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.

BACKGROUND:The results of in vivo and in vitro studies showed that catalpol from Rehmannia glutinosa can significantly reduce the level of inflammatory indexes in the synovial tissue of rats with knee osteoarthritis,and meanwhile,it can delay the progression of knee osteoarthritis.But whether catalpol from Rehmannia glutinosa affects chondrocyte senescence and then delay the progression of knee osteoarthritis has not yet been clarified. OBJECTIVE:To investigate investigate whether catalpol from Rehmannia glutinosa could regulate ATDC5 chondrocyte senescence and the possible mechanisms. METHODS:ATDC5 chondrocytes were divided into blank group(0.1%bovine serum albumin),model group(0.1%bovine serum albumin+1 μmol/L adriamycin),low-dose catalpol group(0.1%bovine serum albumin+1 μmol/L adriamycin+20 μmol/L catalpol from Rehmannia glutinosa)and high-dose catalpol group(0.1%bovine serum albumin+1 μmol/L adriamycin+80 μmol/L catalpol from Rehmannia glutinosa).Adriamycin-induced ATDC5 chondrocyte senescence model was constructed,and the corresponding treatments were given according to the above groups.Cell counting kit-8 assay was used to detect the effects of catalpol from Rehmannia glutinosa on ATDC5 chondrocyte viability,and to screen the optimal concentration of catalpol from Rehmannia glutinosa.The senescence of ATDC5 chondrocytes in each group was detected by β-galactosidase staining after the corresponding treatments.Real-time fluorescence quantitative PCR and western blot were used to detect the mRNA and protein expression of P21,P53,type II collagen,matrix metalloproteinase 13,and interleukin-6.Immunofluorescence method was used to detect the expression of P21,P53 and type II collagen.Flow cytometry was used to detect apoptosis in each group. RESULTS AND CONCLUSION:ATDC5 chondrocytes were identified to be successfully induced and senescence model was induced.Catalpol from Rehmannia glutinosa at the concentrations of 0,20,40,and 80 μmol/L showed no significant effects on the cell viability,suggesting that catalpol from Rehmannia glutinosa is non-cytotoxic and can be used safely(P>0.05);when the concentration was≥100 μmol/L,the cell viability was reduced,suggesting that there may be cytotoxic.Therefore,80 μmol/L was chosen as the high dose for subsequent experiments in this study.The percentage of positive cells in the model group was(86.93±2.18)%,which was significantly higher than that in the blank group[(17.32±0.72)%;P<0.05].Compared with the model group,the percentage of positive cells was significantly lower in the low-and high-dose catalpol groups[(57.28±1.73)%and(27.18±0.97)%,respectively;both P<0.05].Compared with the model group,the relative expression of P21,P53,matrix metalloproteinase 13,and interleukin-6 at mRNA and protein levels was significantly downregulated in the low-and high-dose catalpol groups,while the relative expression of type II collagen at mRNA and protein levels was significantly upregulated in both groups(P<0.05),especially in the high-dose catalpol group(P<0.05).Compared with the model group,the fluorescence intensities of P21 and P53 were significantly weakened in the low-and high-dose catalpol groups,while the fluorescence intensity of type II collagen was significantly enhanced in the low-and high-dose catalpol groups(P<0.05),especially in the high-dose catalpol group(P<0.05).The cell apoptosis detected by Annexin V/PI method showed that there was no significant difference between the model group and the blank group(P>0.05);compared with the model group,the apoptotic index was significantly elevated in the low-and high-dose catalpol groups,especially in the high-dose catalpol group(P<0.05).To conclude,catalpol from Rehmannia glutinosa can slow the progression of osteoarthritis by promoting apoptosis of senescent ATDC5 chondrocytes,further removing senescent ATDC5 chondrocytes,and decreasing the senescence-associated phenotypes.

