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Due to the extent of these errors, the authors no longer have confidence in the presented data. After publication, the authors noticed image duplication errors in Figs. [Extracted from the article]

Heparanase plays important roles in tumor angiogenesis. Our previous study demonstrated that hypoxic preconditioning (HPC) enhanced the angiogenic and therapeutic effects of mesenchymal stem cells (MSCs), effects that were paralleled by enhanced heparanase expression. This study was designed to elucidate the role of heparanase in the improved therapeutic properties of HPC-MSCs and to explore underlying mechanisms using an ischemic rat hind limb model. MSCs transfected with heparanase (MSChpa) or empty vector (MSCnull) were delivered by intramuscular injections to ischemic hind limbs. Hind limbs that received MSChpa recovered blood flow more rapidly at 7 days and acquired higher capillary density at 14 days compared with MSCnull. Conditioned medium from MSChpa increased endothelial cell migration and promoted greater tube formation relative to that from the MSCnull groups. Vascular endothelial growth factor receptor 2 (VEGFR2, Flk-1) and its downstream signaling pathway (p38MAPK/HSP27) were significantly increased in human umbilical vein endothelial cells (HUVECs) after treatment with MSChpa conditioned medium. Each of these responses was decreased by cocultured with MSChpa-KD conditioned medium. MSChpa conditioned medium activated hypoxia-inducible factor-2α (HIF-2α) and increased in parallel the transcript level of Flk-1 as determined by chromatin immunoprecipitation-PCR and luciferase assays. Analyses of integrin expression revealed an important role for integrin β1 in the regulation of HIF-2α. All angiogenic effects of MSChpa conditioned medium were abolished by knockdown of integrin β1, HIF-2α, and Flk-1 in HUVECs with selective shRNAs. These findings identify heparanse as a key regulator of angiogenesis by MSCs. We propose a novel pathway wherein heparanse sequentially activates integrin β1, HIF-2α, Flk-1, and p38MAPK/HSP27 with corresponding enhancement of angiogenesis. S tem C ells 2015;33:1850-1862 [ABSTRACT FROM AUTHOR]

The rapid development of nuclear industry has generated large quantities of low-level radioactive wastewater (LLRW) to pose a potential threat globally. In this study, the feasibility of vacuum membrane distillation (VMD) process for the decontamination of uranium contained LLRW from UO 2 fuel element production has been studied using commercial PTFE hollow fiber membrane. The effects of operation conditions, such as feed temperature/pH, vacuum pressure and feed flow velocity were investigated and optimized with artificial UO 2 (NO 3) 2 solution. The real process wastewater from the UO 2 fuel element factory were then treated by VMD process under the optimized conditions for 1400 min with the concentration factor up to 9. No clear evidence of membrane fouling or wetting were noticed during the VMD operation nor the membrane autopsy studies. With an average permeate flux of 7.3 L m−2 h−1, it exhibited excellent retention towards all major contaminates such as uranium, COD, and NH 4 +-N to meet the Integrated Wastewater Discharge Standard of China (GB 8978-1996) for direct discharge. [Display omitted] • LLRW from UO 2 fuel element production was treated by VMD process with a concentration factor up to 9. • A permeate flux of 11.3 L∙m-2∙h-1 and more than 99.99% rejection against uranium was achieved with simulated wastewater. • It exhibited excellent retention towards all major contaminates in real LLRW treatment to meet national standards for direct discharge. [ABSTRACT FROM AUTHOR]

• Till now, there is no systematically reviewed state of the evidence available on the effectiveness of interventions aimed to improve students' scientific creativity. • In this meta-analysis, the results of interventions focus on improving students' scientific creativity were brought together to determine which intervention is the most effective in improving scientific creativity. • There were four types of interventions were systematically reviewed in this meta-analysis, respectively problem solving , collaborative leaning , conceptual construction and scientific reasoning. As the importance of students' scientific creativity garners increasing attention, many interventions have been designed to cultivate such creativity. To date, however, the available evidence regarding the effectiveness of such interventions has not been systematically reviewed. In this meta-analysis, the results of interventions to improve students' scientific creativity have been brought together to determine which is the most effective. The analysis is based on 20 outcomes from 17 studies published between 1992 and 2019. Four types of intervention were systematically reviewed: problem-solving , collaborative learning , conceptual construction , and scientific reasoning. The findings demonstrate that problem-solving has a large effect on students' scientific creativity (g = 1.54 ; n = 8), as does scientific reasoning (g =. 89 ; n = 3), while collaborative learning has a medium effect (g = 0.76 , n = 6) and conceptual construction has a small effect (g =. 20 ; n = 3). In conclusion, this paper found that interventions aimed at cultivating the product dimension of scientific creativity might be most effective in terms of students' scientific creativity, followed by those based on training traits and process dimension, in that order. [ABSTRACT FROM AUTHOR]

