ObjectiveTo analyze the diversity and structural characteristics of microbial communities in the rhizosphere soil of healthy and diseased Andrographis paniculata and to explore the interactions of soil， plants， and microorganisms during the occurrence of diseases. MethodsThe physicochemical properties of the rhizosphere soil of healthy and diseased A.paniculata were determined， and the composition and diversity of bacterial and fungal communities in the rhizosphere soil were analyzed by Illumina high-throughput sequencing. Furthermore， the correlations between physicochemical properties and microorganisms of the rhizosphere soil were explored. ResultsThe content of total nitrogen， total potassium， and available potassium in the rhizosphere soil of diseased A. paniculata was significantly higher than that of healthy A. paniculata. The alpha diversity and richness （operational taxonomic units） of bacterial and fungal communities in the rhizosphere soil of diseased plants decreased compared with those of healthy plants. The microbial communities in the rhizosphere soil of healthy and diseased A. paniculata showed similar composition but different relative abundance. At the phylum level， the relative abundance of Proteobacteria and Chytridiomycota significantly increased， while that of Bacteroidota significantly decreased in the rhizosphere soil of diseased plants. At the genus level， the relative abundance of Sphingomonas， Pseudomonas， and Bryobacter significantly increased， while that of RB41 showed a significant decrease in the rhizosphere soil of diseased plants. The correlation analysis showed different correlations of microbial phyla with physicochemical properties of the rhizosphere soil between healthy and diseased plants. Organic matter， alkaline nitrogen， available phosphorus， and total potassium were correlated with the relative abundance of some dominant bacterial and fungal phyla in the rhizosphere soil of healthy plants， while available nitrogen and total phosphorus were correlated with the relative abundance of some dominant bacterial and fungal phyla in the rhizosphere soil of diseased plants. ConclusionThere are differences in the diversity and richness of microbial communities in the rhizosphere soil of healthy and diseased A. paniculata. The physicochemical properties of soil may have an impact on the rhizosphere microorganisms of A. paniculata， leading to the development of diseases. The results provide a scientific basis for the prevention and ecological management of A. paniculata diseases.

ObjectiveTo analyze the diversity and structural characteristics of microbial communities in the rhizosphere soil of healthy and diseased Andrographis paniculata and to explore the interactions of soil， plants， and microorganisms during the occurrence of diseases. MethodsThe physicochemical properties of the rhizosphere soil of healthy and diseased A.paniculata were determined， and the composition and diversity of bacterial and fungal communities in the rhizosphere soil were analyzed by Illumina high-throughput sequencing. Furthermore， the correlations between physicochemical properties and microorganisms of the rhizosphere soil were explored. ResultsThe content of total nitrogen， total potassium， and available potassium in the rhizosphere soil of diseased A. paniculata was significantly higher than that of healthy A. paniculata. The alpha diversity and richness （operational taxonomic units） of bacterial and fungal communities in the rhizosphere soil of diseased plants decreased compared with those of healthy plants. The microbial communities in the rhizosphere soil of healthy and diseased A. paniculata showed similar composition but different relative abundance. At the phylum level， the relative abundance of Proteobacteria and Chytridiomycota significantly increased， while that of Bacteroidota significantly decreased in the rhizosphere soil of diseased plants. At the genus level， the relative abundance of Sphingomonas， Pseudomonas， and Bryobacter significantly increased， while that of RB41 showed a significant decrease in the rhizosphere soil of diseased plants. The correlation analysis showed different correlations of microbial phyla with physicochemical properties of the rhizosphere soil between healthy and diseased plants. Organic matter， alkaline nitrogen， available phosphorus， and total potassium were correlated with the relative abundance of some dominant bacterial and fungal phyla in the rhizosphere soil of healthy plants， while available nitrogen and total phosphorus were correlated with the relative abundance of some dominant bacterial and fungal phyla in the rhizosphere soil of diseased plants. ConclusionThere are differences in the diversity and richness of microbial communities in the rhizosphere soil of healthy and diseased A. paniculata. The physicochemical properties of soil may have an impact on the rhizosphere microorganisms of A. paniculata， leading to the development of diseases. The results provide a scientific basis for the prevention and ecological management of A. paniculata diseases.