Data analysis models may assist the transmission of traditional Chinese medicine （TCM） experience and clinical diagnosis and treatment， and the possibility of constructing a “data-knowledge” dual-drive model was explored by taking gastric precancerous state as an example. Data-driven is to make clinical decisions around data analysis， and its syndrome-differentiation decision-making research relies on hidden structural models and partially observable Markov decision-making processes to identify the etiology of diseases， syndrome elements， evolution of pathogenesis， and syndrome differentiation protocols； knowledge-driven is to make use of data and information to promote decision-making and action processes， and its syndrome-differentiation decision-making research relies on convolutional neural networks to improve the accuracy of local disease identification and syndrome differentiation. The “data-knowledge” dual-driven model can make up for the shortcomings of single-drive numerical simulation accuracy， and achieve a balance between local disease identification and macroscopic syndrome differentiation. On the basis of previous research， we explored the construction method of diagnostic assisted decision-making platform for gastric precancerous state， and believed that the diagnostic and decision-making ability of doctors can be extended through the assistance of machines and algorithms. Meanwhile， the related research methods were integrated and the core features of gastric precancerous state based on TCM syndrome differentiation and endoscopic pathology diagnosis and prediction were obtained， and the elements of endoscopic pathology recognition based on TCM syndrome differentiation were explored， so as to provide ideas for the in-depth research and innovative application of cutting-edge data analysis technology in the field of intelligent TCM syndrome differentiation.

Objective As primary Sj?gren's syndrome(pSS)primarily affects the salivary glands,saliva can serve as an indicator of the glands'pathophysiology and the disease's status.This study aims to illustrate the salivary proteomic profiles of pSS patients and identify potential candidate biomarkers for diagnosis. Methods The discovery set contained 49 samples(24 from pSS and 25 from age-and gender-matched healthy controls[HCs])and the validation set included 25 samples(12 from pSS and 13 from HCs).Totally 36 pSS patients and 38 HCs were centrally randomized into the discovery set or to the validation set at a 2:1 ratio.Unstimulated whole saliva samples from pSS patients and HCs were analyzed using a data-independent acquisition(DIA)strategy on a 2D LC-HRMS/MS platform to reveal differential proteins.The crucial proteins were verified using DIA analysis and annotated using gene ontology(GO)and International Pharmaceutical Abstracts(IPA)analysis.A prediction model for SS was established using random forests. Results A total of 1,963 proteins were discovered,and 136 proteins exhibited differential representation in pSS patients.The bioinformatic research indicated that these proteins were primarily linked to immunological functions,metabolism,and inflammation.A panel of 19 protein biomarkers was identified by ranking order based on P-value and random forest algorichm,and was validated as the predictive biomarkers exhibiting good performance with area under the curve(AUC)of 0.817 for discovery set and 0.882 for validation set. Conclusions The candidate protein panel discovered may aid in pSS diagnosis.Salivary proteomic analysis is a promising non-invasive method for prognostic evaluation and early and precise treatments for pSS patients.DIA offers the best time efficiency and data dependability and may be a suitable option for future research on the salivary proteome.