Background: The diagnostic accuracy of CT-derived fractional flow reserve (CT-FFR) in clinical application has been well validated. This advanced technology focus on evaluating anatomical stenosis and functional ischemia simultaneously. However, the effect of CT-FFR on the management of decision making has not been fully evaluated in randomized controlled design.Method/design: TARGET study is a pragmatic, multicenter, prospective, open-label, and randomized controlled trial evaluating the effect of a CCTA/CT-FFR strategy (group A) versus usual care (group B) on intermediate-to-high risk patients with suspected CAD who undergo clinically indicated diagnostic evaluation. A total sample size of 1216 subjects will be enrolled and followed up for 12 months. This study will be performed in 6 Chinese hospitals, and the primary endpoint is the planned ICA without significant obstructive CAD within 90 days. The secondary endpoints include MACE, quality of life, medical expenditure, and cumulative radiation exposure during 1-year follow-up.Discussion: The study will provide information to patients, health care providers, and other stakeholders in China about which strategy could be more effective in the management of intermediate-to-high risk patients with suspect CAD.Trial Registration: ClinicalTrials.gov NCT03901326 . Registered on 3 April 2019. [ABSTRACT FROM AUTHOR]

ABSTRACT Aim Design Methods Results Conclusion Impact Reporting Method Patient or Public Contribution To explore lung transplant recipients' perceptions of well‐being when they are facing uncertain health outcomes, including identifying the factors to enhance well‐being.A qualitative descriptive study.A purposive sample of 11 lung transplantation recipients who were hospitalised in the Department of Organ Transplantation of a tertiary university hospital was recruited in China. A descriptive qualitative study using thematic analysis of semistructured interviews. Themes were organised within a PERMA model. Colaizzi's qualitative analysis was used to analyse the data.Five major themes and 11 categories were generated: (1) mindset shift [optimism and hope and living in the moment]; (2) meaning in life [self‐care, priority change and value realisation]; (3) health benefits [improved health and behavioural changes]; (4) perceived support [support from family, the health care team and others]; (5) unmet support needs.Lung transplant recipients could perceive well‐being from five aspects that caused significantly favourable transformation across a variety of aspects in patients' lives. These findings may support nursing staff when caring for this patient group, making them aware of multifaceted nature of well‐being. They could offer insight into potential pathways for the development of nurse‐led tailored interventions, based on specific elements of PERMA model.This work adds to a growing body of knowledge about well‐being amongst lung transplant patients. These findings may support nursing staff when caring for this patient group, making them aware of multifaceted nature of well‐being and illustrating factors that promote positive well‐being in this group, based on specific elements of PERMA model.This study followed the Consolidated Criteria for Reporting Qualitative Research checklist.Two lung transplant recipients were involved in the early phases of this study. They helped in formulating the interview outline. [ABSTRACT FROM AUTHOR]

An amendment to this paper has been published and can be accessed via a link at the top of the paper. [ABSTRACT FROM AUTHOR]

The primary cause of heart failure is the loss of cardiomyocytes in the diseased adult heart. Previously, we reported that the miR-17-92 cluster plays a key role in cardiomyocyte proliferation. Here, we report that expression of miR-19a/19b, members of the miR-17-92 cluster, is induced in heart failure patients. We show that intra-cardiac injection of miR-19a/19b mimics enhances cardiomyocyte proliferation and stimulates cardiac regeneration in response to myocardial infarction (MI) injury. miR-19a/19b protected the adult heart in two distinctive phases: an early phase immediately after MI and long-term protection. Genome-wide transcriptome analysis demonstrates that genes related to the immune response are repressed by miR-19a/19b. Using an adeno-associated virus approach, we validate that miR-19a/19b reduces MI-induced cardiac damage and protects cardiac function. Finally, we confirm the therapeutic potential of miR-19a/19b in protecting cardiac function by systemically delivering miR-19a/19b into mice post-MI. Our study establishes miR-19a/19b as potential therapeutic targets to treat heart failure. The miR-17-92 cluster has been shown to regulate cardiomyocyte proliferation in vitro and in genetic mutation and overexpression models. Here the authors show that the cluster member miR-19a/19b regulates cardiomyocyte proliferation in vivo, and that delivery of miR-19a/19b to the heart leads to both short-term and long-term protective responses to myocardial infarction. [ABSTRACT FROM AUTHOR]

