BACKGROUND:Eucommia ulmoides has a certain osteogenic effect,which can promote the proliferation and differentiation of osteoblasts.However,it is unclear whether Eucommia ulmoides has effects on alveolar bone formation and Wnt/β-Catenin signaling pathway. OBJECTIVE:To investigate the mechanism by which Eucommia ulmoides promotes alveolar bone formation in ovariectomized rats based on the Wnt/β-Catenin signaling pathway. METHODS:Sixty female Sprague-Dawley rats were selected and randomly divided into five groups:blank control group,sham-operation group,model group,low-dose group Eucommia ulmoides group,and high-dose Eucommia ulmoides group,with twelve rats in each group.Osteoporosis animal models were constructed by bilateral oophorectomy in the model group and the low-dose and high-dose Eucommia ulmoides groups.The sham-operation group underwent the same method to remove adipose tissue of equal mass around the bilateral ovaries.Three months after surgery,the low-and high-dose Eucommia ulmoides groups were given 2.1 g/kg/d and 4.2 g/kg/d Eucommia ulmoides by gavage,respectively.The sham-operation group and model group were given the same amount of physiological saline by gavage.After 12 weeks of drug intervention,the changes in alveolar bone mass of rats in each group were observed through Micro-CT;hematoxylin-eosin staining was used to observe the pathological structural changes of alveolar bone in rats;enzyme linked immunosorbent assay was used to detect the expression levels of alkaline phosphatase and osteocalcin in the serum of rats;western blot was used to detect the expression levels of β-Catenin and Frizzled9 receptor proteins in the alveolar bone of rats;and real-time fluorescence quantitative PCR was used to detect the expression of osteocalcin,Runt-related transcription factor 2(Runx2),alkaline phosphatase,β-catenin,and frizzled9 mRNAs in alveolar bone tissues of rats. RESULTS AND CONCLUSION:Compared with the blank control group,bone volume fraction,trabecular number,trabecular thickness,and bone mineral density were reduced in the model group(P＜0.05),and trabecular separation was elevated(P＜0.05).Pathological observation showed that the arrangement of trabeculae was disordered and irregular,the trabeculae were thinned or broken,and the marrow cavity was enlarged in the model group,with a significant reduction in bone volume;the level of alkaline phosphatase in the serum was increased(P＜0.05),and the level of osteocalcin was decreased(P＜0.05);mRNA expression of alkaline phosphatase,osteocalcin,Runx2,β-catenin,and frizzled9 were decreased(P＜0.05);protein expression of β-Catenin and Frizzled9 was decreased(P＜0.05).Compared with the model group,the low-and high-dose Eucommia ulmoides groups showed an increase in bone volume fraction,trabecular number,trabecular thickness,and bone mineral density(P＜0.05)and a decrease in trabecular separation(P＜0.05).In the low-and high-dose Eucommia ulmoides groups,bone trabeculae were slightly aligned and thickened,with a significant increase in bone mass.Compared with the model group,the serum level of alkaline phosphatase was reduced(P＜0.05)and the serum level of osteocalcin was elevated(P＜0.05)in the low-and high-dose Eucommia ulmoides groups.Compared with the model group,the mRNA expression of alkaline phosphatase,osteocalcin,Runx2,β-catenin,and frizzled9 were increased in the low-and high-dose Eucommia ulmoides groups(P＜0.05).Compared with the model group,the protein expression of Frizzled9 was increased in the low-dose Eucommia ulmoides group(P＜0.05),while the protein expression of β-Catenin and Frizzled9 was increased in the high-dose Eucommia ulmoides group(P＜0.05).Compared with the low-dose Eucommia ulmoides group,the high-dose Eucommia ulmoides group had a more significant improvement in the above indexes.To conclude,Eucommia ulmoides can effectively promote the alveolar bone formation,and its mechanism of action might be related to the activation of the Wnt/β-catenin signaling pathway.

