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.

Objective:To evaluate the developmental toxicity of Cry1Ab protein by studying its effects on cell proliferation and differentiation ability using a developmental toxicity assessment model based on embryonic stem-cell.Methods:Cry1Ab protein was tested in seven dose groups(31.25,62.50,125.00,250.00,320.00,1 000.00,and 2 000.00 μg/L)on mouse embryonic stem cells D3(ES-D3)and 3T3 mouse fibroblast cells,with 5-fluorouracil(5-FU)used as the positive control and phos-phate buffer saline(PBS)as the solvent control.Cell viability was detected by CCK-8 assay to calculate the 50％inhibitory concentration(IC50)of the test substance for different cells.Additionally,Cry1 Ab protein was tested in five dose groups(125.00,250.00,320.00,1 000.00,and 2 000.00 μg/L)on ES-D3 cells,with PBS as the solvent control and 5-FU used for model validation.After cell treatment,cardiac differentiation was induced using the embryonic bodies(EBs)culture method.The growth of EBs was observed under a microscope,and their diameters on the third and fifth days were measured.The proportion of EBs differentiating into beating cardiomyocytes was recorded,and the 50％inhibition con-centration of differentiation(ID50)was calculated.Based on a developmental toxicity discrimination func-tion,the developmental toxicity of the test substances was classified.Furthermore,at the end of the cul-ture period,mRNA expression levels of cardiac differentiation-related markers(Oct3/4,GATAA-4,Nkx2.5,and β-MHC)were quantitatively detected using real-time quantitative polymerase chain reaction(qPCR)in the collected EBs samples.Results:The IC50 of 5-FU was determined as 46.37 μg/L in 3T3 cells and 32.67 μg/L in ES-D3 cells,while the ID50 in ES-D3 cells was 21.28 μg/L.According to the discrimination function results,5-FU was classified as a strong embryotoxic substance.There were no sta-tistically significant differences in cell viability between different concentrations of Cry 1 Ab protein treat-ment groups and the control group in both 3T3 cells and ES-D3 cells(P＞0.05).Moreover,there were no statistically significant differences in the diameter of EBs on the third and fifth days,as well as their morphology,between the Cry1Ab protein treatment groups and the control group(P＞0.05).The cardi-ac differentiation rate showed no statistically significant differences between different concentrations of Cry1Ab protein treatment groups and the control group(P＞0.05).5-FU significantly reduced the mRNA expression levels of β-MHC,Nkx2.5,and GATA-4(P＜0.05),showing a dose-dependent trend(P＜0.05),while the mRNA expression levels of the pluripotency-associated marker Oct3/4 exhibited an increasing trend(P＜0.05).However,there were no statistically significant differences in the mRNA expression levels of mature cardiac marker β-MHC,early cardiac differentiation marker Nkx2.5 and GATA-4,and pluripotency-associated marker Oct3/4 between the Cry1Ab protein treatment groups and the control group(P＞0.05).Conclusion:No developmental toxicity of Cry1Ab protein at concen-trations ranging from 31.25 to 2 000.00 μg/L was observed in this experimental model.

Ureterosciatic hernia is a rare type of pelvic floor herniation with no typical symptoms. The resulting ureteral obstruction may lead to hydronephrosis and complications such as urinary tract infection and urosepsis.Fewer than 40 ureterosciatic hernia cases have been reported all over the world. Active surveillance, manual reduction, ureteral stenting and surgical repair are common treatment options. Among them, the safety and effectiveness of laparoscopic herniorrhaphy have been recognized. This article review the advances in the diagnosis and treatment of ureterosciatic hernia.

ObjectiveTranscription factor NFE2 was observed abnormal expression in myeloproliferative neoplasm (MPN) patients. However, how NFE2 is transcriptionally regulated remains ambiguous. This study aims to explore the elements and molecular mechanisms involved in the transcriptional regulation of NFE2. MethodsActive enhancers were predicted by public NGS data and conformed experimentally via dual luciferase reporter assay. After that, PRO-seq and GRO-seq data was used to detect enhancer RNAs transcribed from these enhancers. RACE was utilized to clone the full length enhancer RNA (eRNA) transcripts, and RT-qPCR was used to measure their expression in different leukemia cell lines as well as the transcript levels during induced differentiation. Finally, to investigate the molecular function of the eRNA, overexpression and knockdown of the eRNA via lentivirus system was performed in K562 cells. ResultsWe identified three enhancers regulating NFE2 transcription, which located at -3.6k, -6.2k and +6.3k from NFE2 transcription start site (TSS) respectively. At the -3.6k enhancer, we cloned an eRNA transcript and characterized that as a lncRNA which was expressed and located in the nucleus in three types of leukemia cell lines. When this lncRNA was overexpressed, expression of NFE2 was upregulated and decreases of K562 cell proliferation and migration ability were observed. While knocking down of this lncRNA, the level of NFE2 decreases correspondingly and the proliferation ability of K562 cells increases accordingly. ConclusionWe identified an enhancer lncRNA that regulates NFE2 transcription positively and suppresses K562 cell proliferation.

