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.

BACKGROUND: Epoxyeicosatrienoic acids (EETs), which are metabolites of arachidonic acid catalyzed by cytochrome P450 epoxygenase, are degraded into inactive dihydroxyeicosatrienoic acids by soluble epoxide hydrolase (sEH). Many studies have revealed that sEH gene deletion exerts protective effects against diabetes. Vascular calcification is a common complication of diabetes, but the potential effects of sEH on diabetic vascular calcification are still unknown. METHODS: The level of aortic calcification in wild-type and Ephx2-/- C57BL/6 diabetic mice induced with streptozotocin was evaluated by measuring the aortic calcium content through alizarin red staining, immunohistochemistry staining, and immunofluorescence staining. Mouse vascular smooth muscle cell lines (MOVAS cells) treated with β-glycerol phosphate (0.01 mol/L) plus advanced glycation end products (50 mg/L) were used to investigate the effects of sEH inhibitors or sEH knockdown and EETs on the calcification of vascular smooth muscle cells, which was detected by Western blotting, alizarin red staining, and Von Kossa staining. RESULTS: sEH gene deletion significantly inhibited diabetic vascular calcification by increasing levels of EETs in the aortas of mice. EETs (especially 11,12-EET and 14,15-EET) efficiently prevented the osteogenic transdifferentiation of MOVAS cells by decreasing nidogen-2 (NID2) expression. Interestingly, suppressing sEH activity by small interfering ribonucleic acid or specific inhibitors did not block osteogenic transdifferentiation of MOVAS cells induced by β-glycerol phosphate and advanced glycation end products. NID2 overexpression significantly abolished the inhibitory effect of sEH gene deletion on diabetic vascular calcification. Moreover, NID2 overexpression mediated by adeno-associated virus 9 vectors markedly increased insulin-like growth factor 2 (IGF2) and phospho-ERK1/2 expression in MOVAS cells. Overall, sEH gene knockout inhibited diabetic vascular calcification by decreasing aortic NID2 expression and, then, inactivating the downstream IGF2-ERK1/2 signaling pathway. CONCLUSIONS sEH gene deletion markedly inhibited diabetic vascular calcification through repressed osteogenic transdifferentiation of vascular smooth muscle cells mediated by increased aortic EET levels, which was associated with decreased NID2 expression and inactivation of the downstream IGF2-ERK1/2 signaling pathway.
Animals ; Mice ; Vascular Calcification/metabolism* ; Mice, Inbred C57BL ; Epoxide Hydrolases/metabolism* ; Diabetes Mellitus, Experimental/genetics* ; Male ; Gene Deletion ; MAP Kinase Signaling System/genetics* ; Cell Line ; Immunohistochemistry ; Muscle, Smooth, Vascular/metabolism* ; Signal Transduction/genetics* ; Mice, Knockout

Background: and Purpose Limited evidence exists on the effectiveness of endovascular treatment (EVT) for acute posterior circulation tandem lesion (PCTL). This study aimed to explore the role of extracranial vertebral artery (VA) stenting in patients with PCTL stroke undergoing EVT. Methods: Individual patient data were pooled from the BASILAR (EVT for Acute Basilar Artery Occlusion Study) and PERSIST (Posterior Circulation Ischemic Stroke) registries. Patients with PCTLs who underwent EVT were included in the present cohort and divided into the stenting and nonstenting groups based on the placement of extracranial VA stents. The primary efficacy outcome was the modified Rankin Scale (mRS) scores at 90 days and 1 year. Safety outcomes included 24-hour symptomatic intracranial hemorrhage (sICH) and all-cause mortality at 90 days and 1 year post-surgery. Results: A combined dataset of 1,320 patients with posterior circulation artery occlusion, including 263 (19.9%) with tandem lesions, of whom 217 (median age, 65 years; 82.9% male) met the inclusion criteria for the analysis. The stenting group had 84 (38.7%) patients, while the non-stenting group had 133 (61.3%). After adjustment for the potential confounders, extracranial VA stenting was associated with favorable shifts in mRS scores at both 90 days (adjusted common odds ratio [OR], 2.30; 95% confidence interval [CI], 1.23–4.28; P<0.01) and 1 year (adjusted OR [aOR], 2.04; 95% CI [1.05–3.97]; P=0.04), along with lower rate of mortality at both 90 days (aOR, 0.45; 95% CI [0.21–0.93]; P=0.01) and 1 year (aOR, 0.36; 95% CI [0.16–0.79]; P=0.01), with no significant difference in sICH incidence (aOR, 0.35; 95% CI [0.06–1.98]; P=0.24). Conclusion Extracranial VA stenting during EVT may improve functional outcomes and reduce mortality in patients with PCTL strokes.

