OBJECTIVE: To explore the efficacy and safety of Juan Bi Pill (JBP) in treatment of active rheumatoid arthritis (RA). METHODS: From February 2017 to May 2018, 115 participants from 4 centers were randomly divided into JBP group (57 cases) and placebo group (58 cases) in a 1:1 ratio using a random number table method. Participants received a dose of JBP (4 g, twice a day, orally) combined with methotrexate (MTX, 10 mg per week) or placebo (4 g, twice a day, orally) combined with MTX for 12 weeks. Participants were required with follow-up visits at 24 and 48 weeks, attending 7 assessment visits. Participants were undergo disease activity assessment 7 times (at baseline and 2, 4, 8, 12, 24, 48 weeks) and safety assessments 6 times (at baseline and 4, 8, 12, 24, 48 weeks). The primary endpoint was 28-joint Disease Activity Score (DAS28-ESR and DAS28-CRP). The secondary endpoints included American College of Rheumatology (ACR) criteria for 20% and 50% improvement (ACR20/50), Health Assessment Questionnaire Disability Index (HAQ-DI), clinical disease activity index (CDAI), visual analog scale (VAS), Short Form-36 (SF-36) score, Medial Outcomes Study (MOS) sleep scale score, serum erythrocyte sedimentation rate (ESR), C-reactive protein (CRP), tender joint count, swollen joint count, and morning stiffness. The adverse reactions were observed during the treatment. RESULTS: After 12 weeks of treatment, DAS28-ESR and DAS28-CRP scores in both groups were lower than before treatment (both P<0.01), while the remission rate of DAS28-ESR and DAS28-CRP and low disease activity of JBP group were higher than those in the placebo group (both P<0.01). JBP demonstrated better efficacy on ACR20 and ACR50 compliance rate at 12 and 48 weeks comparing to placebo (all P<0.05). The CDAI and HAQ-DI score, pain VAS and global VAS change of RA patients and physicians, the serum ESR and CRP levels, and the number of tenderness and swelling joints were lower than before treatment at 4, 8, 12, 24, 48 weeks in both groups (P<0.05 or P<0.01), while the reduction of above indices in the JBP group was more obvious than those in the placebo group at 12 weeks (ESR and CRP, both P<0.05) or at 12 and 48 weeks (all P<0.01). There was no difference in adverse reactions between the 2 groups during treatment (P=0.75). CONCLUSION JBP combined with MTX could effectively reduce disease activity in patients with RA in active stage, reduce the symptoms of arthritis, and improve the quality of life, while ensuring safety, reliability, and fewer adverse effects. (Trial Registration: ClinicalTrials.gov, No. NCT02885597).
Humans ; Arthritis, Rheumatoid/drug therapy* ; Methotrexate/adverse effects* ; Female ; Double-Blind Method ; Male ; Middle Aged ; Treatment Outcome ; Drugs, Chinese Herbal/adverse effects* ; Drug Therapy, Combination ; Adult ; Antirheumatic Agents/adverse effects* ; Aged

Artificial intelligence (AI) has emerged as a transformative technology in accelerating drug discovery and development within natural medicines research. Natural medicines, characterized by their complex chemical compositions and multifaceted pharmacological mechanisms, demonstrate widespread application in treating diverse diseases. However, research and development face significant challenges, including component complexity, extraction difficulties, and efficacy validation. AI technology, particularly through deep learning (DL) and machine learning (ML) approaches, enables efficient analysis of extensive datasets, facilitating drug screening, component analysis, and pharmacological mechanism elucidation. The implementation of AI technology demonstrates considerable potential in virtual screening, compound optimization, and synthetic pathway design, thereby enhancing natural medicines' bioavailability and safety profiles. Nevertheless, current applications encounter limitations regarding data quality, model interpretability, and ethical considerations. As AI technologies continue to evolve, natural medicines research and development will achieve greater efficiency and precision, advancing both personalized medicine and contemporary drug development approaches.
Biological Products/pharmacology* ; Artificial Intelligence ; Humans ; Drug Discovery/methods* ; Machine Learning ; Deep Learning

Human carboxylesterase 2A (hCES2A) plays pivotal roles in prodrug activation and hydrolytic metabolism of ester-bearing chemicals. Targeted inhibition of intestinal hCES2A represents a feasible strategy to mitigate irinotecan-triggered gut toxicity (ITGT), but the orally active, selective, and efficacious hCES2A inhibitors are rarely reported. Here, a novel drug-like hCES2A inhibitor was developed via three rounds of structure-based drug design (SBDD) and structural optimization. Initially, donepezil was identified as a moderate hCES2A inhibitor from 2000 US Food and Drug Administration (FDA)-approved drugs. Following two rounds of SBDD and structural optimization, a donepezil derivative (B7) was identified as a strong reversible hCES2A inhibitor. Subsequently, nine B7 carbamates were rationally designed, synthesized and biologically assayed. Among all synthesized carbamates, C3 showed the most potent time-dependent inhibition on hCES2A (IC₅₀ = 0.56 nmol/L), excellent specificity and favorable drug-like properties. C3 could covalently modify the catalytic serine of hCES2A with high selectivity, while this agent also showed favorable safety profiles, high intestinal exposure, and impressive effects for ameliorating ITGT in both human intestinal organoids and tumor-bearing mice. Collectively, this study showcases a rational strategy for developing drug-like and serine-targeting covalent inhibitors against target serine hydrolase(s), while C3 emerges as a promising orally active drug candidate for ameliorating ITGT.

