Quercetin-induced degradation of RhoC suppresses hepatocellular carcinoma invasion and metastasis.

BACKGROUND: Tumor metastasis and recurrence are major causes of mortality in patients with hepatocellular carcinoma (HCC) that is still lack of effective therapeutic targets and drugs. Previous reports implied that ras homolog family member C (RhoC) plays a toxic role on metastasis and proliferation of cancer. METHODS: In this research, the correlation between RhoC and metastasis ability was confirmed by in vitro experiments and TCGA database. We explored whether quercetin could inhibit cell migration or invasion by transwell assay. Real-time PCR, overexpression and ubiquitination assay, etc. were applied in mechanism study. Primary HCC cells and animal models including patient-derived xenografts (PDXs) were employed to evaluate the anti-metastasis effects of quercetin. RESULTS: Clinical relevance and in vitro experiments further confirmed the level of RhoC was positively correlated with invasion and metastasis ability of HCC. Then we uncovered that quercetin could attenuate invasion and metastasis of HCC by downregulating RhoC's level in vitro, in vivo and PDXs. Furthermore, mechanistic investigations displayed quercetin hindered the E3 ligase expression of SMAD specific E3 ubiquitin protein ligase 2 (SMURF2) leading to enhancement of RhoC's ubiquitination and proteasomal degradation. CONCLUSIONS: Our research has revealed the novel mechanisms quercetin regulates degradation of RhoC level by targeting SMURF2 and identified quercetin may be a potential compound for HCC therapy.

Serinc2 deficiency exacerbates sepsis-induced cardiomyopathy by enhancing necroptosis and apoptosis.

In critical care medicine, sepsis is a potentially fatal syndrome characterized by multi-organ dysfunction and eventual failure. Sepsis-induced cardiomyopathy (SIC) is characterized by decreased venstricular contractility. Serine incorporator 2 (Serinc2) is a protein involved in phosphatidylserine biosynthesis and membrane incorporation. It may also be a protective factor in septic lung injury. However, it is unknown whether Serinc2 influences SIC onset or progression. In the present study, we found that Serinc2 was downregulated in the cardiomyocytes of cecal ligation and puncture (CLP)-induced SIC and in neonatal rat cardiomyocytes (NRCMs) exposed to lipopolysaccharides (LPS). Serinc2 knockout (KO) exacerbated sepsis-induced myocardial inflammation, necroptosis, apoptosis, myocardial damage, and contractility impairment. Furthermore, the lack of Serinc2 in cardiomyocytes aggravated LPS-induced cardiomyopathic inflammation, necroptosis, and apoptosis. An adenovirus overexpressing Serinc2 inhibited the inflammatory response and favored cardiomyocyte survival. A mechanistic analysis revealed that Serinc2 deficiency exacerbated LPS-induced cardiac dysfunction by inhibiting the protein kinase B (Akt)/glycogen synthase kinase 3 beta (GSK-3ß) signaling pathway that regulates necrotic complex formation and apoptotic pathways in cardiomyopathy. The findings of the present work demonstrated that Serinc2 plays an essential role in SIC and is, therefore, promising as a prophylactic and therapeutic target for this condition.

Effect of SH2B1 on glucose metabolism during pressure overload-induced cardiac hypertrophy and cardiac dysfunction.

This study mainly explored the effect and mechanism of Src homology 2 (SH2) B adaptor protein 1 (SH2B1) on cardiac glucose metabolism during pressure overload-induced cardiac hypertrophy and dysfunction. A pressure-overloaded cardiac hypertrophy model was constructed, and SH2B1-siRNA was injected through the tail vein. Haematoxylin and eosin (H&E) staining was used to detect myocardial morphology. ANP, BNP, ß-MHC and the diameter of myocardial fibres were quantitatively measured to evaluate the degree of cardiac hypertrophy, respectively. GLUT1, GLUT4, and IR were detected to assess cardiac glucose metabolism. Cardiac function was determined by echocardiography. Then, glucose oxidation and uptake, glycolysis and fatty acid metabolism were assessed in Langendorff perfusion of hearts. Finally, PI3K/AKT activator was used to further explore the relevant mechanism. The results showed that during cardiac pressure overload, with the aggravation of cardiac hypertrophy and dysfunction, cardiac glucose metabolism and glycolysis increased, and fatty acid metabolism decreased. After SH2B1-siRNA transfection, cardiac SH2B1 expression was knocked down, and the degree of cardiac hypertrophy and dysfunction was alleviated compared with the Control-siRNA transfected group. Simultaneously, cardiac glucose metabolism and glycolysis were reduced, and fatty acid metabolism was enhanced. The SH2B1 expression knockdown mitigated the cardiac hypertrophy and dysfunction by reducing cardiac glucose metabolism. After using PI3K/AKT activator, the effect of SH2B1 expression knockdown on cardiac glucose metabolism was reversed during cardiac hypertrophy and dysfunction. Collectively, SH2B1 regulated cardiac glucose metabolism by activating the PI3K/AKT pathway during pressure overload-induced cardiac hypertrophy and cardiac dysfunction.