italic>Artemisia argyi is a traditional Chinese medicine in China, which is used as medicine with its leaves. The leaves of A. argyi mainly contain flavonoids, phenolic acids, volatile oils and other compounds, and have a variety of pharmacological activities. AP2/ERF transcription factors are abundant in plants and are mainly involved in plant growth and development, abiotic stress response and secondary metabolite biosynthesis regulation. However, there are few reports on the AP2/ERF gene family and its functions in A. argyi. In this study, we systematically identified the AP2/ERF gene family in A. argyi genome, and analyzed its phylogenetic tree, protein physicochemical properties, subcellular localization, conserved motifs, promoter elements, and expression patterns. The results showed that a total of 204 AP2/ERF transcription factors were identified in A. argyi genome, encoding proteins consisting of 88-483 amino acids with a relative molecular mass of 10-52.94 kDa and a theoretical isoelectric point of 4.62-9.88. Subcellular prediction showed that the majority of AP2/ERFs were located in the nucleus, cytoplasm, and the minority of them is located in the membrane and chloroplasts. According to the Arabidopsis AP2/ERF family classification, A. argyi AP2/ERF proteins were divided into four subfamilies: Soloist, AP2, ERF (B3, B4, B5, B6), and DREB (A1, A2, A4, A5, A6), among which DREB family accounted for the largest proportion, and the same subfamily had similar conserved motifs. cis-Acting element analysis showed that AP2/ERF promoters have a large number of elements responding to light and abiotic stress. Expression pattern analysis showed that most of the genes of the AP2/ERF family were dominantly expressed mainly in roots and stems, of which 19 were dominantly expressed in leaves, 77 would be induced to be expressed by methyl jasmonate, of which 16 genes were both dominantly expressed in leaves and induced to be expressed by methyl jasmonate, and these AP2/ERF genes may be the key regulatory genes for the synthesis of active ingredients in A. argyi leaves.This study lays the foundation for the functional study of AP2/ERF family genes and their regulating roles in the active components biosynthesis in A. argyi leaves.

Objective To investigate the risk factors for bronchopulmonary dysplasia(BPD)in twin preterm infants with a gestational age of<34 weeks,and to provide a basis for early identification of BPD in twin preterm infants in clinical practice.Methods A retrospective analysis was performed for the twin preterm infants with a gestational age of<34 weeks who were admitted to 22 hospitals nationwide from January 2018 to December 2020.According to their conditions,they were divided into group A(both twins had BPD),group B(only one twin had BPD),and group C(neither twin had BPD).The risk factors for BPD in twin preterm infants were analyzed.Further analysis was conducted on group B to investigate the postnatal risk factors for BPD within twins.Results A total of 904 pairs of twins with a gestational age of<34 weeks were included in this study.The multivariate logistic regression analysis showed that compared with group C,birth weight discordance of>25%between the twins was an independent risk factor for BPD in one of the twins(OR=3.370,95%CI:1.500-7.568,P<0.05),and high gestational age at birth was a protective factor against BPD(P<0.05).The conditional logistic regression analysis of group B showed that small-for-gestational-age(SGA)birth was an independent risk factor for BPD in individual twins(OR=5.017,95%CI:1.040-24.190,P<0.05).Conclusions The development of BPD in twin preterm infants is associated with gestational age,birth weight discordance between the twins,and SGA birth.

The purpose of this study was to investigate the damage mechanism of pathogenic E.coli on mouse brain microvascular endothelial cells(BMEC cells)and mouse alveolar macrophages(MH-S cells),as well as the lung and brain of healthy mice.In this study,BMEC cells and MH-S cells were infected with pathogenic E.coli strains,and cell morphological changes were observed.Plate counting method was used to detect the adhesion and invasion ability of the strains to cells and the number of bacteria in the lungs and brains of mice.RT-qPCR was used to detect the ex-pression of TNF-α,IL-1β and IL-6 genes in cells and mouse organs at different time periods.West-ern blot was used to detect the expression of p-NF-κB,p-JAK2 and p-STAT3 proteins related to inflammation in cells and mouse organs after infection.The results showed that the cell culture medium of the infection group was turbid,the cell vision became dark and blurred,some cells shrank and died,and more fragments were produced.The adhesion rate and invasion rate of BMEC cells at 3 h were significantly lower than those at 6 h(P＜0.050),and the adhesion rate and inva-sion rate of MH-S cells at 3 h were significantly higher than those at 6 h(P＜0.010).Infected mice had a large area of swelling and bleeding in the brain,and the lungs had different degrees of swell-ing and bleeding.The bacterial load in the brain and lung was the highest at 12 h.Compared with the control group,the mRNA expression levels of IL-1β,IL-6 and TNF-α in the infection group were significantly increased at 3 h and 6 h(P＜0.050),and the mRNA expression levels of inflam-matory factors in BMEC cells and MH-S cells were the highest at 6 and 3 h,respectively.The mR-NA expression of inflammatory factors in the brain and lung of infected mice showed a trend of in-creasing first and then decreasing with time,with the highest expression at 12 h after infection.The expression levels of p-NF-κB protein in BMEC cells,MH-S cells,lung and brain tissues of mice in the infection group were significantly higher than those in the control group(P＜0.001),and the expression levels of p-JAK2 protein and p-STAT3 protein were significantly lower than those in the control group(P＜0.050).The above results showed that pathogenic E.coli could adhere and invade BMEC cells and MH-S cells,colonize in lung and brain tissues of mice,promote the expres-sion of NF-κB protein in cells and tissues,inhibit the expression of JAK2 protein and STAT3 pro-tein,and then stimulate cells and tissues to produce inflammatory response.

