anesthesia between February 24 and April 1, 2025, aged 18-70 yr, with a body mass index of 18-40 kg/m 2, were assigned to anrikefon group ( n=50) and tegileridine group ( n=51) in a 1∶1 ratio using stratified blocked randomization. Double-dummy design was employed to maintain blinding. Each group received an initial intravenous injection of anrikefon 1 μg/kg or tegileridine 1 mg, followed by connection to a patient-controlled intravenous analgesia (PCIA) pump (the PCIA solution contained normal saline in anrikefon group; the PCIA solution contained tegileridine 5 mg in tegileridine pump) within 10 min. If the patient′s NRS score ≥4 at 8 and 16 h after the initial injection, anrikefon 1 μg/kg was intravenously injected in anrikefon group, and tegileridine group received the equal volume of normal saline. The primary efficacy endpoint was the sum of pain intensity difference (SPID) over the first 24 h after the initial dose (SPID 0-24h). The secondary efficacy endpoints included the incidence and severity of vomiting and nausea, incidence of postoperative nausea and vomiting(PONV), the proportion of patients who received antiemetic treatment, and total consumption of antiemetics within 0-24 h after the initial dose, NRS score at rest ≤ 1 at 24 h after the initial dose, and NRS score at rest ≤ 3 over the first 24 h after the initial dose. Safety indicators included adverse events, vital signs, physical examination findings, 12-lead ECG and laboratory test indicators, and adverse events of special interest. Results:Compared with tegileridine group, no significant change was found in the SPID 0-24h ( P>0.05), and the incidence of vomiting, PONV, proportion of patients requiring antiemetic medication, and total consumption of antiemetics were significantly decreased within the first 24 h after the initial dose in tegileridine group ( P<0.05). One treatment-emergent adverse event of Common Terminology Criteria for Adverse Events grade 3 or higher occurred in tegileridine group, while no treatment-emergent adverse events of Common Terminology Criteria for Adverse Events grade 3 or higher were found in anrikefon group. Among the adverse events of special interest, one case of respiratory depression and one case of cough occurred in tegileridine group, while one case of cough occurred in anrikefon group, with no respiratory depression. Conclusions:Anrikefon and tegileridine provide comparable analgesic efficacy for moderate-to-severe pain after abdominal surgery with general anesthesia. However, anrikefon exhibits an advantage in reducing the risk of PONV, with a superior safety profile.

Objective:To examine the effect of cumulative hemoglobin A 1c (HbA 1c) levels and insulin dosage on insulin resistance (IR)-related metabolic disturbances in newly diagnosed patients with type 1 diabetes (T1D). Methods:This retrospective cohort study included T1D patients admitted to the Second Xiangya Hospital of Central South University from November 2015 to March 2023. Clinical data collected comprised age, sex, disease duration, insulin dosage, body mass index, waist circumference, blood pressure, HbA 1c levels, islet autoantibodies, and fasting blood lipid profiles. IR-related metabolic disturbances assessed were overweight, obesity, central obesity, hypertension, and dyslipidemia. Cox regression and cluster analyses were applied to assess the influence of cumulative HbA 1c and insulin dosage on these metabolic disturbances. Results:A total of 235 patients were included, with 97 males (41.3%) and 138 females (58.7%). The median age was 19.8 (13.3, 31.1) years, and the median follow-up duration was 30.8 (20.8, 45.6) months. During follow-up, 41.6% (72/173) of patients developed IR-related metabolic disturbances. Multivariate Cox regression analysis revealed that a cumulative HbA 1c ≥60 mmol/mol was an independent risk factor for any IR-related metabolic disturbance [ HR (95% CI): 1.739 (1.067-2.835) ] and for triglyceride abnormalities [ HR (95% CI): 3.277 (1.176-9.127)]. Additionally, a cumulative insulin dosage ≥0.5 U·kg -1·d -1 was identified as an independent risk factor for overweight, obesity, or central obesity [ HR (95% CI): 2.374 (1.059-5.323)]. Cluster analysis further identified that patients with higher levels of cumulative HbA 1c and insulin dosage, particularly those with adolescent-onset diabetes, had the highest likelihood of developing hypertension ( HR=2.460, 95% CI 1.008-6.005), overweight/obesity/central obesity ( HR=2.707, 95% CI 1.062-6.900), triglyceride abnormalities ( HR=5.495, 95% CI 1.842-16.391), high-density lipoprotein cholesterol abnormalities ( HR=11.054, 95% CI 4.107-29.751), and any IR-related metabolic disturbance ( HR=5.833, 95% CI 2.602-13.077). Conclusions:Elevated cumulative HbA 1c and insulin dosage levels in T1D patients are associated with an increased risk of developing IR-related metabolic disturbances. These findings underscore the urgent need for novel therapeutic strategies tailored to this population.