Co-delivery of EGCG and melittin with self-assembled fluoro-nanoparticles for enhanced cancer therapy.

PURPOSE: Melittin (MPI) is a potential anticancer peptide due to its abilities of antitumor and immunomodulatory functions. Epigallocatechin-3-Ogallate (EGCG), a major extract of green tea, has shown great affinity for various types of biological molecules, especially for peptide/protein drugs. The aim of this study is to prepare a fluoro- nanoparticle (NP) formed by self-assembly of fluorinated EGCG (FEGCG) and MPI, and evaluate the effect of fluorine modification on MPI delivery and their synergistic antitumor effect. METHODS: Characterization of FEGCG@MPI NPs was determined by dynamic light scattering (DLS) and transmission electron microscope (TEM). Biology functions of FEGCG@MPI NPs were detected by hemolysis effect, cytotoxicity, apoptosis, cellular uptake with confocal microscopy and flow cytometry. The protein expression levels of Bcl-2/Bax, IRF, STATT-1, P-STAT-1, and PD-L1 were determined via western blotting. A transwell assay and wound healing assay were used to detect the cell migration and invasion. The antitumor efficacy of FEGCG@MPI NPs was demonstrated in a subcutaneous tumor model. RESULTS: Fluoro-nanoparticles could be formed by self-assembly of FEGCG and MPI, and fluorine modification on EGCG could ameliorate the side effect and delivery of MPI. The promoted therapeutics of FEGCG@MPI NPs could be achieved by regulating PD-L1 and apoptosis signaling, which might involve pathways of IRF, STAT-1/pSTAT-1, PD-L1, Bcl-2, and Bax in vitro. Moreover, FEGCG@MPI NPs could significantly inhibit the growth of tumor in vivo. CONCLUSIONS: FEGCG@MPI NPs may offer a potential platform and promising strategy in cancer therapy.

Carnosic acid protects against doxorubicin-induced cardiotoxicity through enhancing the Nrf2/HO-1 pathway.

Doxorubicin (DOX) is used extensively in anticancer therapy, but its clinical application is limited due to its cardiotoxicity. Carnosic acid (CA) is a bioactive compound found in rosemary. It has been shown to reduce inflammation and reactive oxygen species. The purpose of this study was to investigate the potential cardioprotective effects of CA in response to DOX-induced cardiotoxicity. Here, C57BL/6 mice were administered an intraperitoneal injection of DOX (5 mg kg-1, ip) once a week for three consecutive weeks and treated with CA (40 mg kg-1, ig) for a three-week experimental period. For in vitro study, neonatal rat ventricular cardiomyocytes were used to validate the protective effects of CA (20 µM) in response to DOX-induced cardiotoxicity. CA markedly suppressed oxidative stress, apoptosis, and pyroptosis responses in the mouse hearts, eventually improving cardiac function. CA showed its antioxidant effect by activating nuclear factor erythroid 2-related factor (Nrf2) and its downstream heme oxygenase-1 (HO-1); CA also reduced oxidative stress by lowering the MDA and lipid ROS levels and raising the SOD and GSH-px levels. Additionally, CA treatment significantly increased Bcl-2 and inhibited Bax and Caspase-3 cleavage in DOX-induced cardiotoxicity. Moreover, CA suppressed the NOD-like receptor protein 3 (NLRP3) pathway to mitigate pyroptosis, as evidenced by lowered caspase1, interleukin-18, and interleukin-1ß. Consistently, the transfection of Nrf2-siRNA eliminated the protective effects of CA on cardiomyocytes. Altogether, our findings demonstrated that CA inhibited NLRP3 inflammasomes via activating the Nrf2-related cytoprotective system and protected the heart from oxidative damage, apoptosis, and pyroptosis, implying that the use of CA could be a potential therapeutic strategy in the prevention of DOX-associated myocardiopathy.