The study was aimed to assess the impact of Brucea javanica oil emulsion(BJOE)on the responsiveness of programmed death receptor-1(PD-1)monoclonal antibody to lung adenocarcinoma in mice.The experimental approach involved subcutaneously inoculating Lewis's lung adenocarcinoma(LLC)cells into C57BL/6 mice,which were then divided into four groups:model group,25 ml·kg-1 BJOE group,10 mg·kg-1 PD-1 group,and combination group(25 ml·kg-1 BJOE and 10 mg·kg-1 PD-1).Tumor volume,mass,and inhibition rate were evaluated;the apoptosis within tumor tissue was detected by TUNEL staining;CD4+and CD8+T cell proportions within tumor tissues were analyzed by flow cytometry;the levels of tumor necrosis factor-α(TNF-α),interferon-γ(IFN-γ)and granzyme B in tumor tissue were measured by enzyme-linked immunosorbent assay(ELISA).Additionally,LLC cells were categorized into a control group and three BJOE treatment groups(10,30,50 μl·ml-1),and programmed death ligand 1(PD-L1)expression in tumor tissues and LLC cells were assessed by Western blotting.Data showed that as compared with the model group,PD-1 monoclonal antibody alone did not significantly alter tumor volume,tumor mass,CD4+and CD8+T cell proportions,cytokine levels(IFN-γ,TNF-α,Granzyme B),or apoptosis in lung cancer-bearing mice.However,BJOE treatment reduced tumor volume and mass,enhanced CD4+and CD8+T cell proportions,increased cytokine levels,and augmented apoptosis(all P<0.05).Furthermore,the combination therapy of BJOE and PD-1 monoclonal antibody yielded significantly greater reductions in tumor volume and mass,with heightened CD4+and CD8+T cell proportions,cytokine levels,and apoptosis compared to either treatment alone(all P<0.05).Both BJOE treatment and the combination therapy significantly upregulated PD-L1 protein expression in tumor tissues compared to the model or PD-1 monoclonal antibody groups(P<0.05).Similarly,BJOE treatment at all tested concentrations significantly increased PD-L1 protein expression in LLC cells as compared to the control group(P<0.05).In conclusion,BJOE could upregulate PD-L1 expression in LLC cells and enhance the sensitivity of lung adenocarcinoma-bearing mice to PD-1 monoclonal antibodies.

Patients with severe trauma require an extremely timely treatment and transfusion plays an irreplaceable role in the emergency treatment of such patients. An increasing number of evidence-based medicinal evidences and clinical practices suggest that patients with severe traumatic bleeding benefit from early transfusion of low-titer group O whole blood or hemostatic resuscitation with red blood cells, plasma and platelet of a balanced ratio. However, the current domestic mode of blood supply cannot fully meet the requirements of timely and effective blood transfusion for emergency treatment of patients with severe trauma in clinical practice. In order to solve the key problems in blood supply and blood transfusion strategies for emergency treatment of severe trauma, Branch of Clinical Transfusion Medicine of Chinese Medical Association, Group for Trauma Emergency Care and Multiple Injuries of Trauma Branch of Chinese Medical Association, Young Scholar Group of Disaster Medicine Branch of Chinese Medical Association organized domestic experts of blood transfusion medicine and trauma treatment to jointly formulate Chinese expert consensus on blood support mode and blood transfusion strategies for emergency treatment of severe trauma patients ( version 2024). Based on the evidence-based medical evidence and Delphi method of expert consultation and voting, 10 recommendations were put forward from two aspects of blood support mode and transfusion strategies, aiming to provide a reference for transfusion resuscitation in the emergency treatment of severe trauma and further improve the success rate of treatment of patients with severe trauma.