ObjectiveThe theory of homotherapy for heteropathy is one of the classical rules in traditional Chinese medicine. Taking this theory as a breakthrough point， this study employed gas chromatography-mass spectrometry （GC-MS） to elucidate the mechanism underlying the therapeutic effects of Zhuyuwan on both intrahepatic cholestasis （IC） and ulcerative colitis （UC） from the viewpoint of serum metabolic homeostasis. MethodsThe rat models of α-naphthylisothiocyanate （ANIT）-induced cholestasis and 2，4，6-trinitro-benzenesulfonic acid （TNBS）-induced UC were treated with low （0.6 g·kg^-1） and high （1.2 g·kg^-1） doses of Zhuyuwan by gavage. In the experiment regarding IC， 24 Sprague-Dawley （SD） rats were randomly assigned into four groups： normal， ANIT model， low-dose Zhuyuwan， and high-dose Zhuyuwan. In the experiment regarding UC， 24 SD rats were randomly allocated into four groups： normal， TNBS model， low-dose Zhuyuwan， and high-dose Zhuyuwan. Firstly， the two disease models and the intervention effects of Zhuyuwan on the two diseases were evaluated based on serum levels of biochemical indicators ［alanine aminotransferase （ALT）， aspartate transaminase （AST）， γ-glutamyltranspeptidase （γ-GT）， and total bile acid （TBA）］， colon damage score， colon weight index， disease activity index， and histopathological changes in rats. Secondly， the rat serum samples were analyzed by gas chromatography-mass spectrometry （GC-MS） to screen the common core pathways of the two disease models， and the expression of core genes in the pathways was determined by Real-time PCR， on the basis of which the biological mechanism of the treatment of the two disease models by Zhuyuwan was ultimately elucidated. ResultsThe results of the experiment regarding IC showed that the ANIT model group had higher ALT， AST， γ-GT， and TBA levels than the normal group （P<0.01）. Compared with the ANIT model group， the low-dose Zhuyuwan group showed declined ALT and TBA levels （P<0.01） and the high-dose Zhuyuwan group showed lowered ALT， TBA， AST， and γ-GT levels （P<0.01）. The results of the experiment regarding UC showed that compared with the normal group， the TNBS model group presented increases in the colonic damage score， colon weight index， and disease activity index （P<0.01）. Compared with the TNBS model group， the low-dose Zhuyuwan group showcased declines in colon weight index （P<0.01） and disease activity index （P<0.05）， and the high-dose Zhuyuwan group showed reductions in the colon damage score， colon weight index， and disease activity index （P<0.01）. GC-MS metabolomics analysis combined with qRT-PCR demonstrated that Zhuyuwan had a similar inverse regulatory effect on arginine metabolism disruption in the above two disease models. ConclusionZhuyuwan exhibited definite therapeutic effects on both IC and UC， and the regulation of arginine biosynthesis pathway is the core mechanism for the treatment of both diseases by Zhuyuwan.