Allyl phenyl selenides as H2O2 acceptors to develop ROS-responsive theranostic prodrugs.

Reactive oxygen species (ROS)-responsive prodrugs have received significant attention due to their capacity to target tumors to relieve the side effects caused by chemotherapy. Herein, a series of novel H2O2-activated theranostic prodrugs (CPTSe1-CPTSe7) were developed containing allyl phenyl selenide moieties as H2O2 acceptors. Compared with conventional boronate ester-based prodrug CPT-B, CPTSe1 was more stable in human plasma and showed a more complete release of camptothecin (CPT) in H2O2 inducing experiment. The selectively activated fluorescence signals of CPTSe1 in tumor cells make it useful for real-time monitoring of CPT release and H2O2 detection. Furthermore, excellent selectivity of CPTSe1 was achieved for tumor cells over normal cells. Our results provide a new platform for the development of H2O2-responsive theranostic prodrugs.

Manipulating Offense and Defense Signaling to Fight Cold Tumors with Carrier-Free Nanoassembly of Fluorinated Prodrug and siRNA.

Chemoimmunotherapy has shown great potential to activate an immune response, but the immunosuppressive microenvironment associated with T cell exhaustion remains a challenge in cancer therapy. The proper immune-modulatory strategy to provoke a robust immune response is to simultaneously regulate T-cell exhaustion and infiltration. Here, a new kind of carrier-free nanoparticle is developed to simultaneously deliver chemotherapeutic drug (doxorubicin, DOX), cytolytic peptide (melittin, MPI), and anti-TOX small interfering RNA (thymocyte selection-associated high mobility group box protein, TOX) using a fluorinated prodrug strategy. In this way, the enhanced immunogenic cell death (ICD) induced by the combination of DOX and MPI can act as "offense" signaling to increase CD8+ T-cell infiltration, while the decreased TOX expression interfered with siTOX can serve as "defense" signaling to mitigate CD8+ T-cell exhaustion. As a result, the integration of DOX, MPI, and siTOX in such a bifunctional system produced a potent antitumor immune response in liver cancer and metastasis, making it a promising delivery platform and effective strategy for converting "cold" tumors into "hot" ones.

Engineered EGCG-Containing Biomimetic Nanoassemblies as Effective Delivery Platform for Enhanced Cancer Therapy.

Nano-based immunotherapy of therapeutic biomolecules is attractive but tremendously hampered by the poor delivery efficiency. This study reports a novel delivery system of fluorinated-coordinative-epigallocatechin gallate (EGCG), referring as FEGCG/Zn, through the integration of fluorination and zinc ions (Zn2+ ) into EGCG. The robust therapeutics of FEGCG/Zn are measured in terms of the regulating effect on programmed cell death ligand 1 (PD-L1), the effective delivery of diverse biomolecules, and the hitchhiking ability using living cells. Taking small interfering RNA of PD-L1 (siPD-L1) and erythrocytes as an example, the fabricated biomimetic system achieves excellent siPD-L1 delivery and further improves siPD-L1 accumulation in tumors. Finally, the combination of FEGCG/Zn and siPD-L1 promotes antitumor immunotherapy through alleviation of T cells exhaustion by regulating PD-L1 expression in tumor cells. The results demonstrate that FEGCG/Zn substantially regulates PD-L1 expression and improves immune-biomolecule delivery by forming biomimetic nanoassemblies, offering a versatile platform for cancer immunotherapy.

Discovery of Potent PROTACs Targeting EGFR Mutants through the Optimization of Covalent EGFR Ligands.