Introduction: Amyloidosis caused by TTR mutations (ATTRv) is a rare inherited and autosomal dominant disease. More than 150 mutants of TTR have been reported, whereas some of them remain to be investigated. Methods: A 52-year-old male presented with heart failure and clinically diagnosed ATTR cardiac amyloidosis (ATTR-CA) was recruited. Whole-exome sequencing (WES) was performed. Biochemical and biophysical experiments characterized protein stability using urea-mediated tryptophan fluorescence. Drug response was analyzed by fibril formation assay. Finally, tetramer TTR concentration in patient's serum sample was measured by ultra-performance liquid chromatography (UPLC). Results: For the proband, WES revealed a mutation (c.200G>T; p.Gly67Val and referred to as G47V) in TTR gene. Biochemical and biophysical kinetics study showed that the thermodynamic stability of G47V-TTR (Cm = 2.4 m) was significantly lower than that of WT-TTR (Cm = 3.4 m) and comparable to that of L55P-TTR (Cm = 2.3 m), an early age-of-onset mutation. G47V:WT-TTR heterozygous tetramer kinetic stability (t1/2 = 1.4 h) was further compromised compared to that of the homozygous G47V-TTR (t1/2 = 3.1 h). Among three small molecule stabilizers, AG10 exhibited the best inhibition of the fibrillation of G47V-TTR homozygous protein. Using a UPLC assay, nearly 40% of TTR in this patient was calculated to be non-tetrameric. Conclusion: In this work, we reported a patient presented early onset of clinically typical ATTR-CA due to G47V-TTR mutation. Our work for the first time not only characterized the biochemical properties of G47V-TTR mutation, but also provided hints for the pathogenicity of this mutation. [ABSTRACT FROM AUTHOR]

Background: Numerous studies have shown that Schistosoma japonicum infection correlates with an increased risk of liver hepatocellular carcinoma (LIHC). However, data regarding the role of this infection in LIHC oncogenesis are scarce. This study aimed to investigate the potential mechanisms of hepatocarcinogenesis associated with Schistosoma japonicum infection. Methods: By examining chronic liver disease as a mediator, we identified the genes contributing to Schistosoma japonicum infection and LIHC. We selected 15 key differentially expressed genes (DEGs) using weighted gene co-expression network analysis (WGCNA) and random survival forest models. Consensus clustering revealed two subgroups with distinct prognoses. Least Absolute Shrinkage and Selection Operator (LASSO) and Cox regression identified six prognostic DEGs, forming an Schistosoma japonicum infection-associated signature for strong prognosis prediction. This signature, which is an independent LIHC risk factor, was significantly correlated with clinical variables. Four DEGs, including BMI1, were selected based on their protein expression levels in cancerous and normal tissues. We confirmed BMI1's role in LIHC using Schistosoma japonicum-infected mouse models and molecular experiments. Results: We identified a series of DEGs that mediate schistosomiasis, the parasitic disease caused by Schistosoma japonicum infection, and hepatocarcinogenesis, and constructed a suitable prognostic model. We analyzed the mechanisms by which these DEGs regulate disease and present the differences in prognosis between the different genotypes. Finally, we verified our findings using molecular biology experiments. Conclusion: Bioinformatics and molecular biology analyses confirmed a relationship between schistosomiasis and liver hepatocellular cancer. Furthermore, we validated the role of a potential oncoprotein factor that may be associated with infection and carcinogenesis. These findings enhance our understanding of Schistosoma japonicum infection's role in LIHC carcinogenesis. [ABSTRACT FROM AUTHOR]