Objective This study aimed to investigate the potential relationship between urinary metals copper (Cu), arsenic (As), strontium (Sr), barium (Ba), iron (Fe), lead (Pb) and manganese (Mn) and grip strength. Methods We used linear regression models, quantile g-computation and Bayesian kernel machine regression (BKMR) to assess the relationship between metals and grip strength.Results In the multimetal linear regression, Cu (β=-2.119), As (β=-1.318), Sr (β=-2.480), Ba (β=0.781), Fe (β= 1.130) and Mn (β=-0.404) were significantly correlated with grip strength (P < 0.05). The results of the quantile g-computation showed that the risk of occurrence of grip strength reduction was -1.007 (95％ confidence interval:-1.362, -0.652; P < 0.001) when each quartile of the mixture of the seven metals was increased. Bayesian kernel function regression model analysis showed that mixtures of the seven metals had a negative overall effect on grip strength, with Cu, As and Sr being negatively associated with grip strength levels. In the total population, potential interactions were observed between As and Mn and between Cu and Mn (Pinteractions of 0.003 and 0.018, respectively).Conclusion In summary, this study suggests that combined exposure to metal mixtures is negatively associated with grip strength. Cu, Sr and As were negatively correlated with grip strength levels, and there were potential interactions between As and Mn and between Cu and Mn.

AIM To investigate the effects of different compatibility ratios and processing method on the content of rutin,isoquercetin,ferulic acid,quercetin,isotoosendanin,kaempferol,toosendanin,α-pinene,trans-anethole in the combination use of Toosendan Fructus and Foeniculi Fructus,and to explore the optimal compatibility ratio for its use.METHODS The analysis of HPLC-DAD was performed on a 30℃thermostatic ZORBAX SB C18 column(4.6 mm×250 mm,5 μm),with the mobile phase comprising of acetonitrile-0.1%phosphoric acid flowing at 1.0 mL/min in a gradient elution manner,and the use of DAD detector.SPSS 24.0 software was used to analyze the data differences.RESULTS Nine constituents showed good linear relationships within their own ranges(r≥0.999 1),whose average recoveries were 96.19%-103.13%with the RSDs of 1.86%-2.67%.Generally higher total content of nine constituents were detected in the combination use groups when Toosendan Fructus-Foeniculi Fructus were at ratios of 1 ∶ 1,1 ∶ 2,and 2 ∶ 1 than those single uses(P<0.05),and among which the 1 ∶ 1 ratio contributed the highest total content.After salt processing,decreased content of toosendanin and isotoosendanin,α-pinene and trans-anethole(P<0.05,P<0.01)),increased isoquercetin content(P<0.01),and no significant content changes of other ingredients were detected.CONCLUSION Through this method of high accuracy and good reproducibility,we learn that the combination use of Toosendan Fructus and Foeniculi Fructus promotes the dissolution of the nine constituents,and the maximum content is achieved at ratio of 1 ∶ 1.

AIM To study the chemical constituents from the leaves of Cyanocarya paliurus(Batalin)Iljinskaja and their α-glucosidase inhibitory activities.METHODS The 95%ethanol extract from the leaves of C.paliurus was isolated and purified by macroporous resin,silica gel,Sephadex LH-20,polyamide,C18 reversed-phase silica gel and semi-preparative HPLC,then the structures of obtained compounds were identified by physicochemical properties and spectral data.Their α-glucosidase inhibitory activities were evaluated by PNPG.RESULTS Fifteen compounds were isolated and identified as cyclopaloside C(1),cyclopaloside A(2),juglanosides E(3),vaccinin A(4),ent-murin A(5),kaempferol 3-O-α-L-rhamnopyranoside(6),kaempferol-3-O-β-D-glucopyranoside(7),kaempferol-3-O-β-D-glucuronide methyl ester(8),kaempferol-3-O-β-D-glucuronide ethyl ester(9),kaempferol-3-O-β-D-glucuronide butyl ester(10),quercetin-3-O-α-L-rhamnopyranoside(11)quercetin-3-O-β-D-glucopyranoside(12),quercetin-3-O-β-D-galactopyranoside(13),quercetin-3-O-β-D-glucuronide butyl ester(14),dihydrokaempferol(15).The IC50 value of total extracts ihibited α-glucosidase was(1.83±0.04)μg/mL,and the IC50 values of compounds 1,4-5 were(29.48±1.86),(0.50±0.07),(0.71±0.07)μmol/L,respectively.CONCLUSION Compound 1 is a new tetrahydronaphthalene glycoside.Compounds 4-5,8-10 and 14 are isolated from the leaves of C.paliurus for the first time.Compounds 4-5 are relatively rare flavonoid lignans with potential inhibitory activities against α-glucosidase.