Drug resistance caused by epidermal growth factor receptor (EGFR) mutation has largely limited the clinical use of EGFR tyrosine kinase inhibitors (EGFR-TKIs) for the treatment of non-small-cell lung cancer (NSCLC). Herein, to overcome the intractable problem of drug resistance, proteolysis targeting chimeras (PROTACs) targeting EGFR mutants were developed by optimizing covalent EGFR ligands. Covalent or reversible covalent pyrimidine- or purine-containing PROTACs were designed, synthesized, and evaluated. As a consequence, covalent PROTAC CP17, with a novel purine-containing EGFR ligand, was discovered as a highly potent degrader against EGFRL858R/T790M and EGFRdel19, reaching the lowest DC50 values among all reported EGFR-targeting PROTACs. Furthermore, CP17 exhibited excellent cellular activity against the H1975 and HCC827 cell lines with high selectivity. Mechanism investigation indicated that the lysosome was involved in the degradation process. Importantly, the covalent binding strategy was proven to be an effective approach for the design of PROTACs targeting EGFRL858R/T790M, which laid the practical foundation for further development of potent EGFR-targeting PROTACs.

MiR-183-5p overexpression in bone mesenchymal stem cell-derived exosomes protects against myocardial ischemia/reperfusion injury by targeting FOXO1.

OBJECTIVE: Exosomes have been suggested to serve as possible drug delivery vehicles due to their nanometer-size range and capability of transferring biological materials to recipient cells. Thus, whether miR-183-5p-overexpressing bone marrow mesenchymal stem cell-derived exosomes (BMSC-Exos) could protect against myocardial ischemia/reperfusion (MI/R) injury by targeting FOXO1 was investigated. METHODS: Exosomes were isolated from rat BMSCs, and ischemia/reperfusion (I/R) rat models were established. I/R rats were treated with Exo/NC-Exo/miR-183-5p-Exo/anti-miR-183-5p-Exo. Cardiac function, serum biochemical indices, apoptosis, myocardial infarction size, and the expression of miR-183-5p, FOXO1 and cleaved caspase 3 were assessed. Primary cardiomyocytes were isolated to establish hypoxia/reoxygenation (H/R) models to observe the function of miR-183-5p-Exo in vitro. RESULTS: Rats in the I/R group exhibited a decreased left ventricular ejection fraction (LVEF), left ventricular fraction shortening (LVFS) and left ventricular systolic pressure (LVSP) but an increased left ventricular end-diastolic pressure (LVEDP), myocardial infarct size and apoptosis index (AI). In addition, in I/R rats, miR-183-5p expression was decreased, but FOXO1 and cleaved caspase 3 expression was increased. Both Exo and miR-183-5p-Exo improved the above indices in I/R rats, but miR-183-5p-Exo showed better effects. However, anti-miR-183-5p-Exo reversed the protective effect of Exo. FOXO1 was a target gene of miR-183-5p. Experiments in vitro revealed that Exo and miR-183-5p-Exo suppressed apoptosis and oxidative stress injury in H/R-induced cardiomyocytes, whereas overexpressed FOXO1 reversed the protective role of miR-183-5p-Exo. CONCLUSION: BMSC-derived exosomal miR-183-5p could target FOXO1 to reduce apoptosis and oxidative stress in I/R cardiomyocytes and improve cardiac function, thereby protecting against MI/R injury.

High­glucose microenvironment promotes perineural invasion of pancreatic cancer via activation of hypoxia inducible factor 1α.

Pancreatic cancer (PC) is one of the most lethal diseases, with a 5­year survival rate of <9%. Perineural invasion (PNI) is a common pathological hallmark of PC and is correlated with a poor prognosis in this disease. Hyperglycemia has been shown to promote the invasion and migration of PC cells; however, the effect of hyperglycemia on the PNI of PC and its underlying mechanism remains unclear. In the present study, Western blotting was utilized to detect the expression of hypoxia inducible factor 1α (HIF1α) and nerve growth factor (NGF). Transwell and wound­healing assays were performed to detect the influence of hyperglycemia on the invasion and migration ability of PC cells. An in vitro PC­dorsal root ganglion (DRG) co­culture system and an in vivo PNI sciatic nerve­infiltrating tumor model were used to evaluate the severity of PNI in hyperglycemic conditions. In the results, hyperglycemia promoted the invasion/migration ability and elevated the expression of NGF in PC by upregulating HIF1α. Moreover, in vitro short­term hyperglycemia caused little damage on the DRG axons and accelerated both the PNI of the PC and the outgrowth of the DRGs by increasing the expression of NGF via activation of HIF1α. Indeed, in vivo long­term hyperglycemia promoted the infiltration and growth of PC, and then disrupted the function of the sciatic nerve in a HIF1α­dependent manner. In conclusion, a high­glucose microenvironment promotes PNI of PC via activation of HIF1α.