OBJECTIVE To estimate the cost-utility of sacituzumab govitecan （SG） versus single-agent chemotherapy in the treatment of hormone receptor-positive （HR+）/human epidermal growth factor receptor 2-negative （HER2－） advanced metastatic breast cancer. METHODS From the perspective of the Chinese medical system， a three-state partitioned survival model was constructed to examine the cost-utility of SG versus single-agent chemotherapy based on TROPiCS-02 trial. The cycle length was set to 1 month， and the time horizon was 10 years. The annual discount was 5%. The model output included total costs and quality adjusted life month （QALM）， and incremental cost-effectiveness ratio （ICER） was calculated for cost-utility analysis， by setting willingness-to-pay （WTP） threshold at 3 times gross domestic product （GDP） per capita of China in 2023 （22 340 yuan/QALM）. Univariate sensitivity analyses， probability sensitivity analyses， and scenario analyses were performed to evaluate the robustness of the results and calculate the price threshold when SG had economic advantages. RESULTS SG group gained incremental 4.25 QALM and 561 570 yuan compared with single-agent chemotherapy， which resulted in an ICER of 132 102/QALM that was higher than WTP. The results of the univariate sensitivity analysis showed that the monthly average cost of SG had the greatest impact on the results； the results of probability sensitivity analysis showed that the probability of SG scheme being cost-effective at the WTP threshold was 0. The results of scenario analysis showed that the conclusions of this study were robust under different time horizons （5， 10， 15 years）. The price threshold for SG being cost-effective was 1 344 yuan per 180 mg. CONCLUSIONS Based on the perspective of Chinese medical system， SG appears to be not cost-effective compared with single-agent chemotherapy for HR+/ HER2－ advanced metastatic breast cancer at the price of 8 400 yuan per 180 mg. A substantial price cut should be taken to be cost- effective.

Objective:To investigate the correlation between the expression of GLI1 and im-mune invasion and clinical prognosis in gastric cancer.To study the effect of GLI1 expression on drug resistance in gastric cancer.Methods:The expression difference of GLI1 in gastric cancer and normal tissues was analyzed by using TCGA database,and the effect of clinical features and GLI1 gene ex-pression level on prognosis of patients with gastric cancer was analyzed.The correlation between GLI1 gene expression and tumor immune cell infiltration in gastric cancer tissues was analyzed to explore its influence on drug resistance of chemotherapy drugs and targeted drugs.Clinical samples were collect-ed to analyze the difference of GLI1 expression in gastric cancer and paracancer tissues.Results:The expression of GLI1 in gastric cancer tissues was 1.7 times that in normal tissues,and the overall sur-vival and disease-free survival of patients with high expression are shorter than those with low ex-pression(P＜0.05).The interstitial score,immune score and abundance of immunoinfiltrating cells were higher in the high expression of GLI1 in gastric cancer tissues.High expression of GLI1 reduces drug sensitivity and is positively correlated with the expression of immune checkpoint markers PDCD1(P＜0.05).GLI1 expression was significantly increased in patients with subdifferentiated gastric cancer.Conclusions:GLI1 expression is associated with the prognosis and immune infiltration of patients with gastric cancer,and it may lead to poor prognosis of patients by regulating chemotherapy resis-tance,which may be a potential therapeutic target and molecular marker for gastric cancer.