ObjectiveThe theory of homotherapy for heteropathy is one of the classical rules in traditional Chinese medicine. Taking this theory as a breakthrough point， this study employed gas chromatography-mass spectrometry （GC-MS） to elucidate the mechanism underlying the therapeutic effects of Zhuyuwan on both intrahepatic cholestasis （IC） and ulcerative colitis （UC） from the viewpoint of serum metabolic homeostasis. MethodsThe rat models of α-naphthylisothiocyanate （ANIT）-induced cholestasis and 2，4，6-trinitro-benzenesulfonic acid （TNBS）-induced UC were treated with low （0.6 g·kg^-1） and high （1.2 g·kg^-1） doses of Zhuyuwan by gavage. In the experiment regarding IC， 24 Sprague-Dawley （SD） rats were randomly assigned into four groups： normal， ANIT model， low-dose Zhuyuwan， and high-dose Zhuyuwan. In the experiment regarding UC， 24 SD rats were randomly allocated into four groups： normal， TNBS model， low-dose Zhuyuwan， and high-dose Zhuyuwan. Firstly， the two disease models and the intervention effects of Zhuyuwan on the two diseases were evaluated based on serum levels of biochemical indicators ［alanine aminotransferase （ALT）， aspartate transaminase （AST）， γ-glutamyltranspeptidase （γ-GT）， and total bile acid （TBA）］， colon damage score， colon weight index， disease activity index， and histopathological changes in rats. Secondly， the rat serum samples were analyzed by gas chromatography-mass spectrometry （GC-MS） to screen the common core pathways of the two disease models， and the expression of core genes in the pathways was determined by Real-time PCR， on the basis of which the biological mechanism of the treatment of the two disease models by Zhuyuwan was ultimately elucidated. ResultsThe results of the experiment regarding IC showed that the ANIT model group had higher ALT， AST， γ-GT， and TBA levels than the normal group （P<0.01）. Compared with the ANIT model group， the low-dose Zhuyuwan group showed declined ALT and TBA levels （P<0.01） and the high-dose Zhuyuwan group showed lowered ALT， TBA， AST， and γ-GT levels （P<0.01）. The results of the experiment regarding UC showed that compared with the normal group， the TNBS model group presented increases in the colonic damage score， colon weight index， and disease activity index （P<0.01）. Compared with the TNBS model group， the low-dose Zhuyuwan group showcased declines in colon weight index （P<0.01） and disease activity index （P<0.05）， and the high-dose Zhuyuwan group showed reductions in the colon damage score， colon weight index， and disease activity index （P<0.01）. GC-MS metabolomics analysis combined with qRT-PCR demonstrated that Zhuyuwan had a similar inverse regulatory effect on arginine metabolism disruption in the above two disease models. ConclusionZhuyuwan exhibited definite therapeutic effects on both IC and UC， and the regulation of arginine biosynthesis pathway is the core mechanism for the treatment of both diseases by Zhuyuwan.

OBJECTIVE: To evaluate the advantages and limitations of transcutaneous electrical acupoint stimulation (TEAS) in the treatment of patients with severe gastrointestinal function injury in intensive care unit (ICU) by analyzing dynamic changes of intestinal fatty acid binding protein (I-FABP), D-lactic acid and citrulline. METHODS: A prospective single-center randomized controlled trial was conducted. Patients with severe gastrointestinal function injury admitted to the ICU from February 2021 to January 2024 were enrolled [age > 18 years old, acute gastrointestinal injury (AGI) grade 2 to 3, stable hemodynamics]. Patients with different AGI grades were randomly assigned in a 1:1 ratio to the TEAS group and the control group using simple randomization. Both groups received conventional treatment and enteral nutrition (EN). In addition, the TEAS group underwent TEAS at the Neiguan and Zusanli points for 30 minutes per session, twice daily for 7 days. Baseline data, including age, gender, underlying diseases, and primary diagnoses, were recorded. Three intestinal biomarkers, such as I-FABP, D-lactic acid, and citrulline were measured before and after 7 days of treatment. EN tolerance indicators and 28 days survival status were documented. The differences in various indicators were compared between the two groups, subgroup analyses were conducted based on AGI grading, and interaction between AGI grade and TEAS were analyzed. The 28-day Kaplan-Meier survival curves were generated for both groups. RESULTS: Finally, 133 patients were included, with 68 in the TEAS group and 65 in the control group. Baseline characteristics were comparable between the two groups. A comparison of the dynamic changes in intestinal biomarkers revealed that the I-FABP level in both groups decreased after treatment compared to pre-treatment, with a more pronounced reduction in the TEAS group. The least square mean difference (LS Mean difference) for the corrected I-FABP level between the two groups during the observation period was -0.23 μg/L [95% confidence interval (95%CI) was -0.45 to -0.01], which was statistically significant (P = 0.041). Additionally, a