Background: and Purpose Limited evidence exists on the effectiveness of endovascular treatment (EVT) for acute posterior circulation tandem lesion (PCTL). This study aimed to explore the role of extracranial vertebral artery (VA) stenting in patients with PCTL stroke undergoing EVT. Methods: Individual patient data were pooled from the BASILAR (EVT for Acute Basilar Artery Occlusion Study) and PERSIST (Posterior Circulation Ischemic Stroke) registries. Patients with PCTLs who underwent EVT were included in the present cohort and divided into the stenting and nonstenting groups based on the placement of extracranial VA stents. The primary efficacy outcome was the modified Rankin Scale (mRS) scores at 90 days and 1 year. Safety outcomes included 24-hour symptomatic intracranial hemorrhage (sICH) and all-cause mortality at 90 days and 1 year post-surgery. Results: A combined dataset of 1,320 patients with posterior circulation artery occlusion, including 263 (19.9%) with tandem lesions, of whom 217 (median age, 65 years; 82.9% male) met the inclusion criteria for the analysis. The stenting group had 84 (38.7%) patients, while the non-stenting group had 133 (61.3%). After adjustment for the potential confounders, extracranial VA stenting was associated with favorable shifts in mRS scores at both 90 days (adjusted common odds ratio [OR], 2.30; 95% confidence interval [CI], 1.23–4.28; P<0.01) and 1 year (adjusted OR [aOR], 2.04; 95% CI [1.05–3.97]; P=0.04), along with lower rate of mortality at both 90 days (aOR, 0.45; 95% CI [0.21–0.93]; P=0.01) and 1 year (aOR, 0.36; 95% CI [0.16–0.79]; P=0.01), with no significant difference in sICH incidence (aOR, 0.35; 95% CI [0.06–1.98]; P=0.24). Conclusion Extracranial VA stenting during EVT may improve functional outcomes and reduce mortality in patients with PCTL strokes.

Objective:To analyze the current employment status and the reasons for not engaging in general practice among general practice residents who completed training during 2018-2020.Methods:This study was a cross-sectional study. A questionnaire survey on the current employment was conducted among general practice residents who completed redidency training from 2018 to 2020, participants were selected by stratified random sampling in 57 training centers from each 5 provinces(municipalities) of the eastern, middle and western regions in China. The reasons for not engaging in general practice were investigated through telephone contact.Results:Of the 1 037 general practice residents who responded to the questionnaire, 677 residents(65.3%, 677/1 037) were engaged in general practice after training, while 360 residents(34.7%, 360/1 037) left general practice career or were awaiting employment. The three provinces with the highest proportion of residents leaving general practice career were Hubei(76.5%, 26/360), Sichuan(74.4%, 29/360) and Shandong provinces(59.6%, 28/360). There were significant differences in proportion of residents leaving general practice career after completing the training among eastern, middle and western regions(χ 2=42.911, P<0.001). A total of 261 participants(25.2%, 261/1 037) were engaged in non-general practice clinical career like internal medicine, surgery, gynecology, pediatrics or medical imaging; and the proportion in the eastern(27.3%, 67/245) and middle(33.3%, 106/318) regions was significantly higher thant that in the western region(18.6%, 88/474)(χ 2=6.855, P<0.05; χ 2=21.651, P<0.05). Among 259(71.9%, 259/360) participants who left general practice career, the main reasons were personal choice(63.3%, 164/259) or employers′ arrangement(22.4%, 58/259); the three provinces with the highest percentage of personal choice were Hubei(92.0%, 23/25), Sichuan(85.2%, 23/27) and Henan provinces(80.0%, 20/25). The proportion of personal choice in the middle region(82.4%, 84/102) was significantly higher than that in the eastern(52.1%, 37/71) and western(50.0%, 43/86) regions(χ 2=16.799, P<0.05; χ 2=20.830, P<0.05). The three provinces with the highest proportion of employers′ arrangement were Xinjiang Uygur Autonomous Region(66.7%, 22/33), Zhejiang province(9/13), and Inner Mongolia Autonomous Region(38.5%, 10/26). The proportion of employers′ arrangement in the western region(41.9%,36/86) was significantly higher than that in the eastern(18.3%, 13/71) and middle(8.8%, 9/102) regions(χ 2=8.980, P<0.05; χ 2=26.186, P<0.05). Conclusions:The majority of general practice residents are engaged in general practice after training. The proportion of residents who left the general practice career and the related reasons in different regions are not the same.