Objective:To investigate the concern about pollen broadcasting in Chinese population from multiple dimensions and to understand the information about allergic rhinitis (AR) in China by analyzing related factors.Methods:From March 1 to September 30, 2022, a large-scale multi-center cross-sectional survey was conducted based on the Questionnaire Star platform in 21 Chinese hospitals. A total of 7 056 subjects from 7 regions in China: Northeast, North, East, Central, South, Southwest, and Northwest China were included. Basic characteristics (including social demographic characteristics and disease characteristics of AR patients), concern about pollen broadcasting, the willingness of pollen-induced AR (PiAR) patients to receive pollen broadcasting, and the treatment satisfaction rate of AR patients were collected. The chi-square test, multivariate linear regression model, and Logistic regression analysis were used to analyze the concern about pollen broadcasting in the Chinese population and related factors from multiple dimensions.Results:Among 7 056 subjects, 23.02% were concerned about pollen broadcasting. Among 3 176 self-reported AR and 1 019 PiAR patients, 25.60% and 39.16% were concerned about pollen broadcasting, respectively, which was higher than that of non-AR or non-PiAR subjects ( χ2 value was 21.74 and 175.11, respectively, both P<0.001). Among AR patients, the proportion of spring and autumn allergen-positive patients concerned about pollen broadcasting was higher than that in perennial allergen-positive patients ( χ2 value was 20.90 and 19.51, respectively, both P<0.001). The proportion of AR patients with asthma, sinusitis, allergic conjunctivitis, and cardiovascular and cerebrovascular diseases was higher than those without complications ( χ2 value was 50.83, 21.97, 56.78, 7.62, respectively, all P<0.05). The proportion of AR patients in North China who could find pollen broadcasting locally was 31.01%, significantly higher than those in other regions (all P<0.05). Multivariate linear regression model analysis showed that among PiAR patients, those with higher per capita household income and higher AR disease cognition levels had been concerned about pollen broadcasting in the past, and those complicated with allergic conjunctivitis had stronger intention to receive pollen broadcasting (B value was 0.24, 0.13, 0.66, 0.47, respectively, all P<0.05). The higher the disease cognition level of PiAR patients, the stronger their willingness to actively participate in treatment ( R2=0.72, P<0.001). Only 18.89% of AR patients felt satisfied with the treatment effect. Logistic regression analysis showed that in AR patients, the treatment satisfaction rate was significantly higher among those concerned about pollen broadcasting compared to those who were not ( OR=1.83, P<0.001). Conclusions:Currently, the dissemination of pollen broadcasting in China is hindered by various factors such as disease cognition level. The treatment satisfaction among AR patients remains unsatisfactory.

Objective To analyze the effects of vesicoprostatic muscle(VPM)reconstruction on the early urinary control recovery and safety of patients undergoing robot-assisted radical prostatectomy(RARP).Methods A total of 128 patients who underwent RARP in our hospital during Sep.1,2021 and Aug.31,2023 were enrolled and divided into the non-reconstruction group(n=64)and reconstruction group(n=64)using random number table method.The reconstruction group received Montsouris+VPM reconstruction surgery,while the non-reconstructive group underwent Montsouris surgery only.Urinary control and perioperative data were collected with telephone interview,outpatient follow-up and inpatient records.The two groups were matched using overlap weighting and the Kaplan-Meier method was used to calculate urinary incontinence rates at 1,2 and 3 months after extubation.Early urinary control(3 months after extubation),operation time,intraoperative bleeding,positive rate of incision margin,and incidence of early postoperative complications(＜30 days)(Clavien-Dindo scale)were compared between the two groups.Results The recovery rate of urinary control at 1,2 and 3 months after extubation was significantly higher in the reconstruction group than that in the non-reconstruction group(33.9％vs.11.2％;46.7％vs.16.1％;70.6％vs.45.6％,P＜0.05),but the positive rate of resection margin was lower(16.1％vs.41.7％,P＜0.05).There were no significant differences in operation time,intraoperative bleeding and early postoperative complications between the two groups(P＞0.05).Conclusion VPM reconstruction can improve urinary control recovery in RARP patients early after extubation without increasing the risk of surgery.

Objective Establish the fingerprint of the group and optimize the extraction process of the Yunpi Huatan Tongqiao decoction.Methods The macroscopic characterization and similarity analysis of the extract fingerprint were carried out by applying the total statistical moment method.With baicalin,wogonin,rosmarinic acid,liquiritin,glycyrrhizic acid and paste yield as key quality attributes,and extraction time,water addition and extraction times as key process parameters,the optimal extraction process was selected by AHP-independent weight method,and the process was verified.Results Establishing a total statistical moment similarity evaluation method,and the average statistical moment similarity of the total amount of fingerprints of different extraction methods was 0.8807.The ANOVA results of the process evaluation model function are displayed that P<0.0001,R2=0.9904,indicating that the model was statistically significant.The best extraction process was determined as follows:adding 10-fold volume of water in the whole prescription,extracting for 1.5 h and extracting twice.Conclusion The total statistical moment analysis method that conforms to the fingerprint characteristics of the fingerprint of the extract was established,which was stable and reliable,which provided a reference basis for the quality control of the whole process of the subsequent process research.