Objective: Interpersonal psychotherapy (IPT) has been proposed as a treatment strategy for eating disorders (EDs). However, cognitive behavioural therapy (CBT) is the treatment more widely used than IPT. Method: Our study aimed to conduct a systematic review and meta‐analysis of randomized controlled trials (RCTs) in order to compare the effectiveness of IPT with CBT in treating eating disorders (EDs). To achieve this goal, we conducted a comprehensive search on PubMed, Embase, Medline, Cochrane, Web of Science, and the Clinical Trials Database for RCTs that compared the effectiveness of IPT with CBT in treating EDs. Results: After reviewing 468 potential studies, we selected 10 suitable for our meta‐analysis, which included 833 participants. Results showed that both IPT and CBT had similar effects on the primary outcome measure (i.e., ED score) (SMD = 0.08). However, IPT had a more significant effect on the secondary outcome measure (i.e., Inventory of Interpersonal Problems) (SMD = 0.32) compared to CBT. Additionally, IPT had a better treatment effect for individuals with EDs who had a lower body mass index (SMD = 0.27) and were younger (SMD = 0.43) than those receiving CBT. Both IPT and CBT demonstrated follow‐up effects at pretest and after follow‐up periods of less than 6 months (SMD = 1.61, 1.83), between 6 and 12 months (SMD = 1.48, 1.65), and greater than 12 months (SMD = 1.29, 1.33). However, only CBT demonstrated a dose–response relationship trend (β = 0.017, p = 0.067). Conclusions: The meta‐analysis yielded compelling evidence that IPT is an effective treatment for individuals with EDs. However, the review highlights the need for future research to further elucidate the effects of IPT on ED treatment. [ABSTRACT FROM AUTHOR]

BACKGROUND: The importance of mitochondria in normal heart function are well recognized and recent studies have implicated changes in mitochondrial metabolism with some forms of heart disease. Previous studies demonstrated that knockdown of the mitochondrial ribosomal protein S5 (MRPS5) by small interfering RNA (siRNA) inhibits mitochondrial translation and thereby causes a mitonuclear protein imbalance. Therefore, we decided to examine the effects of MRPS5 loss and the role of these processes on cardiomyocyte proliferation. METHODS: We deleted a single allele of MRPS5 in mice and used left anterior descending coronary artery ligation surgery to induce myocardial damage in these animals. We examined cardiomyocyte proliferation and cardiac regeneration both in vivo and in vitro. Doxycycline treatment was used to inhibit protein translation. Heart function in mice was assessed by echocardiography. Quantitative real-time polymerase chain reaction and RNA sequencing were used to assess changes in transcription and chromatin immunoprecipitation (ChIP) and BioChIP were used to assess chromatin effects. Protein levels were assessed by Western blotting and cell proliferation or death by histology and terminal deoxynucleotidyl transferase dUTP nick-end labeling (TUNEL) assays. Adeno-associated virus was used to overexpress genes. The luciferase reporter assay was used to assess promoter activity. Mitochondrial oxygen consumption rate, ATP levels, and reactive oxygen species were also analyzed. RESULTS: We determined that deletion of a single allele of MRPS5 in mice results in elevated cardiomyocyte proliferation and cardiac regeneration; this observation correlates with improved cardiac function after induction of myocardial infarction. We identified ATF4 (activating transcription factor 4) as a key regulator of the mitochondrial stress response in cardiomyocytes from Mrps5+/- mice; furthermore, ATF4 regulates Knl1 (kinetochore scaffold 1) leading to an increase in cytokinesis during cardiomyocyte proliferation. The increased cardiomyocyte proliferation observed in Mrps5+/- mice was attenuated when one allele of Atf4 was deleted genetically (Mrps5+/-/Atf4+/-), resulting in the loss in the capacity for cardiac regeneration. Either MRPS5 inhibition (or as we also demonstrate, doxycycline treatment) activate a conserved regulatory mechanism that increases the proliferation of human induced pluripotent stem cell–derived cardiomyocytes. CONCLUSIONS: These data highlight a critical role for MRPS5/ATF4 in cardiomyocytes and an exciting new avenue of study for therapies to treat myocardial injury. [ABSTRACT FROM AUTHOR]