significant interaction with AGI was observed (P = 0.004). Post-treatment, D-lactic acid level decreased in both groups compared to pre-treatment, with a more significant reduction in the TEAS group. The LS Mean difference for the corrected D-lactic acid level was -0.08 mmol/L (95%CI was -0.11 to -0.05), which was statistically significant (P < 0.001), and the interaction with AGI was also significant (P = 0.005). There was no significant change in citrulline levels between the two groups before and after treatment. The LS Mean difference for the corrected citrulline level was -0.17 μmol/L (95%CI was -1.87 to 1.53), which was not statistically significant (P = 0.845), and no significant interaction with AGI was observed (P = 0.913). Comparison of EN tolerance parameters between the two groups revealed that the TEAS group had a longer total EN time (hours: 72±31 vs. 60±28) and higher total EN calories (kJ: 11 469.23±7 237.34 vs. 6 638.76±5 098.37), as well as a higher 70% target caloric attainment rate (52.9% vs. 32.3%) compared to the control group (all P < 0.05). The incidence of abdominal distension after EN was lower in the TEAS group than that in the control group (23.5% vs. 43.1%, P < 0.05), while the incidence of diarrhea after EN was higher in the TEAS group (22.1% vs. 7.7%, P < 0.05). There were no significantly differences in AGI grade reduction rate, post-EN vomiting/gastric retention rate, incidence of feeding interruption, and 28-day survival rate between the two groups. Furthermore, there were no significantly interaction between these observation measures and AGI. Kaplan-Meier survival analysis showed that there was no significantly difference in 28-day cumulative survival rate between the TEAS group and the control group [Log-Rank test: P = 0.501, hazard ratio (HR) = 0.81, 95%CI was 0.43-1.51), and there was no significantly interaction with AGI (P = 0.702). CONCLUSIONS The advantage of TEAS in the treatment of ICU patients with severe gastrointestinal function injury lies in its ability to reverse intestinal cell necrosis and promote the reconstruction of intestinal barrier function. Additionally, gastrointestinal tolerance is significantly improved, and both the duration and total calories of EN are increased. However, the limitation of TEAS therapy is that it does not promote the recovery of intestinal cell absorption and synthesis function in the target patients. Moreover, it may lead to nutrient solution overload due to improved gastrointestinal tolerance. Furthermore, TEAS does not appear to improve 28-day cumulative survival rate in the target patients.
Humans ; Prospective Studies ; Intensive Care Units ; Acupuncture Points ; Fatty Acid-Binding Proteins/metabolism* ; Transcutaneous Electric Nerve Stimulation ; Male ; Female ; Citrulline/metabolism* ; Lactic Acid/metabolism* ; Gastrointestinal Diseases/therapy* ; Middle Aged ; Enteral Nutrition ; Adult

Objective:To investigate the effects of different levels of ophthalmic surgical stimulation on blood glucose in patients with type 2 diabetes mellitus(T2DM).Methods:From Mar to Oct 2021,236 patients with T2DM who underwent ophthalmic surgery in our hospital were enrolled,including 71 cases of secondary surgery,89 cases of tertiary surgery,and 76 cases of quaternary surgery.According to the operation time,the 236 patients were divided into groups A(＜60 min),B(60-120 min)and C(＞120 min).The preoperative and postoperative blood glucose levels were compared in patients with different levels of surgery,and in groups A,B and C.Results:The postoperative blood glucose level was lower than that before surgery in secondary and tertiary surgery,and it was higher than that before surgery in quaternary surgery(P＜0.05).The fluctuation value of blood glucose in secondary and tertiary surgery was higher than that in quaternary surgery(P＜0.05).In groups A,B and C,the postoperative blood glucose level was lower than that before surgery in secondary and tertiary surgery(P＜0.05).In group A,there was no significant difference in the blood glucose before and after surgery in quaternary surgery(P＞0.05),and in groups B and C,the postoperative blood glucose was higher than that before surgery in quaternary surgery(P＜0.05).In group A,there was no difference in the fluctuation value of blood glucose at different levels of surgery(P＞0.05).In group B,the fluctuation value of blood glucose in patients with secondary and tertiary surgery was higher than that in quaternary surgery(P＜0.05).In group C,the fluctuation value of blood glucose in patients with tertiary and quaternary surgery was higher than that in patients with secondary surgery(P＜0.05).Conclusions:For ophthalmic surgery patients with T2DM,the postoperative blood glucose values of patients undergoing secondary and tertiary surgery generally show a downward trend,while the postoperative blood glucose value of patients undergoing quaternary surgery generally shows an upward trend.It is suggested that clinical workers should actively manage the perioperative blood glucose of patients with high-level surgery.