Background Air pollution exposure has a significant impact on maternal and child health. However, the research on the association between ambient ozone (O₃) exposure during pregnancy and the risk of premature birth in newborns is limited, and the conclusions are inconsistent. Objective To investigate the association of ambient O₃ exposure during pregnancy with the risk of preterm birth in Guangdong Province. Methods Data of pregnant women in Guangzhou from 2013 to 2019 and Foshan from 2018 to 2023 were collected, and O₃ concentrations during different trimesters were assessed according to maternal residential addresses. Bilinear interpolation was used to evaluate the concentrations of air pollution. A cohort study design was adopted in our study. Restricted cubic spline curves were used to evaluate the exposure-response relationship between O₃ exposure and preterm birth risk and explore potential exposure threshold of O₃. Logistic regression models were used to evaluate the association of O₃ exposure with preterm birth. Results A total of 702 924 pregnant women were included in this study, of whom 43 051 (6.12%) were preterm. The average O₃ exposure concentrations of pregnant women during the first, second, third, and whole trimesters were 95.51, 97.51, 100.60, and 97.87 μg·m⁻³, respectively. We observed J-shaped associations between O₃ exposure and preterm birth risk during the second, third, and whole trimesters of pregnancy using restricted cubic spline curves. This study found that there were threshold concentrations between O₃ exposure and preterm birth risk during different gestational periods, and the threshold concentrations in the first, second, third, and whole trimesters were 112.32, 99.83, 111.74, and 112.46 μg·m⁻³, respectively. During the second, third, and whole trimesters of pregnancy, after adjusting for maternal age, baby sex, pre-pregnancy body mass index, mode of delivery, baby birth weight, gestational diabetes, and gestational hypertension, the odds ratios (OR) of preterm birth were 1.02 (95%CI: 1.01, 1.04), 1.02 (95%CI: 1.00, 1.03), and 1.17 (95%CI: 1.13, 1.21) for each 10 μg·m⁻³ increase in O₃ concentration above the O₃ threshold. No significant association was found between O₃ exposure and the risk of preterm birth during the first trimester. Conclusion There is a nonlinear association between the risk of preterm birth and O₃ exposure during pregnancy, and higher concentrations of O₃ exposure during pregnancy are associated with the risk of preterm birth. Above the O₃ threshold concentration during pregnancy, especially during the second, third, and whole trimesters, the risk of preterm birth elevates with the increase of O₃ exposure concentrations.

Bispecific antibodies （BsAbs）， as an important recent innovation in the field of tumor immunotherapy in recent years， can simultaneously or sequentially target different antigens or two different epitopes of the same antigen. Compared with traditional monoclonal antibodies， they can produce superior therapeutic effects. This article reviews the progress in clinical applications and safety research of BsAbs in cancer therapy， revealing that they （such as blinatumomab， glofitamab， teclistamab， amivantamab， etc.） exhibit significant therapeutic efficacy against hematological malignancies， lung cancer， cervical cancer， melanoma， and other cancers. For cytokine release syndrome （CRS） induced by BsAbs， prophylactic or pre-emptive medication is commonly administered in clinical practice； for neurotoxicity and infections triggered by BsAbs， clinical practice necessitates rigorous monitoring of patients’ vital signs and the provision of essential treatments. In addition， different BsAbs exhibit variations in escalation dose， infusion rate， storage duration， and equipment requirements. Therefore， strict adherence to the instructions in the drug package inserts is essential during clinical operations to ensure safety and therapeutic efficacy. In the future， more multicenter trials need to be conducted to validate the efficacy and safety of BsAbs across different tumor types and patient populations， and long-term follow-up data should be accumulated to optimize treatment cycles and dosage regimens.

Interactions between brain-resident and peripheral infiltrated immune cells are thought to contribute to neuroplasticity after cerebral ischemia. However, conventional bulk sequencing makes it challenging to depict this complex immune network. Using single-cell RNA sequencing, we mapped compositional and transcriptional features of peri-infarct immune cells. Microglia were the predominant cell type in the peri-infarct region, displaying a more diverse activation pattern than the typical pro- and anti-inflammatory state, with axon tract-associated microglia (ATMs) being associated with neuronal regeneration. Trajectory inference suggested that infiltrated monocyte-derived macrophages (MDMs) exhibited a gradual fate trajectory transition to activated MDMs. Inter-cellular crosstalk between MDMs and microglia orchestrated anti-inflammatory and repair-promoting microglia phenotypes and promoted post-stroke neurogenesis, with SOX2 and related Akt/CREB signaling as the underlying mechanisms. This description of the brain's immune landscape and its relationship with neurogenesis provides new insight into promoting neural repair by regulating neuroinflammatory responses.
Humans ; Ischemic Stroke ; Brain/metabolism* ; Macrophages ; Brain Ischemia/metabolism* ; Microglia/metabolism* ; Gene Expression Profiling ; Anti-Inflammatory Agents ; Neuronal Plasticity/physiology* ; Infarction/metabolism*