A pan-cancer analysis of the prognostic and immunological roles of matrix metalloprotease-1 (MMP1) in human tumors.

Objective: Cancer remains the leading killer of human health worldwide. It has been shown that matrix metalloproteinase-1(MMP1) is related to poor prognosis in cancers such as BRCA, CESC and COAD. However, systematic pan-cancer analysis about the prognostic and immunological roles of MMP1 has not been explored. Here, the purpose of this study was to investigate the prognostic and immunological roles of MMP1 in pan-cancer and confirm cancer-promoting effect in pancreatic cancer. Methods: In our study, bioinformatics were first used to analyze data from multiple databases. Then, several bioinformatics tools were utilized to investigate the role of MMP1 in 33 tumor types. Finally, molecular biology experiments were carried out to prove the cancer-promoting effect of MMP1 in pancreatic cancer. Results: MMP1 expression was higher in tumor tissues than in control tissues in most tumor types. High expression of MMP1 was associated with poor overall survival (OS) and disease-free survival (DFS) in some tumor types. Further analysis of MMP1 gene mutation data showed that MMP1 mutations significantly influenced the prognosis of STAD. In addition, MMP1 expression was closely related to cancer-associated fibroblast (CAFs) infiltration in a variety of cancers and played an important role on immune infiltration score, tumor mutational burden (TMB) and microsatellite instability (MSI). Gene Ontology enrichment analysis indicated that these 20 genes were mainly related to extracellular structure organization/extracellular matrix organization/extracellular matrix disassembly/collagen metabolic process in the enriched biological processes. Finally, molecular biology experiments confirmed the cancer-promoting effect of MMP1 in pancreatic cancer. Conclusions: Our pan-cancer analysis comprehensively proved that MMP1 expression is related with clinical prognosis and tumor immune infiltration, and MMP1 can become a prognostic and immunological biomarker.

Exosome CTLA-4 Regulates PTEN/CD44 Signal Pathway in Spleen Deficiency Internal Environment to Promote Invasion and Metastasis of Hepatocellular Carcinoma.

Hepatocellular carcinoma (HCC) is one of the most common primary cancers, and its pathogenesis is complicated and difficult to screen. Currently, there is no effective treatment. In traditional Chinese medicine, a large proportion of patients with HCC have been diagnosed with spleen deficiency (SD) syndrome and treated with tonifying traditional Chinese medicine, which has significant clinical efficacy. However, the role and molecular mechanism of SD in HCC remain unclear. In this study, 40 mice were randomly divided into four groups: control, SD, HCC, and SD-HCC groups. The liver cancer model of SD was established by reserpine induction and orthotopic transplantation. The effects of SD on the proliferation, apoptosis, invasion, and metastasis of HCC cells were studied by cell proliferation, cell apoptosis, cell scratch, and transwell assay. We found that compared with the HCC group, the protein expressions of cytotoxic T lymphocyte antigen 4 (CTLA-4), programmed cell death protein 1 (PD-1), phosphatase and tensin homolog (PTEN), and AKT (also known as protein kinase B or PKB) in the exosomes of the SD-HCC group were upregulated. In addition, the metastases and self-renewal of exosomes in the SD-HCC group were more aggressive than those in the HCC group, which could be partially reversed with the addition of CTLA-4 inhibitors. Further studies showed that in the internal environment of SD, CTLA-4 promoted tumor invasion and metastasis by regulating the PTEN/CD44 pathway. In conclusion, our findings suggest that during SD in the internal environment, exosome CTLA-4 regulates the PTEN/CD44 signal pathway to promote the proliferation, self-renewal, and metastasis of liver cancer.

Recent Progress of Small Molecule Menin-MLL Interaction Inhibitors as Therapeutic Agents for Acute Leukemia.

Mixed lineage leukemia (MLL) gene rearrangements are associated with acute leukemia. The protein menin is regarded as a critical oncogenic cofactor of the resulting MLL fusion proteins in acute leukemia. A direct interaction between menin and the MLL amino terminal sequences is necessary for MLL fusion protein-mediated leukemogenesis. Thus, inhibition of the interaction between menin and MLL has emerged as a novel therapeutic strategy. Recent improvements in structural biology and chemical reactivity have promoted the design and development of selective and potent menin-MLL interaction inhibitors. In this Perspective, different classes of menin-MLL interaction inhibitors are comprehensively summarized. Further research potential, challenges, and opportunities in the field are also discussed.