Background:The therapeutic efficiency of bone marrow mononuclear cells (BMMNCs) autologous transplantation for myocardial infarction (MI) remains low. Here we developed a novel strategy to improve cardiac repair by preconditioning BMMNCs via angiotensin II type 2 receptor (AT2R) stimulation. Methods and Results:Acute MI in rats led to a significant increase of AT2R expression in BMMNCs. Preconditioning of BMMNCs via AT2R stimulation directly with an AT2R agonist CGP42112A or indirectly with angiotensin II plus AT1R antagonist valsartan led to ERK activation and increased eNOS expression as well as subsequent nitric oxide generation, ultimately improved cardiomyocyte protection invitro as measured by co-culture approach. Intramyocardial transplantation of BMMNCs preconditioned via AT2R stimulation improved survival of transplanted cells in ischemic region of heart tissue and reduced cardiomyocyte apoptosis and inflammation at 3 days after MI. At 4 weeks after transplantation, compared to DMEM and non-preconditioned BMMNCs group, AT2R stimulated BMMNCs group showed enhanced vessel density in peri-infarct region and attenuated infarct size, leading to global heart function improvement. Conclusions:Preconditioning of BMMNCs via AT2R stimulation exerts protective effect against MI. Stimulation of AT2R in BMMNCs may provide a new strategy to improving therapeutic efficiency of stem cells for post MI cardiac repair. [ABSTRACT FROM AUTHOR]

We explored changes in pregnancy-specific glycoprotein 9 (PSG9) levels in the serum of patients with preeclampsia and the effects and underlying mechanisms of PSG9 effects on calcium (Ca2+) homeostasis and nitric oxide (NO) release in human umbilical vein endothelial cells (HUVECs). Western blotting was used to detect protein expression levels, and an NO fluorescence probe was used to examine NO production. Intracellular Ca2+ concentrations were measured using a Ca2+-sensitive fluorescent dye under a fluorescence microscope. Compared with those in healthy pregnant women, serum PSG9 levels were significantly decreased in patients with preeclampsia. PSG9 (0.1 μg/mL) treatment of HUVECs significantly enhanced the expression levels of store-operated calcium entry (SOCE) channel proteins Orai1 and Orai2, but not Orai3, and of endothelial nitric oxide synthase (eNOS) and NO production. Pretreatment with an inhibitor of SOCE (BTP2) abolished PSG9-enhanced Orai1, Orai2, and eNOS expression levels and NO production in HUVECs. The mechanisms underlying SOCE that were PSG9 enhanced in HUVECs appear to involve the Ca2+/eNOS/NO signaling pathway. These findings suggest that serum PSG9 levels may be a potential biomarker for monitoring the occurrence or development of preeclampsia in pregnancy and that PSG9 may be a potential therapeutic target for the treatment of preeclampsia. [ABSTRACT FROM AUTHOR]

Objectives: We attempted to improve the accuracy of coronary CT angiography (CCTA)-derived fractional flow reserve (FFR) (FFRCT) by expanding the coronary tree in the computational fluid dynamics (CFD) domain. An observational study was performed to evaluate the effects of extending the coronary tree analysis for FFRCT from a minimal diameter of 1.2 to 0.8 mm. Methods: Patients who underwent CCTA and interventional FFR were enrolled retrospectively. Seventy-six patients qualified based on the inclusion criteria. The three-dimensional (3D) coronary artery tree was reconstructed to generate a finite element mesh for each subject with different lower limits of luminal diameter (1.2 mm and 0.8 mm). Outlet boundary conditions were defined according to Murray's law. The Newton–Krylov–Schwarz (NKS) method was applied to solve the governing equations of CFD to derive FFRCT. Results: At the individual patient level, extending the minimal diameter of the coronary tree from 1.2 to 0.8 mm improved the sensitivity of FFRCT by 16.7% (p = 0.022). This led to the conversion of four false-negative cases into true-positive cases. The AUC value of the ROC curve increased from 0.74 to 0.83. Moreover, the NKS method can solve the computational problem of extending the coronary tree to an 0.8-mm luminal diameter in 10.5 min with 2160 processor cores. Conclusions: Extending the reconstructed coronary tree to a smaller luminal diameter can considerably improve the sensitivity of FFRCT. The NKS method can achieve favorable computational times for future clinical applications. Key Points: • Extending the reconstructed coronary tree to a smaller luminal diameter can considerably improve the sensitivity of FFRCT. • The NKS method applied in our study can effectively reduce the computational time of this process for future clinical applications. [ABSTRACT FROM AUTHOR]