Objective To develop a nomogram for predicting the risks of early anastomotic recurrence(EAR)after primary bowel resection in patients with Crohn's disease(CD).Methods The patients with CD under-going preoperative magnetic resonance enterography(MRE)and primary bowel resection were enrolled in this retrospective study and divided into an EAR group(18 patients)and EAR-free group(12 patients).The EAR group included the patients having an endoscopic Rutgeerts score of≥I2 month or the need for anastomotic resection within 12 months after surgery.All the 38 indexes including preoperative demographic characteristics,laboratory examina-tions,multi-parameter MRE features of the resected intestine and its adjacent mesentery,histological findings,and postoperative pharmacotherapy were analyzed.Least absolute shrinkage and selection operator(LASSO)regression and multivariate binary logistic regression analysis were performed to identify independent risk factors to be incorpo-rated into the nomogram for predicting the risks of early anastomotic recurrence and the prediction performance was evaluated.Results Mesenteric creeping fat index on MRE and comb sign were independent risks of EAR,with a concordance index of 0.882(95%CI:0.764～1).The calibration plot revealed a strong relationship between actual observation and predicted probability of EAR.Conclusions The preoperative MRE-based nomogram may be a potential tool for predicting EAR following surgery in patients with CD,which is beneficial to individual management in those patients.It provides reference for the formulation of early postoperative individualized drug adjuvant therapy in patients at high risk of EAR.

Pulmonary hypertension has a high mortality rate,and although targeted therapy is available,it is still incurable,and the long-term prognosis for patients is poor.As a tyrosine kinase inhibitor,imatinib was approved for marketing in China in 2002 for the treatment of chronic myelogenous leukemia and other tumor diseases.In addition to the antitumor effects,imatinib was found to improve hemodynamics and exercise tolerance in patients with severe pulmonary arterial hypertension,but the safety was suboptimal.With the emergence of new formulations of imatinib targeted at the lungs,it is expected to become a new targeted drug for pulmonary arterial hypertension.

ObjectiveTo explore the recognition of oral breath odor map of chronic atrophic gastritis （CAG） patients with dampness-heat syndrome by electronic nose technique. MethodsPatients with chronic gastritis were recruited， including 60 cases in CAG group of dampness-heat syndrome， 50 cases in CAG group of non-dampness-heat syndrome， 60 cases in chronic non-atrophic gastritis （CNAG） group of dampness-heat syndrome， 50 cases in CNAG group of non-dampness-heat syndrome， and 30 cases of healthy volunteers were selected to set up the health control group. Ten cases in the CAG dampness-heat group and 50 cases in the CAG non-dampness-heat group were selected to form the CAG group， and 10 cases in CNAG dampness-heat group and 50 cases in CNAG non-dampness-heat group were selected to form the CNAG group. In addition to the health control group， the remaining patients were tested for Helicobacter pylori （Hp）； the electronic nose （GISXM-MQWA01） was used to collect the oral breath odor of all the participants to draw the mapping， and amplitudes and slopes of each curve （including curves A， B， C， D， E， F， G， H， I， J） of the oral odor mapping of health control group， CAG group， CNAG group， CAG dampness-heat group， CAG non-dampness-heat group， and CNAG dampness-heat group was compared. The modified transformer model was used to classify the odor mapping characteristics， and the confusion matrix method was used to evaluate the classification model， with metrics including accuracy and area under ROC curve （AUC）. ResultsThe Hp positivity rate in CAG dampness-heat group was 80.00% （48/60）， CAG non-dampness-heat group was 62.00% （31/50）， CNAG dampness-heat group was 46.67% （28/60）， and CNAG non-dampness-heat group was 42.00% （21/50）； the difference in Hp positivity rate between CAG dampness-heat group and CAG non-dampness-heat group was statistically significant （P＜0.05）. The amplitudes of response curves A， B， C， D， F， G， and I， and slopes of A and F in the odor mapping of the CAG group were lower than those in health control group， while the amplitude and slope of curve E were higher than those in the health control group and CNAG group （P＜0.05 or P＜0.01）； The amplitude of the response curves A， B， C， D， F， G， and I， and slopes of A， D， and F in the CNAG group were lower than those in the health control group （P＜0.05 or P＜0.01）. The amplitude of response curve D and slope of response curve J in the odor mapping of the CAG dampness-heat group were higher than those in CNAG dampness-heat group， the amplitude of curve F was lower than that in CAG non-dampness-heat group， and the amplitude of curve H and slopes of curve A， H， and J were higher than those in CAG non-dampness-heat group （P＜0.05）. The recognition accuracy of CAG group and health control group reached 77.78%， AUC = 0.88； the recognition accuracy of CAG group and CNAG group was 69.44%， AUC = 0.61； the recognition accuracy of CAG dampness-heat group and CAG non-dampness-heat group reached 75.8%， AUC=0.70. ConclusionElectronic nose technology can make a more accurate identification of the oral breath odor in CAG patients with dampness-heat syndrome， with a decrease in the amplitude of the curve F and an increase in the amplitude of the curve H and in the slopes of the curves A， H， and J may as the characteristics of their odor mapping.

