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 study the cyclic peptides from sponge Reniochalina sp. under the guidance of mass spectrometry. Methods Mass spectrometry-guided procedural separation methods were used to track and isolate the cyclic peptides from the sponge genus Reniochalina. The structures of compounds were elucidated by the determination of physicochemical parameters and comparison of spectroscopic data. The preliminary cytotoxic activity of compounds was assessed by the Cell Counting Kit-8 (CCK-8) method. Results Three cyclic peptides were isolated from the sponge Reniochalina sp. and identified as stylopeptide 1 (1), hymenamide D (2) and axinastatin 2 (3). Compound 1 exhibited cytotoxicity against six human cancer cell lines with IC₅₀ values ranging from 6.09 to 17.26 μmol/L. Conclusion Compound 1 - 3 were isolated from Reniochalina sp. for the first time, and compound 1 was a cytotoxic cyclic heptapeptide.

BACKGROUND: Angiogenesis is described as a complex process in which new microvessels sprout from endothelial cells of existing vasculature. This study aimed to determine whether long non-coding RNA (lncRNA) H19 induced the angiogenesis of gastric cancer (GC) and its possible mechanism. METHODS: Gene expression level was determined by quantitative real-time polymerase chain reaction and western blotting. Cell counting kit-8, transwell, 5-Ethynyl-2'-deoxyuridine (EdU), colony formation assay, and human umbilical vein endothelial cells (HUVECs) angiogenesis assay as well as Matrigel plug assay were conducted to study the proliferation, migration, and angiogenesis of GC in vitro and in vivo . The binding protein of H19 was found by RNA pull-down and RNA Immunoprecipitation (RIP). High-throughput sequencing was performed and next Gene Ontology (GO) as well as Kyoto Encyclopedia of Genes and Genomes (KEGG) analysis was conducted to analyze the genes that are under H19 regulation. Methylated RIP (me-RIP) assay was used to investigate the sites and abundance among target mRNA. The transcription factor acted as upstream of H19 was determined through chromatin immunoprecipitation (ChIP) and luciferase assay. RESULTS: In this study, we found that hypoxia-induced factor (HIF)-1α could bind to the promoter region of H19, leading to H19 overexpression. High expression of H19 was correlated with angiogenesis in GC, and H19 knocking down could inhibit cell proliferation, migration and angiogenesis. Mechanistically, the oncogenic role of H19 was achieved by binding with the N 6 -methyladenosine (m 6 A) reader YTH domain-containing family protein 1 (YTHDF1), which could recognize the m 6 A site on the 3'-untransated regions (3'-UTR) of scavenger receptor class B member 1 (SCARB1) mRNA, resulting in over-translation of SCARB1 and thus promoting the proliferation, migration, and angiogenesis of GC cells. CONCLUSION HIF-1α induced overexpression of H19 via binding with the promoter of H19, and H19 promoted GC cells proliferation, migration and angiogenesis through YTHDF1/SCARB1, which might be a beneficial target for antiangiogenic therapy for GC.
Humans ; Cell Line, Tumor ; Cell Proliferation/genetics* ; Endothelial Cells/metabolism* ; Gene Expression Regulation ; Gene Expression Regulation, Neoplastic/genetics* ; Hypoxia ; MicroRNAs/genetics* ; RNA ; RNA, Long Noncoding/metabolism* ; RNA-Binding Proteins/metabolism* ; Scavenger Receptors, Class B/metabolism* ; Stomach Neoplasms/genetics*

BACKGROUND: Sarcoplasmic reticulum calcium ATPase 2a (SERCA2a) is a key protein that maintains myocardial Ca 2+ homeostasis. The present study aimed to investigate the mechanism underlying the SERCA2a-SUMOylation (small ubiquitin-like modifier) process after ischemia/reperfusion injury (I/RI) in vitro and in vivo . METHODS: Calcium transient and systolic/diastolic function of cardiomyocytes isolated from Serca2a knockout (KO) and wild-type mice with I/RI were compared. SUMO-relevant protein expression and localization were detected by quantitative real-time PCR (RT-qPCR), Western blotting, and immunofluorescence in vitro and in vivo . Serca2a-SUMOylation, infarct size, and cardiac function of Senp1 or Senp2 overexpressed/suppressed adenovirus infected cardiomyocytes, were detected by immunoprecipitation, triphenyltetrazolium chloride (TTC)-Evans blue staining, and echocardiography respectively. RESULTS: The results showed that the changes of Fura-2 fluorescence intensity and contraction amplitude of cardiomyocytes decreased in the I/RI groups and were further reduced in the Serca2a KO + I/RI groups. Senp1 and Senp2 messenger ribose nucleic acid (mRNA) and protein expression levels in vivo and in cardiomyocytes were highest at 6 h and declined at 12 h after I/RI. However, the highest levels in HL-1 cells were recorded at 12 h. Senp2 expression increased in the cytoplasm, unlike that of Senp1. Inhibition of Senp2 protein reversed the I/RI-induced Serca2a-SUMOylation decline, reduced the infarction area, and improved cardiac function, while inhibition of Senp1 protein could not restore the above indicators. CONCLUSION I/RI activated Senp1 and Senp2 protein expression, which promoted Serca2a-deSUMOylation, while inhibition of Senp2 expression reversed Serca2a-SUMOylation and improved cardiac function.
Animals ; Mice ; Calcium/metabolism* ; Cysteine Endopeptidases/metabolism* ; Myocardial Reperfusion Injury/metabolism* ; Myocardium/metabolism* ; Myocytes, Cardiac/metabolism* ; Proteins/metabolism* ; Sarcoplasmic Reticulum Calcium-Transporting ATPases/genetics*