Objective:To explore the role of interleukin-18 (IL-18) in the pathogenesis of dermatomyositis (DM) associated with positive anti-melanoma differentiation-associated gene 5 antibodies(MDA5-DM).Methods:Twenty-eight cases of MDA5-DM in the department of rheumatology and immunology, the first hospital of Nanjing medical university and the first affiliated hospital od Wannan medical colledge from August 2018 to December 2011 were included in this study, comprising 15 cases with combined rapidly progressive interstitial pneumonia (RPILD) and 13 cases without RPILD (nonRPILD). Additionally, 28 cases of antisynthetase syndrome (ASS) and 28 healthy volunteers (HC) were included for comparison. Clinical, laboratory, and imaging data were collected for both the DM and ASS groups. Serum IL-18 levels were measured using ELISA. Independent t test, Mann-whitney U test, χ2 test and Fisher′s exact probability method were used for analysis. Results:Significant differences were observed in LDH, hydroxybutyrate dehydrogenase (HBDH), ESR, CRP, serum ferritin (SFE), and IL-18 levels between the MDA5-DM group, the ASS group and the HC group ( F=46.65, 43.19, 31.28, 23.94, 30.94, 49.44, all P<0.001). Additionally, lymphocyte counts and hemoglobin levels differed significantly among the three groups( F=35.26, P<0.001; F=18.59, P<0.001). MDA5-DM patients exhibited higher incidences of Gottron′s sign, helitrope rash, periungual erythema, skin ulcers, and RPILD compared to ASS patients ( χ2=20.96, P<0.001; χ2=5.85, P=0.016; χ2=13.69, P<0.001; χ2=9.16, P=0.002; χ2=4.79, P=0.029). However, the incidence of mechanic′s hand was lower in MDA5-DM patients ( χ2=3.90, P=0.048). The level of IL-18 significantly decreased in MDA5-DM after treatment[(104.28(71.96,151.10)pg/ml vs. 78.30(56.20, 94.80)pg/ml, =2.27, P=0.023)]. Similar reductions were observed in the ASS group[(72.30(61.39, 95.94)pg/ml vs. 45.30(29.00,84.10)pg/ml, Z=2.691, P=0.007]. The IL-18 level changes in the MDA5-DM combined with RPILD group were not statistically significant [99.49 (77.65, 130.87)pg/ml vs. 89.40(54.80, 120.20)pg/ml, Z=0.65, P=0.515]. In the MDA5-DM survival group, IL-18 levels decreased significantly after treatment [59.45(53.58, 81.63)pg/ml vs. 106.37(83.62, 152.07)pg/ml, Z=2.80, P=0.005], while the changes in the IL-18 levels of patients in the MDA5-DM death group were not statistically significant [99.49(56.70, 140.15)pg/ml vs. 94.80(71.40, 155.45)pg/ml, Z=1.75, P=0.080]. Conclusion:MDA5-DM patients are different from the ASS patients in clinical manifestations and indicators involved in laboratory tests. The expression level of IL-18 tends to increase during the active phase of MDA5-DM and ASS, and decrease with remission of the disease. MDA5-DM may play an important role in the pathogenesis, and persistent high level of IL-18 is responsible for RPILD and death of MDA5-DM. Sustained high level of IL-18 can be used as a potential biomarker for the estimating development of MDA5-DM into RPILD.