Objective To investigate the effects and mechanisms of Zhenxin Anshen Prescription(composed of Os Draconis,Ostreae Concha,Lophatheri Herba,Drynariae Rhizoma,Poria)on mice with atopic dermatitis(AD)based on the calcium channel regulator 1(ORAI1)/nuclear factor of T-cells(NFAT)signalling axis.Methods Thirty-six BALB/c mice were randomly divided into a blank control group,a model group,a Cetirizine group(1.3 mg·kg-1)and a Zhenxin Anshen Prescription group(36.36 g·kg-1),with nine mice in each group.AD mouse model was established using 1-chloro-2,4-dinitrobenzene(DNCB)induction.The drug was administered by gavage once a day for 2 weeks.At the end of drug administration,the area of skin lesions was measured and the severity of skin lesions was scored;spleen mass was measured and spleen index was calculated;pathological changes of skin lesion tissues were observed by HE staining;interleukin 4(IL-4),IL-13 and thymic stromal lymphopoietin(TSLP)in serum were detected by ELISA;and the protein expression levels of ORAI1,calmodulin phosphatase A(CaN)and nuclear factor of T cells 2(NFAT2)were detected by Western Blot.Results Compared with the blank control group,the skin lesion score of mice in the model group was significantly increased(P＜0.01),the skin lesion area was significantly enlarged(P＜0.01);the thickness of the epidermis and dermis were significantly increased(P＜0.01),hyperkeratosis of the epidermis,hypertrophy of the stratum spinosum,and infiltration of inflammatory cells such as eosinophils and lymphocytes can be seen in the dermis;the splenic index and serum IL-4,IL-13,TSLP levels were significantly increased(P＜0.01);protein expression levels of CaN,NFAT2,ORAI1 were significantly increased in the skin lesion tissues(P＜0.01).Compared with the model group,the dermatitis score of mice in the Zhenxin Anshen Prescription group was significantly decreased(P＜0.01),the lesion area was significantly reduced(P＜0.01),the epidermal and dermal thicknesses(P＜0.01),the hyperkeratosis of epidermis was alleviated,the spinous layer was slightly hypertrophic,and there was a small amount of inflammatory cell infiltration in the dermis;the splenic index and the levels of serum IL-4,IL-13,and TSLP were significantly decreased(P＜0.01);the protein expressions levels of CaN,NFAT2,and ORAI1 in the skin lesion tissues were significantly decreased(P＜0.01).Conclusion Zhenxin Anshen Prescription can ameliorate dermatopathological injury in DNCB-induced AD mice,and the mechanism may be related to its ability to inhibit the protein expressions of ORAI1,CaN and NFAT2,reduce the levels of serum type 2 inflammatory factors TSLP,IL-4 and IL-13,and ameliorate cutaneous inflammation and itching through immunomodulation.