The stable adhesion of hydrogel-based bioadhesives with tissue-matchable mechanical properties in biological environments remains a significant challenge. In this work, we propose a polyethyleneimine-polyacrylic acid (PEI-PAA, PEA) double-network polyelectrolyte hydrogel with swelling resistant capacity and tunable mechanical properties via one-step UV-initiated polymerization. Driven by electrostatic interactions and polymer-chain entanglement, this PEA hydrogel displays a distinctive microphase separation behavior, which facilitates a wide tunability in mechanical properties. Specifically, the modulus varies from 0.4 MPa to 106 MPa, and the toughness ranges from 1479 kJ/m3 to 7641 kJ/m3, respectively. Besides, the microphase separation endows PEA hydrogel with notable anti-swelling properties in saline, TBS buffer, and blood, leading to consistent adhesion to diverse moist tissues. We further demonstrate that our PEA hydrogels provide matchable mechanical properties and long-lasting adhesion to rat skin and arteries, which promote skin injury healing and effectively halt artery rupture bleeding in vivo. This work presents a straightforward method to generate non-swelling hydrogels and offers novel insight into the development of bioadhesives to meet diverse mechanical requirements. • A facile method is developed to prepare polyelectrolyte hydrogels with ultrahigh mechanical tunability. • Microphase separation structure endows hydrogels with excellent mechanical and anti-swelling performances. •The tissue-matchable hydrogels exhibit instant and stable adhesion for versatile wound healing. [ABSTRACT FROM AUTHOR]

Keywords: cardiomyocyte proliferation; myocardial infarction; PTEN; regeneration EN cardiomyocyte proliferation myocardial infarction PTEN regeneration 2196 2199 4 12/01/20 20201201 NES 201201 The loss of cardiomyocytes after myocardial infarction (MI) in adult mammals leads to heart failure. E, Left, Immunofluorescence staining of EdU incorporation in the MI border region in transverse sections from post-MI 15-week mouse hearts from control and Pten cKO mice. Finally, using the I R26R-Confetti Cre-reporter i lineage tracing system (Figure [R]), we demonstrated that PTEN inhibition by VO-OHpic stimulated cardiomyocyte proliferation in MI-injured adult mouse hearts (Figure [S] and [T]). [Extracted from the article]

Background: Age and other cardiovascular risk factors have been reported to impair the activities of mesenchymal stem cells (MSCs), which will affect the efficacy of stem cell transplantation. The objective of the study is to investigate whether exosomes derived from human umbilical cord MSCs (UMSCs) could enhance the activities of bone marrow MSCs from old person (OMSCs), and improve their capacity for cardiac repair. Methods: Exosomes extracted from conditioned medium of UMSCs were used to treat OMSCs to generate OMSCsExo. The key molecule in the exosomes that have potential to rejuvenate aged MSCs were screened, and the role of OMSC was tested in the mouse model of mycardial infarction (MI). Results: We found the activity of senescence-associated β-galactosidase and the expression of aging-related factors such as p53, p21, and p16 were significantly higher in OMSCs than those in UMSCs. After treatment with UMSC exosomes, these senescence phenotypes of OMSCs were remarkably reduced. The proliferation, migration, differentiation, and anti-apoptotic and paracrine effect were increased in OMSCsExo. In vivo study, mice with cardiac infarction had significantly better cardiac function, less fibrosis, and more angiogenesis after they were injected with OMSCsExo as compared with those with OMSC. There was more miR-136 expression in UMSCs and OMSCsExo than in OMSCs. Upregulation of miR-136 by transfection of miR-136 mimic into OMSCs significantly attenuated the apoptosis and senescence of OMSCs. Apoptotic peptidase activating factor (Apaf1) was found to be the downstream gene that is negatively regulated by miR-136 via directly targeting at its 3′UTR. Conclusion: Our data suggest that exosomes from young MSCs can improve activities of aged MSCs and enhance their function for myocardial repair by transferring exosomal miR-136 and downregulating Apaf1. [ABSTRACT FROM AUTHOR]