BACKGROUND:This review explores the current research status and frontier hot spots of functional magnetic resonance imaging(fMRI)in the field of traditional Chinese medicine(TCM)for the treatment of ischemic stroke,and attempts to grasp future research trends,with a view to providing a reference for subsequent research in this field. OBJECTIVE:To visualize and analyze the hotspots and frontiers in the TCM treatment of ischemic stroke based on fMRI using CiteSpace knowledge mapping combined with binary logistic regression equations,in order to grasp the future research trends and further explore the distribution of brain regions with abnormal neural activity related to the types of post-stroke dysfunction. METHODS:CNKI,WanFang,VIP,Chinese Biomedical Literature Database and Web of Science core set database were searched.CiteSpace was used to plot keyword co-occurrence,keyword clustering timeline,burst term detection,co-cited literature mapping to analyze hotpots and frontiers in this field.Binary logistic regression analysis fitted the distribution of brain regions with abnormal neural activity associated with different dysfunction after ischemic stroke. RESULTS AND CONCLUSION:A total of 354 articles were included for CiteSpace knowledge mapping analysis.The number of annual publications showed that the research popularity has been raised from 2000 to 2022 with a good development prospect,but the core strength is mainly concentrated in China.Keywords co-occurrence and clustering time line analysis showed that aphasia,hemiplegia and cognitive impairment are the hot poststroke dysfunction types.Electroacupuncture,acupuncture and head acupuncture are hotspot intervention measures.Functional connectivity is a hotspot analysis method,and resting fMRI is a hotspot scanning technology.The time span of each research hotspot is long,indicating that it has a certain research value and the relevant research is gradually deepening,promoting the research progress in this field.However,acupuncture is the main intervention measure,and there is a lack of research on traditional Chinese medicine,Chinese patent medicine,acupuncture and medicine combination and other TCM therapy.Burst term detection results showed that functional connectivity,graph theory,degree centrality,default mode network,randomized controlled trials have great influence and strong explosive power.They are the current and future frontier hot spots in this field,suggesting that future research should focus on the brain network information integration and strengthen the scientific and rigorous clinical trial design.The results of co-cited literature analysis showed that the epidemiological investigation of ischemic stroke,the safety and effectiveness of acupuncture in the treatment of stroke,the brain activation patterns under different tasks,and the neuropathological mechanism of brain network dysfunction after stroke are the theoretical basis of this field.Future research direction in this field is to explore TCM-targeted brain regions and neural networks to reveal the brain effect mechanism of TCM promoting neural remodeling after stroke.A total of 255 articles were included for binary Logistic regression analysis.The results showed that sensorimotor cortex and premotor area dysfunction are positively correlated with the incidence of motor dysfunction after stroke;hippocampus,cerebellum posterior lobe,precuneus,inferior temporal gyrus and anterior cingulate nerve dysfunction are positively correlated with the incidence of cognitive impairment after stroke;cuneus,angular gyrus and prefrontal lobe neural dysfunction were positively correlated with the incidence of affective disorder after stroke;anterior cingulate,cerebellum posterior lobe neural dysfunction are positively correlated with the incidence of swallowing disorder after stroke.The above brain regions are the core brain regions of the sensorimotor network,default mode network and reward loop,suggesting that functional abnormalities within or between brain networks related to dysfunction may be potential target areas for TCM intervention,but the specific changes in neural activity activation or inhibition still need to be refined.