Objective:To analyze the infection status of HBV among the healthy population in Tongchuan city in 2023, and compare it against the data from 2006, 2014, and 2020, thereby elucidating epidemiological trends and providing reference for optimizing hepatitis B prevention and control strategies in Tongchuan city.Methods:By using the method of multi-stage stratified random sampling, healthy people aged 1-59 from eight villages/communities in the four districts and counties of Tongchuan city were selected for on-site investigation and blood sample collection. ELISA was used to detect the five hepatitis B markers of the survey respondents, including HBsAg and HBsAb, and the seroprevalence rates of the populations with different characteristics were analyzed. Statistical analysis was performed using Chi-square test.Results:In 2023, a total of 1 926 healthy people were surveyed. After standardization, the positive rates of HBsAg, HBsAb, and HBV, and the rate of all five hepatitis B markers being negative were 0.56%, 54.57%, 26.77%, and 33.05%, respectively. Children aged 1-4 had the lowest positive rates of HBsAg, HBcAb, HBeAb, and HBV, as well as the lowest rate of all five hepatitis B markers being negative, while they had the highest positive rate of HBsAb. In the population aged 1-29, the positive rates of HBsAg and HBV, and the rate of all five hepatitis B markers being negative showed an upward trend with increasing age, while the positive rate of HBsAb showed a downward trend. In particular, the positive rate of HBsAb dropped sharply in the 5-14 age group. In 2023, the positive rate of HBV in the population aged 1-29 was 10.93% (111/1 016), and the rate of all five hepatitis B markers being negative was 38.39% (390/1 016), both lower than the results of the previous three surveys. The positive rate of HBsAb was 56.69% (576/1 016) in people aged 1-29 in 2023, which was higher than the results of the previous three surveys.Conclusions:Although certain achievements have been made in the prevention and control of hepatitis B in Tongchuan city in 2023, with more than one-third of the population showing all negative results in the five hepatitis B tests, the positive rate of HBsAb in the 5-14 age group has dropped sharply. Further actions required for hepatitis B prevention and control in Tongchuan city include optimizing the childhood immunization schedule for national immunization program vaccines, implementing booster programs for adolescents, and developing tailored immunization strategies for adults.

Background: and Purpose Limited evidence exists on the effectiveness of endovascular treatment (EVT) for acute posterior circulation tandem lesion (PCTL). This study aimed to explore the role of extracranial vertebral artery (VA) stenting in patients with PCTL stroke undergoing EVT. Methods: Individual patient data were pooled from the BASILAR (EVT for Acute Basilar Artery Occlusion Study) and PERSIST (Posterior Circulation Ischemic Stroke) registries. Patients with PCTLs who underwent EVT were included in the present cohort and divided into the stenting and nonstenting groups based on the placement of extracranial VA stents. The primary efficacy outcome was the modified Rankin Scale (mRS) scores at 90 days and 1 year. Safety outcomes included 24-hour symptomatic intracranial hemorrhage (sICH) and all-cause mortality at 90 days and 1 year post-surgery. Results: A combined dataset of 1,320 patients with posterior circulation artery occlusion, including 263 (19.9%) with tandem lesions, of whom 217 (median age, 65 years; 82.9% male) met the inclusion criteria for the analysis. The stenting group had 84 (38.7%) patients, while the non-stenting group had 133 (61.3%). After adjustment for the potential confounders, extracranial VA stenting was associated with favorable shifts in mRS scores at both 90 days (adjusted common odds ratio [OR], 2.30; 95% confidence interval [CI], 1.23–4.28; P<0.01) and 1 year (adjusted OR [aOR], 2.04; 95% CI [1.05–3.97]; P=0.04), along with lower rate of mortality at both 90 days (aOR, 0.45; 95% CI [0.21–0.93]; P=0.01) and 1 year (aOR, 0.36; 95% CI [0.16–0.79]; P=0.01), with no significant difference in sICH incidence (aOR, 0.35; 95% CI [0.06–1.98]; P=0.24). Conclusion Extracranial VA stenting during EVT may improve functional outcomes and reduce mortality in patients with PCTL strokes.