Mitochondrial homeostasis is critical for keeping functional heart in response to metabolic or environmental stresses. Mitochondrial fission and fusion (mitochondrial dynamics) play essential roles in maintaining mitochondrial homeostasis, defects in mitochondrial dynamics lead to cardiac diseases such as ischemia-reperfusion injury (IRI), heart failure and diabetic cardiomyopathy. Mitochondrial dynamics is determined by mitochondrial fission and fusion proteins, including OPA1, mitofusins and Drp1. These proteins are tightly regulated by a series of signaling pathways through different aspects such as transcription, post translation modifications (PTMs) and proteasome-dependent protein degradation. By modulating these mitochondrial fission and fusion proteins, mitochondria fine-tune their metabolic status to meet the energy demands of the heart. Moreover, these mitochondrial fission and fusion proteins are essential for mediating mitochondrial autophagy (mitophagy), leading to clearance of damaged mitochondria to maintain a healthy population of mitochondria in heart under stressed conditions. Mitochondrial dynamics dependent improvement in mitochondrial metabolism and quality could partially reverse the pathological conditions of heart. This review describes an overview of mechanisms on mitochondrial dynamics regulation and provides potential therapeutic targets for treating cardiovascular diseases. [ABSTRACT FROM AUTHOR]

Cardiac ankyrin repeat protein (CARP) is a nuclear transcriptional co-factor that has additional functions in the myoplasm as a component of the muscle sarcomere. Previous studies have demonstrated increased expression of CARP in cardiovascular diseases, however, its role in cardiomyocyte apoptosis is unclear and controversial. In the present study, we investigated possible roles of CARP in hypoxia/reoxygenation (H/R) -induced cardiomyocyte apoptosis and the underlying mechanisms. Neonatal mouse ventricular cardiomyocytes were isolated and infected with adenovirus encoding Flag-tagged CARP (Ad-CARP) and lentivirus encoding CARP targeted shRNA (sh-CARP), respectively. Cardiomyocyte apoptosis induced by exposure to H/R conditions was evaluated by TUNEL staining and western blot analysis of cleaved caspase-3. The results showed that H/R-induced apoptosis was significantly decreased in Ad-CARP cardiomyocytes and increased in sh-CARP cardiomyocytes, suggesting a protective anti-apoptosis role for CARP. Interestingly, over-expressed CARP was mainly distributed in the nucleus, consistent with its role in regulating transcriptional activity. qPCR analysis showed that Bcl-2 transcripts were significantly increased in Ad-CARP cardiomyocytes. ChIP and co-IP assays confirmed the binding of CARP to the Bcl-2 promoter through interaction with transcription factor GATA4. Collectively, our results suggest that CARP can protect against H/R induced cardiomyocyte apoptosis, possibly through increasing anti-apoptosis Bcl-2 gene expression. [ABSTRACT FROM AUTHOR]

Background Previous studies have demonstrated that biological aging has a negative influence on the therapeutic effects of mesenchymal stem cells (MSCs)-based therapy. Using a rat myocardial infarction (MI) model, we tested the hypothesis that silent mating type information regulation 2 homolog 1 (SIRT1) may ameliorate the phenotype and improve the function of aged MSCs and thus enhance the efficacy of aged MSCs-based therapy. Methods Sixty female rats underwent left anterior descending coronary artery ligation and were randomly assigned to receiving: intramyocardial injection of cell culture medium (DMEM group); SIRT1 overexpression vector-treated aged MSCs (SIRT1-aged MSCs group) obtained from aged male SD rats or empty vector-treated aged MSCs (vector-aged MSCs group). Another 20 sham-operated rats that underwent open-chest surgery without coronary ligation or any other intervention served as controls. Results SIRT1-aged MSC group exhibited enhanced blood vessel density in the border zone of MI hearts, which was associated with reduced cardiac remodeling, leading to improved cardiac performance. Consistent with the in vivo data, our in vitro experiments also demonstrated that SIRT1 overexpression ameliorated aged MSCs senescent phenotype and recapitulated the pro-angiogenesis property of MSCs and conferred the anti-stress response capabilities, as indicated by increases in pro-angiogenic factors, angiopoietin 1 (Ang1) and basic fibroblast growth factor (bFGF), expressions and a decrease in anti-angiogenic factor thrombospondin-1 (TBS1) at mRNA levels, and increases in Bcl-2/Bax ratio at protein level. Conclusions Up-regulating SIRT1 expression could enhance the efficacy of aged MSCs-based therapy for MI as it relates to the amelioration of senescent phenotype and hence improved biological function of aged MSCs. [ABSTRACT FROM AUTHOR]