N-myc downstream regulated gene 2 ameliorates myocardial remodeling and cardiac function in heart failure rats.

This study aims to explore the effect of NDRG2 (N-myc downstream regulated gene 2)-mediated Transforming growth factor-beta 1 (TGF-ß1)/ Sma- and Mad-related protein (Smad) pathway in heart failure (HF) rats. HF rat models were established and treated with AdEGFP (adenovirus encoding enhanced green fluorescent protein) or AdNDRG2 (adenovirus encoding NDRG2). The echocardiography and hemodynamic parameters were detected, and the infarct size was calculated via 2,3,5-triphenyltetrazolium chloride (TTC) staining. Masson staining was performed to observe the collagen volume fraction (CVF), quantitative reverse transcriptase polymerase chain reaction (qRT-PCR) to detect the expression of Collagen I (Col-I) and Collagen III (Col-III), and Transferase (TdT)-mediated D-UTP-biotin nick end labeling (TUNEL) staining to evaluate the apoptosis. Rats in the Model group presented with the decreases in left ventricular ejection fraction (LVEF), left ventricular shortening fraction (LVFS), left ventricular systolic pressure (LVSP) and maximal/minimum rate of left ventricular pressure (±dp/dt max), and significant increases in left ventricular end-diastolic pressure (LVEDP) and CVF. At the meantime, the expression of Col-I and Col-III as well as the apoptotic rate of myocardial cells was also elevated with increased infarct size in the Model group. The Model rats also had the significant reduction in the expression of NDRG2 and up-regulations of TGF-ß1, p-Smad2/Smad2, p-Smad3/Smad3 and tissue inhibitor of metalloproteinases-2 (TIMP-2). However, model rats treated with AdNDRG2 had evident amelioration in aforementioned indicators. In conclusion, NDRG2 reduces the apoptosis of myocardial cells and improves the heart function and myocardial remodeling in HF rats via inhibiting the activity of TGF-ß1/Smad.

Development of 2,5-dihydro-4H-pyrazolo[3,4-d]pyrimidin-4-one inhibitors of aldehyde dehydrogenase 1A (ALDH1A) as potential adjuncts to ovarian cancer chemotherapy.

There is strong evidence that inhibition of one or more Aldehyde Dehydrogenase 1A (ALDH1A) isoforms may be beneficial in chemotherapy-resistant ovarian cancer and other tumor types. While many previous efforts have focused on development of ALDH1A1 selective inhibitors, the most deadly ovarian cancer subtype, high-grade serous (HGSOC), exhibits elevated expression of ALDH1A3. Herein, we report continued development of pan-ALDH1A inhibitors to assess whether broad spectrum ALDH1A inhibition is an effective adjunct to chemotherapy in this critical tumor subtype. Optimization of the CM39 scaffold, aided by metabolite ID and several new ALDH1A1 crystal structures, led to improved biochemical potencies, improved cellular ALDH inhibition in HGSOC cell lines, and substantial improvements in microsomal stability culminating in orally bioavailable compounds. We demonstrate that two compounds 68 and 69 are able to synergize with chemotherapy in a resistant cell line and patient-derived HGSOC tumor spheroids, indicating their suitability for future in vivo proof of concept experiments.

Synthesis and Biological Evaluation of 10-Substituted Camptothecin Derivatives with Improved Water Solubility and Activity.

Despite remarkable clinical achievements, camptothecin (CPT) still suffers from poor solubility and severe toxicity. Therefore, it is necessary to redevelop CPT derivatives as supplementary antitumor agents with good water solubility and small side effects. In this work, 27 camptothecin derivatives were synthesized and screened for their cytotoxicity against A549 (lung) and HCT-116 (colon) cancer cell lines. Among them, compound B7, 7-ethyl-10-(2-oxo-2-(4-methylpiperidin-1-yl)ethoxy)camptothecin,was demonstrated in vitro to be a more potent antitumor agent than SN-38 by comparison of their inhibitory activities against cell proliferation and colony formation and interference effect on process of cell cycle and cell apoptosis. Additionally, a molecular docking model revealed that B7 can interact with the topoisomerase I-DNA complex, and that the solubility of B7 reached 5.73 µg/mL in water. Moreover, B7 significantly inhibited tumor growth in an A549 xenograft model at dosages of 0.4 and 2.0 mg/kg, and exhibited minimum lethal doses comparable to those of irinotecan. These results indicated that B7, with improved solubility, enhanced activity and acceptable acute toxicity, can be used as a lead compound for the development of novel anticancer agents.