Using conventional broth microdilution assays,the synthetic phenolic antioxidant 2,6-di-tert-butyl-4-methylphenol(butylated hydroxytoluene,BHT)was screened for synergistic antimi-crobial activity with β-lactam antibiotics.Further validation through checkerboard assays,growth curve analysis,and time-kill curve experiments confirmed the synergistic effect of BHT and β-lac-tams against methicillin-resistant Staphylococcus aureus(MRSA)(FICI≤0.5).To elucidate the underlying mechanism of synergy,this study evaluated changes in membrane permeability and pro-ton transmembrane gradients-key factors in biofilm functionality-along with critical indicators of bacterial energy metabolism,including ATP levels and the NAD+/NADH ratio.The results dem-onstrated that BHT disrupts the proton motive force(PMF),impairs membrane potential,and perturbs bacterial energy homeostasis,thereby significantly enhancing the antibacterial efficacy ofβ-lactams.Furthermore,a murine pneumonia infection model was established to assess the in vivo therapeutic efficacy of BHT combined with amoxicillin.The combination therapy alleviated pulmo-nary tissue damage,reduced bacterial loads in target organs(liver,spleen,and lungs),and decreased systemic inflammatory responses.This study elucidates the synergistic antimicrobial action and mechanistic basis of BHT combined with amoxicillin,offering a novel combinatorial therapeutic strategy to address MRSA resistance.The findings hold significant clinical potential and research value for overcoming antibiotic resistance in MRSA infections.

Sigma-1 receptor (σ ₁R) has become a focus point of drug discovery for central nervous system (CNS) diseases. A series of novel 1-phenylethan-1-one O-(2-aminoethyl) oxime derivatives were synthesized. In vitro biological evaluation led to the identification of 1a, 14a, 15d and 16d as the most high-affinity (K _i < 4 nmol/L) and selective σ ₁R agonists. Among these, 15d, the most metabolically stable derivative exhibited high selectivity for σ ₁R in relation to σ ₂R and 52 other human targets. In addition to low CYP450 inhibition and induction, 15d also exhibited high brain permeability and excellent oral bioavailability. Importantly, 15d demonstrated effective antipsychotic potency, particularly for alleviating negative symptoms and improving cognitive impairment in experimental animal models, both of which are major challenges for schizophrenia treatment. Moreover, 15d produced no significant extrapyramidal symptoms, exhibiting superior pharmacological profiles in relation to current antipsychotic drugs. Mechanistically, 15d inhibited GSK3β and enhanced prefrontal BDNF expression and excitatory synaptic transmission in pyramidal neurons. Collectively, these in vivo proof-of-concept findings provide substantial experimental evidence to demonstrate that modulating σ ₁R represents a potential new therapeutic approach for schizophrenia. The novel chemical entity along with its favorable drug-like and pharmacological profile of 15d renders it a promising candidate for treating schizophrenia.

Objective:To survey the post competency of general practitioners who had completed residency training in China.Methods:This study was a cross-sectional survey. An online questionnaire survey was conducted among general practitioners, institution leaders and patients from January to February 2021. The participants were selected from 45 general practice residential training bases in the eastern, central and western regions of China by a combination of stratified sampling and proportional random sampling methods. The post competency self-assessment questionnaire was used for the general practitioners, and the competency evaluation questionnaire was used for institution leaders and the patients.Results:A total of 677 valid self-assessment questionnaires were returned from general practitioners, 600 from institution leaders, and 2 579 from patients. The professionalism and humanistic literacy of the self-assessment questionnaire had the highest score (4.41±0.60),and the teaching, learning and research abilities had the lowest score(3.57±0.84). There was no significant difference in the post competency score of general practitioners among different regions ( P>0.05). The highest score of general practitioners′ post competency evaluated by leaders was the professionalism and humanistic literacy (4.64±0.57), and the lowest one was the basic public health service ability (4.31±0.95). The score of professionalism and humanistic ability in the eastern region was significantly higher than that in the central and western regions ( P<0.05). The highest score of general practitioners′ post competency evaluated by patients was the professionalism and humanistic literacy (4.73±0.55), and the lowest score was the basic medical service ability (4.11±1.35). There were significant differences in scores of the ability for basic medical service, ability for basic public health service, ability for interpersonal communication and ability for professionalism and humanistic literacy among different regions ( P<0.05). For institution leaders, 68.2% (409/600) believed that the general practitioners were fully competent for their current jobs, 28.7% (172/600) believed that the general practitioners were basically competent for their current jobs. For patients, 70.5% (1 817/2 579) were very satisfied with the general practitioners′ service, and 27.1% (700/2 579) were basically satisfied with the general practitioners′ service. Conclusions:The competency of general practitioners who had received training in some provinces is basically up to standard, but the basic public health service ability and teaching, learning and research ability need to be improved.