Objective To explore the effect of Tongdu Tiaoshen acupuncture,a needling method for dredging governor vessel and regulating mind,on cerebral hemodynamics and oxygen free radicals in the patients with post-stroke epilepsy(PSE).Methods A total of 60 patients with PSE were randomly divided into a treatment group and a control group,with 30 cases in each group.Both groups were given basic treatment for lowering lipid level,controlling blood pressure and glucose contents,and counteracting platelet aggregation.Moreover,the control group was treated with Sodium Valproate Sustained-Release Tablets,and the treatment group was treated with Tongdu Tiaoshen acupuncture mainly on the acupoints of Baihui(GV20),Shenting(GV24),Shuigou(GV26),Fengfu(GV 16),Fengchi(GB20)based on the treatment for the control group.One month constituted a course of treatment,and the treatment for the two groups covered three courses of treatment.The number of epileptic seizures,the severity of electroencephalogram(EEG),the peak systolic velocity(Vs)and end diastolic velocity(Vd)of bilateral anterior cerebral arteries,middle cerebral arteries and posterior cerebral arteries detected by transcranial Doppler ultrasonography(TCD),and the changes in the peripheral levels of oxygen free radicals such as malondialdehyde(MDA),hydroxyl radical(OH),lipid peroxide(LPO)and superoxide dismutase(SOD)in the two groups were observed before and after treatment.After treatment,the clinical efficacy and safety of the two groups were evaluated.Results(1)After three months of treatment,the total effective rate of the treatment group was 93.33％(28/30),and that of the control group was 73.33％(23/30).The intergroup comparison(tested by chi-square test)showed that the efficacy of the treatment group was significantly superior to that of the control group(P＜0.05).(2)After treatment,the average monthly epileptic seizure frequency in the two groups was decreased when compared with that before treatment(P＜0.05),and the decrease in the treatment group was more significant than that in the control group(P＜0.05).(3)After treatment,the grading of EEG severity in the two groups was significantly improved when compared with that before treatment(P＜0.05),and the improvement in the treatment group was significantly superior to that in the control group(P＜0.05).(4)After treatment,the peripheral levels of oxygen free radicals of MDA,OH and LPO in the two groups were lower than those before treatment(P＜0.05),and the peripheral level of SOD was higher than that before treatment(P＜0.05).The decrease of MDA,OH and LPO levels and the increase of SOD level in the treatment group were significantly superior to those in the control group(P＜0.05 or P＜0.01).(5)After treatment,the values of cerebral hemodynamic indicators of Vs and Vd of both left and right anterior cerebral artery,middle cerebral artery and posterior cerebral artery in the two groups were higher than those before treatment(P＜0.05),and the increase in the treatment group was significantly superior to that in the control group,the differences being statistically significant(P＜0.05).(6)During the treatment,there were no fainting,sticking of needle,bleeding and rash occurring during acupuncture in the two groups,which indicated that the therapy had high safety.Conclusion Tongdu Tiaoshen acupuncture can significantly reduce the seizure frequency of PSE and improve the severity of epileptic EEG.Its therapeutic mechanism may be related with the decrease of the oxygen free radical levels and with the improvement of cerebral hemodynamics.

Objective To investigate the effect of salvianolic acid B on the antioxidant stress capacity of human umbilical cord mesenchymal stem cells(HUCMSCs)and to improve the clinical application efficiency of mesenchymal stem cells.Methods The 5th generation HUMSCs were used for the experiment and divided into control group,model group,and experimental-L,-M,-H groups.The control group was cultured normally;the model group was treated with 800 μmol·L-1 hydrogen peroxide(H2 O2)for 2 h;and the experimental-L,-M,-H groups were pretreated with 2,10,20 μg·mL-1salvianolic acid B for 24 h before adding 800 μmol·L-1 H2 O2 for 2 h.The levels of glutathione(GSH),superoxide dismutase(SOD),and malondialdehyde(MDA)in the cell supernatant of each group were detected using test kits;real-time fluorescence quantitative reverse transcription polymerase chain reaction was used to detect the mRNA expression of apoptosis-related genes Caspase 1,and B-cell lymphoma-2(Bcl-2).Results After treatment with 800 μmol·L-1H2 O2 for 2 h,the levels of MDA in the cell supernatants of the control group,model group,and experimental-H group were(3.27±0.41),(6.50±0.21)and(4.79±0.40)nmol·mL-1,respectively;the GSH levels were(35.43±0.72),(20.13±0.58)and(32.30±3.87)μmoL·L-1;the SOD levels were(5.34±0.18),(3.34±0.20)and(5.09±0.15)U·mL-1;the expression of Caspase 1 mRNA were 1.02±0.21,2.78±0.26 and 2.37±0.32;the expression of Bcl-2 mRNA were 1.01±0.12,0.43±0.03 and 0.60±0.17.Compared with the control group,the above indexes in the model group were statistically significant(P＜0.05,P＜0.01).Compared with the model group,the above indexes in the experimental-H group were statistically significant(P＜0.05,P＜0.01).Conclusion Salvianolic acid B can reduce apoptosis caused by oxidative stress and enhance the antioxidant stress capacity of HUCMSCs.