ObjectiveTo determine the syndrome of a rat model of follicular dysplasia induced by Tripterygium glycosides based on prescriptions and investigate the mechanism of traditional Chinese medicine intervention via the adenosine monophosphate-activated protein kinase （AMPK）/mammalian target of rapamycin （mTOR）/hypoxia-inducible factor-1 （HIF-1）/vascular endothelial growth factor （VEGF） pathway. MethodForty-eight rats with regular estrous cycles were randomly assigned into a normal group （n=8） and a modeling group （n=40）. The rats in the modeling group were administrated with Tripterygium glycoside suspension （75 mL·kg^-1） by gavage for 30 days. The modeled rats were assigned into model， Siwutang （3.69 g·kg^-1）， Youguiyin （3.11 g·kg^-1）， Zuoguiyin （7.29 g·kg^-1）， and Guishenwan （10.35 g·kg^-1） groups， with 8 rats in each group. The drug intervention lasted for 14 days. The changes of estrous cycle were detected by Pap staining， and a stereoscope was used to observe the morphology of the ovarian tissue. Hematoxylin-eosin staining was employed to observe the pathological changes and follicle count in the ovarian tissue. Enzyme-related immunosorbent assay （ELISA） was used to measure the levels of follicle-stimulating hormone （FSH）， luteinizing hormone （LH）， and estradiol （E₂） in the serum. Real-time fluorescence quantitative polymerase chain reaction and Western blot were employed to determine the mRNA and protein levels， respectively， of AMPK， mTOR， HIF-1， and VEGF in the ovarian tissue. ResultCompared with the normal group， the model group had a disordered estrous cycle， reduced secondary and mature follicles， increased atretic follicles， elevated FSH and LH levels， lowered E₂ level， up-regulated mRNA and protein levels of AMPK， and down-regulated mRNA and protein levels of mTOR， HIF-1， and VEGF （P<0.01）. Compared with the model group， Guishenwan increased secondary and mature follicles， decreased atretic follicles， lowered the FSH and LH levels， elevated the E₂ level， down-regulated the mRNA and protein levels of AMPK， and up-regulated the mRNA and protein levels of mTOR， HIF-1， and VEGF （P<0.01）. Compared with Guishenwan group， Siwutang， Youguiyin， and Zuoguiyin decreased mature follicles， increased atretic follicles （P<0.01）， elevated the LH （P<0.01） and FSH （P<0.05） levels， and lowered the E₂ level （P<0.05）. In addition， Youguiyin up-regulated the protein level of AMPK （P<0.05） and down-regulated the mRNA levels of mTOR and HIF-1 （P<0.01） as well as the mRNA and protein levels of VEGF （P<0.01）. Siwutang down-regulated the mRNA levels of mTOR and HIF-1 as well as the mRNA and protein levels of VEGF （P<0.05）. Zuoguiyin down-regulated the mRNA level of mTOR and the protein and mRNA levels of VEGF （P<0.05）. ConclusionGuishenwan may improve the ovarian function and promote follicle maturation in a rat model of follicular dysplasia by inhibiting the AMPK/mTOR/HIF-1/VEGF pathway， with the therapeutic effect superior to Zuoguiyin， Youguiyin， and Siwutang. It was hypothesized that this model presented the syndrome of kidney-essence deficiency.

OBJECTIVE To investigate the mechanism of Yifei xuanfei jiangzhuo formula （YFXF） against vascular dementia （VD）. METHODS The differentially expressed genes of YFXF （YDEGs） were obtained by network pharmacology. High-risk genes were screened from YDEGs by using the nomogram model. The optimal machine learning models in generalized linear， support vector machine， extreme gradient boosting and random forest models were screened based on high-risk genes. VD model rats were established by bilateral common carotid artery occlusion， and were randomly divided into model group and YFXF group （12.18 g/kg， by the total amount of crude drugs）， and sham operation group was established additionally， with 6 rats in each group. The effects of YFXF on behavior （using escape latency and times of crossing platform as indexes）， histopathologic changes of cerebral cortex， and the expression of proteins related to the secreted phosphoprotein 1 （SPP1）/phosphoinositide 3-kinase （PI3K）/protein kinase B （aka Akt） signaling pathway and the mRNA expression of SPP1 in cerebral cortex of VD rats were evaluated. RESULTS A total of 6 YDEGs were obtained， among which SPP1， CCL2， HMOX1 and HSPB1 may be high-risk genes of VD. The generalized linear model based on high-risk genes had the highest prediction accuracy （area under the curve of 0.954）. Compared with the model group， YFXF could significantly shorten the escape latency of VD rats， significantly increase the times of crossing platform （P＜0.05）； improve the pathological damage of cerebral cortex， such as neuronal shrinkage and neuronal necrosis； significantly reduce the expressions of SPP1 protein and mRNA （P＜0.05）， while significantly increase the phosphorylation levels of PI3K and Akt （P＜0.05）. CONCLUSIONS VD high-risk genes SPP1， CCL2， HMOX1 and HSPB1 may be the important targets of YFXF. YFXF may play an anti-VD role by down-regulating the protein and mRNA expressions of SPP1 and activating PI3K/Akt signaling pathway.