Objective:To investigate the diagnostic value of lung ultrasound in hospitalized children with community-acquired pneumonia (CAP).Methods:In the cross-sectional study, a total of 422 children with CAP who were hospitalized in the Second Affiliated Hospital and Yuying Children′s Hospital of Wenzhou Medical University, from February 2021 to August 2022 and completed lung ultrasound examination within 48 hours after admission were enrolled. The clinical characteristics, lung ultrasound and chest CT were collected. The patients were divided into two groups according to the signs of pneumonia indicated by chest CT, and the signs of lung ultrasound with diagnostic value were screened according to the signs of pneumonia indicated by chest CT by least absolute shrinkage and selection operator (Lasso) regression. According to severity of the disease, the children were divided into the severe group and the mild group, and the differences of lung ultrasound signs between the two groups were compared. Kruskal-Wallis test, Fisher′s exact test was selected for comparison between groups. Random forest classifier wes used to evaluate the value of lung ultrasound in the diagnosis of CAP and prediction of severe pneumonia in children. The receiver operating characteristic curve was used to evaluate the prediction effect. Use DeLong test to compare the area under the curve.Results:Among the 422 cases of CAP, there were 258 males and 164 females, and the age of onset was 2.8 (1.3, 4.3) years. The confluent B-line, consolidation and pleural effusion detected by lung ultrasound were 309 cases (73.2%), 232 cases (55.0%) and 16 cases (3.8%), respectively, and the size of consolidation was 3.0 (0, 11.0) mm. One hundred and ten children (26.1%) with CAP completed chest CT. There were 90 cases with signs of pneumonia in chest CT and 20 cases without signs of pneumonia. Lasso was used for feature selection.Lung consolidation ( OR=2.46), bilateral lung consolidation ( OR=1.16) and confluent B-line ( OR=1.34) were the main index. With random forest classifier, the accuracy of models using full variables and Lasso-selected variables were 0.79 (95% CI 0.70-0.86) and 0.79 (95% CI 0.70-0.86), the sensitivity were 0.81 and 0.81, and the specificity were 0.75 and 0.70, and the area under curve were 0.87 (95% CI 0.81-0.94, P<0.001) and 0.84 (95% CI 0.76-0.91, P<0.001), respectively. There were 97 cases in severe group and 325 cases in mild group. Compared with the mild group, the detection rate of consolidation, multiple consolidation, the size of consolidation and the size of consolidation was adjusted by body surface area (consolidation size/body surface area) in severe group were higher (66 cases (68.0%) vs. 166 cases (51.1%), 42 cases (43.3%) vs. 93 cases (28.6%), 8.0 (0, 17.0) vs. 1.0 (0, 9.0) mm, 12.5 (0, 24.6) vs. 2.1 (0, 17.6), χ2=8.59, 9.98, Z=14.40, 12.79, all P<0.05). Using lung ultrasound lung consolidation size and consolidation size/body surface area to predict the severe CAP, the optimal cut-off value were 6.7 mm and 10.2, the accuracy was 0.80 (95% CI 0.75-0.83) and 0.89 (95% CI 0.86-0.92), the sensitivity was 0.99 and 0.99, the specificity was 0.14 and 0.56, respectively, and the area under the curve was 0.66 (95% CI 0.60-0.72, P<0.001) and 0.76 (95% CI 0.70-0.83, P<0.001), respectively. The area under the curve of consolidation size/body surface area was higher than that of consolidation size ( Z=5.50, P<0.001). Conclusions:Consolidation and confluent B-line, are important index for lung ultrasound diagnosis of CAP in children. The actual consolidation size adjusted by body surface area is superior to the size of consolidation in predicting severe CAP.