Beneficial Effects of Baduanjin Exercise on Left Ventricular Remodelling in Patients after Acute Myocardial Infarction: an Exploratory Clinical Trial and Proteomic Analysis.

BACKGROUND: The beneficial effects of physical exercise on cardiac remodelling improvement after myocardial infarction have already been suggested. However, the results of previous clinical trials have not been consistent. Moreover, the putative molecular mechanisms leading to the clinically observed effects of physical exercise still remain elusive. AIM: We aimed to evaluate whether the well-defined and strictly controlled traditional Chinese Qigong Baduanjin exercise (BE) would attenuate the adverse left ventricular (LV) remodelling in patients with ST-elevation myocardial infarction (STEMI). METHODS: A total of 110 clinically stable STEMI patients, following successful revascularization of their infarcted coronary arteries, were randomized and enrolled in two groups: 56 were subjected to a 12-week BE-based cardiac rehabilitation programme (BE group), and the remaining 54 were exposed to the usual physical exercise (control group) for the same time period. The primary outcome was the change from baseline to 6 months in the echocardiographic LV end-diastolic volume index (ΔLVEDVi). Proteomic analysis was also performed to uncover associated mechanisms. RESULTS: Compared with the control group, the BE group showed significantly lower ΔLVEDVi (-5.1 ± 1.1 vs. 0.3 ± 1.2 mL/m2, P < 0.01). Proteomic analysis revealed BE-induced variations in the expression of 80 proteins linked to regulation the of metabolic process, immune process, and extracellular matrix reorganization. Furthermore, correlation analyses between the validated serum proteomes and primary endpoint demonstrated a positive association between ΔLVEDVi and MMP-9 expression, but a negative correlation between ΔLVEDVi and CXCL1 expression. CONCLUSION: This is the first study indicating that BE in STEMI patients can alleviate adverse LV remodelling associated with beneficial energy metabolism adaptation, inflammation curbing, and extracellular matrix organization adjustment.

Conversion from a failed proximal femoral nail anti-rotation to a cemented or uncemented total hip arthroplasty device: a retrospective review of 198 hips with previous intertrochanteric femur fractures.

BACKGROUND: At present, it is unclear which device (uncemented or cemented total hip arthroplasty [UTA or CTA, respectively]) is more suitable for the conversion of a failed proximal femoral nail anti-rotation (PFNA). The aim of this review was to assess the outcomes of failed PFNAs converted to a UTA or CTA device in elderly individuals with intertrochanteric femoral fractures (IFFs). METHODS: Two hundred fifty-eight elderly individuals (258 hips) with IFFs who underwent a conversion to a UTA or CTA device following failed PFNAs during 2007-2017 were retrospectively identified from the China Southern Medical Centre (CSMC) database. The primary endpoint was the Harris Hip Score (HHS); secondary endpoint was the key orthopaedic complication rate. RESULTS: The median follow-up was 65 months (60-69 months). Significant distinctions were observed (87.26 ± 16.62 for UTA vs. 89.32 ± 16.08 for CTA, p = 0.021; 86.61 ± 12.24 for symptomatic UTA vs. 88.68 ± 13.30 for symptomatic CTA, p = 0.026). A significant difference in the overall key orthopaedic complication rate was detected (40.8% [40/98] vs. 19.0% [19/100], p = 0.001). Apparent distinctions were detected in terms of the rate of revision, loosening, and periprosthetic fracture (11.2% for UTA vs 3.0% for CTA, p = 0.025; 13.2% for UTA vs 5.0% for CTA, p = 0.043; 10.2% for UTA vs 3.0% for CTA, p = 0.041, respectively). CONCLUSION: For elderly individuals with IFFs who suffered a failed PFNA, CTA devices may have a noteworthy advantage in regard to the revision rate and the rate of key orthopaedic complications compared with UTA devices, and CTA revision should be performed as soon as possible, regardless of whether these individuals have symptoms.