As an active hydroxyanthraquinone ingredient, emodin is abundant in Chinese medicine herbs, such as Rheum palmatum, Polygonum cuspidatum and Polygonum multiflorum.Modern pharmacological studies have shown that emodin has a variety of pharmacological activities including anti-tumor, anti-inflammatory and immunoregulatory, antibacterial and anti-viral effects, myocardial protection, neuroprotection, renal protection, bone protection, antifibrosis and so on, which indicate its high medicinal value and broad application prospects.This article aims to summarize the progress in the pharmacological activity and mechanism of action of emodin published in domestic and international journals over the last 5 years and highlight the potential targets and molecular signaling pathways linked with emodin, so as to provide some clues and references for further development and clinical application of emodin.

Objective:To investigate the application of transbronchial needle aspiration (TBNA) in the diagnosis of tuberculosis with mediastinal lymphadenopathy in children.Methods:A retrospective study was conducted on clinical data in 8 children of tuberculosis with mediastinal lymphadenopathy treated in the Center for Respiratory Intervention, Children′s Hospital Affiliated to Shandong University from March 2014 to July 2019.TBNA was performed after the mediastinal lymphadenopathy were diagnosed by chest enhanced CT and the final diagnosis was made.The diagnostic experience of TBNA was summarized.Results:Eight children with mediastinal lymphadenopathy included in this present study aged from 7 months to 8 years and 6 months (infants accounted for 75.0%), with a median age of 22.5 months.There were 3 males (37.5%) and 5 females (62.5%). The body mass was 8.5-39.0 kg, and the median body mass was 10.7 kg.The course of disease was 15-90 days, and the median number of days was 18.5 days.The clinical manifestations included cough in 8 cases, fever in 4 cases, wheezing in 1 case and laryngeal ringing in 1 case.Bronchoscopy and TBNA biopsy were performed.Cytology, etiology and pathology were examined after TBNA.A definite diagnosis could be made in 6 children, with a diagnosis rate of 75.0%.Among them, 4 cases were found with acid-fast bacilli in smear but pathological examination was negative; 1 case was pathologically conformed to the characteristics of tuberculosis infection but the smear was negative; the smear and pathology of 1 case were both suggestive of tuberculosis; 2 cases did not present etiological and histological evidence with TBNA.The diagnosis was made according to the positive acid-fast bacilli of alveolar lavage fluid smear.There were no complications during and after operation.Conclusions:TBNA is an important method to diagnose tuberculosis in children, which is effective, safe and has high clinical application value.

Pulmonary endothelial barrier dysfunction is a hallmark of clinical pulmonary edema and contributes to the development of acute lung injury (ALI). Here we reported that ruscogenin (RUS), an effective steroidal sapogenin of Radix Ophiopogon japonicus, attenuated lipopolysaccharides (LPS)-induced pulmonary endothelial barrier disruption through mediating non-muscle myosin heavy chain IIA (NMMHC IIA)‒Toll-like receptor 4 (TLR4) interactions. By in vivo and in vitro experiments, we observed that RUS administration significantly ameliorated LPS-triggered pulmonary endothelial barrier dysfunction and ALI. Moreover, we identified that RUS directly targeted NMMHC IIA on its N-terminal and head domain by serial affinity chromatography, molecular docking, biolayer interferometry, and microscale thermophoresis analyses. Downregulation of endothelial NMMHC IIA expression in vivo and in vitro abolished the protective effect of RUS. It was also observed that NMMHC IIA was dissociated from TLR4 and then activating TLR4 downstream Src/vascular endothelial cadherin (VE-cadherin) signaling in pulmonary vascular endothelial cells after LPS treatment, which could be restored by RUS. Collectively, these findings provide pharmacological evidence showing that RUS attenuates LPS-induced pulmonary endothelial barrier dysfunction by inhibiting TLR4/Src/VE-cadherin pathway through targeting NMMHC IIA and mediating NMMHC IIA‒TLR4 interactions.