Objective To investigate the effect and mechanism of colchicine on mouse liver cancer via Hippo sig-naling pathway.Methods The 6-week-old male C57BL/6J mice were randomly divided into 3 groups:diethylni-trosamine(DEN)/carbon tetrachloride(CCl4)/ethanol(C2H5OH)induced mouse liver cancer model and col-chicine(0.1 mg/kg)intervention were established in control group,model group and colchicine group.From week 1st to week 2nd,the model group and the colchicine group were intraperitoneally injected with 1.0％DEN once a week.From week 3rd to week 7th,20％CCl4 dissolved in olive oil solution(5 ml/kg)was intragastric ad-ministration twice a week.From week 8th to week 18th,20％CC14 dissolved in olive oil solution(6 ml/kg)was intragastric twice a week.The colchicine group was given continuous intragastric administration for 20 weeks.The control group was given the corresponding solvent.Liver index,alanine aminotransferase(ALT)and aspartate ami-notransferase(AST)serum biochemical indexes were detected.Western blot and immunofluorescence were used to detect the expression levels of MST1,pYAP,YAP,pTAZ and TAZ proteins in liver tissues of mice in each group.Results The liver surface of mice in the control group was smooth and soft,while the liver of mice in the model group was rough and hard with granular nodules.The above lesions were significantly improved in the colchicine group.HE staining showed that the liver lobular structure of mice in the control group was normal,while the liver lobular structure of mice in the model group was disordered,with a small amount of fat droplets,extensive tissue necrosis,inflammatory cell infiltration,and fat vacuoles.The degree of liver lesions of mice after colchicine inter-vention was significantly reduced.The results of immunofluorescence and Western blot showed that compared with the control group,the protein expression levels of pYAP and pTAZ in liver tissue of model group mice were signifi-cantly decreased,while the protein expression levels of MST1,YAP and TAZ increased.After colchicine interven-tion,the protein expression levels of MST1,pYAP and pTAZ were significantly up-regulated,while the protein ex-pression levels of YAP and TAZ were down-regulated.Conclusion The therapeutic effect of colchicine on mouse liver cancer may be related to its activated Hippo signaling pathway.

Chemotherapy-induced complications, particularly lethal cardiovascular diseases, pose significant challenges for cancer survivors. The intertwined adverse effects, brought by cancer and its complication, further complicate anticancer therapy and lead to diminished clinical outcomes. Simple supplementation of cardioprotective agents falls short in addressing these challenges. Developing bi-functional co-therapy agents provided another potential solution to consolidate the chemotherapy and reduce cardiac events simultaneously. Drug repurposing was naturally endowed with co-therapeutic potential of two indications, implying a unique chance in the development of bi-functional agents. Herein, we further proposed a novel "trilogy of drug repurposing" strategy that comprises function-based, target-focused, and scaffold-driven repurposing approaches, aiming to systematically elucidate the advantages of repurposed drugs in rationally developing bi-functional agent. Through function-based repurposing, a cardioprotective agent, carvedilol (CAR), was identified as a potential neddylation inhibitor to suppress lung cancer growth. Employing target-focused SAR studies and scaffold-driven drug design, we synthesized 44 CAR derivatives to achieve a balance between anticancer and cardioprotection. Remarkably, optimal derivative 43 displayed promising bi-functional effects, especially in various self-established heart failure mice models with and without tumor-bearing. Collectively, the present study validated the practicability of the "trilogy of drug repurposing" strategy in the development of bi-functional co-therapy agents.