Objective:To investigate the correlation between neutrophil/lymphocyte ratio (NLR) combined with low-density lipoprotein cholesterol/high-density lipoprotein cholesterol ratio (LDL-C/HDL-C) and severity of coronary lesions in patients with acute coronary syndrome (ACS).Methods:Patients who were diagnosed with ACS due to chest pain and received emergency coronary angiography in the First Affiliated Hospital of University of Science and Technology of China and the Affiliated Hospital of Anhui Medical University from January 2017 to June 2020 were enrolled in the final analysis. The data of gender, age, body mass index (BMI), past history, emergency blood routine indicators [neutrophil (NEU), lymphocyte (LYM), monocyte (MON), eosinophil (EOS), basophil (BAS), red blood cell (RBC), mean corpuscular volume (MCV), blood red cell distribution width (RDW), mean platelet volume (MPV), platelet volume distribution width (PDW)], blood lipid index [triglyceride (TG), total cholesterol (TC), HDL-C, LDL-C, very low-density lipoprotein cholesterol (VLDL-C)], and coronary angiography were collected. The results of coronary angiography were evaluated by the Gensini score. According to the Gensini score, the patients were divided into the control group (Gensini score = 0, 55 cases) and the study group (Gensini score > 0, 889 cases), and then the patients in the study group were divided into the low-Gensini-score group (Gensini score < 66, 419 cases) and the high-Gensini-score group (Gensini score ≥ 66, 470 cases). The differences in the general baseline data of the four groups were compared, and the correlation between the statistically significant data and the Gensini score was linearly analyzed, and then the combined diagnostic factors (NLR combined with LDL-C/HDL-C ratio) were obtained by Logistic regression analysis. The receiver operator characteristic curve (ROC curve) was used to evaluate the predictive value of NLR combined with LDL-C/HDL-C ratio in predicting the severity of coronary artery lesions in patients with ACS. Finally, multivariate linear regression analysis was used to establish the predictive model between NLR combined with LDL-C/HDL-C ratio and Gensini score.Results:A total of 944 patients were finally included. The differences in gender, age, BMI, hypertension, diabetes, smoking history, NEU, LYM, MON, EOS, RDW, TC, HDL-C, LDL-C, NLR, LDL-C/HDL-C ratio between the control group and the study group were statistically significant. The differences in BMI, hypertension, diabetes, smoking history, NEU, LYM, MON, EOS, TG, TC, HDL-C, LDL-C, NLR and LDL-C/HDL-C ratio between the low-Gensini-score group and the high-Gensini-score group were statistically significant. Linear regression analysis showed that compared with other indicators, the correlation between NLR, LDL-C/HDL-C ratio and Gensini score was stronger in the study group ( r values were 0.634 and 0.663, respectively, both P < 0.05). Binary Logistic regression analysis of the indicators related to Gensini score showed that NEU, LYM, HDL-C and LDL-C were independent risk factors for coronary stenosis in patients with ACS [odds ratio ( OR) were 0.189, 10.309, 13.993, 0.251, 95% confidence intervals (95% CI) were 0.114-0.313, 4.679-22.714, 3.402-57.559, 0.121-0.519, respectively, all P < 0.05]. ROC curve analysis showed that NLR combined with LDL-C/HDL-C ratio had higher predictive value in predicting the severity of coronary lesions in ACS patients [area under the ROC curve (AUC) was 0.952, 95% CI was 0.93-0.969], when the cutoff value was -3.152, the sensitivity was 98.20%, and the specificity was 81.60%. According to the results of multivariate linear regression analysis, the prediction model between NLR, LDL-C/HDL-C ratio and Gensini score was established, and the formula was Gensini score = -7.772+15.675×LDL-C/HDL-C ratio+8.288×NLR ( R2 = 0.862). Conclusion:There is a significant correlation between emergency NLR combined with LDL-C/HDL-C ratio and Gensini score in patients with ACS at admission, which has a certain predictive value for the severity of coronary artery stenosis in patients with ACS, and can be used as a predictor for evaluating the severity of coronary artery disease.

[This corrects the article DOI: 10.1016/j.apsb.2021.09.017.].

The management of drainage tube is an important part of nursing work. Patient restraint and tube fixation cannot effectively prevent unplanned extubation (UEX) when the tube is accidentally pulled by violence. The nursing innovation team of Henan Provincial People's Hospital designed a medical drainage tube anti-pull device in order to change the existing technology of preventing drainage tube disconnecting by means of restraint and fixation, and to interfere with the basic cause of drainage tube disconnection, and obtained the national utility model patent (patent number: ZL 2020 2 2843025.1). The design of sleeve and clasp is that when the drainage tube is pulled by accidental violence, the friction fastener clamps the drainage tube mechanically to achieve the purpose of braking the drainage tube and prevent the drainage tube from coming out. Card sleeve ring fracture design can be applied to drainage tubes of different diameters, and the buzzer device at the instant of the snap ring into the card set warning medical staff to the occurrence of risk events, so that the nurse can come in the first place for effective treatment, which is a fuse for surgical drainage tubes and is to timely and effectively prevent UEX.