Highlights: [•] SIRT1 and AMPK might mediate calorie restriction effect on MSCs differentiation. [•] SIRT1 favors MSCs differentiation toward osteoblast instead of adipocyte lineage. [•] AMPK favors MSCs differentiation toward osteoblast instead of adipocyte lineage. [•] Mechanisms of SIRT1 and AMPK action on MSCs differentiation were reviewed. [•] Synergistic interaction of SIRT1 and AMPK in MSCs differentiation was discussed. [ABSTRACT FROM AUTHOR]

[Display omitted] • A ROS-scavenging and O 2 -generating hydrogel (RCGel) is used for cell delivery. • Mesenchymal stem cells (MSCs) encapsulated in RCGel (MSC/RCGel) can resist ROS. • MSC/RCGel rescues cardiomyocytes both in oxidative stress and hypoxia conditions. • RCGel encapsulating boosts the engraftment of MSCs in infarcted rat hearts. • MSC/RCGel injected to infarcted rat hearts greatly improves the cardiac function. Stem cell especially mesenchymal stem cell (MSC) transplantation is a promising therapeutic strategy for myocardial infarction (MI) repair. However, major obstacles remain due to the poor retention and survival rate of transplanted MSCs in the harmful MI microenvironment (e.g., oxidative stress and hypoxia). Here, a novel injectable hydrogel (RCGel) with dual functions of reactive oxygen species (ROS)-scavenging and O 2 -generating was employed to encapsulate MSCs for MI treatment. The RCGel encapsulating exhibited anti-ROS protection through inhibiting JNK/p38 apoptosis signaling pathway to improve the viability of MSCs under oxidative stress conditions in vitro. The survival of cardiomyocytes was also improved both in the oxidative stress and hypoxia environments when being co-cultured with MSCs-encapsulated RCGel (MSC/RCGel). The RCGel encapsulating boosted the engraftment of transplanted MSCs in vivo. More viable MSCs endowed with regenerative abilities in the infarcted rat heart along with the ameliorated MI microenvironment (decreased oxidative stress and hypoxia) by the RCGel substantially inhibited cardiac apoptosis, enhanced cardiomyocyte viability, promoted angiogenesis and reduced fibrosis to improve the cardiac functions. The encapsulation of MSCs in RCGel, which exhibits beneficial effects in resisting harsh environments, provides a new way in MI repair and stem cell delivery, and has great potential in cell-based regenerative medicine. [ABSTRACT FROM AUTHOR]

Microtubules play a vital role in cell mitosis. Drugs targeting taxol or vinca binding site of tubulin have been proved an effective way to against cancer. However, drug resistance and cancer recurrence are inevitable, there is an urgent need to search for new microtubule-targeting agents (MTAs). In our study, a series of novel 2-aryl-3-sulfonamido-pyridines (HoAns) had been designed, synthesized, and evaluated for their antiproliferative activities in vitro and in vivo. Among them, compound HoAn32 exhibited the most potent activity with IC 50 values ranging from 0.170 to 1.193 μ M in a panel of cancer cell lines. Mechanism studies indicated that compound HoAn32 bound to the colchicine site of β-tubulin, resulting in colony formation inhibition, G2/M phase cell cycle arrest, cell apoptosis as well as increased the generation of ROS in both RKO and SW620 cells. In addition, compound HoAn32 showed potent anti-vascular activity in vitro. Furthermore, compound HoAn32 also exhibited outstanding antitumor activity in SW620 xenograft tumor models without observable toxic effects, which was more potent than that of ABT-751. In conclusion, our findings suggest that compound HoAn32 may be a promising microtubule destabilizing agent and deserves for further development in cancer therapy. Image 1 • 40 novel 2-aryl-3-sulfonamido-pyridines were designed and synthesized. • The most active compound HoAn32 showed excellent antiproliferative activity in vitro. • Compound HoAn32 was identified as a novel tubulin polymerization inhibitor and binding in the colchicine site of β-tubulin. • Compound HoAn32 exhibited excellent antitumor activity in SW620 xenograft models, which was more potent than that of ABT-751. [ABSTRACT FROM AUTHOR]

Background: The association between coronary microcirculation and clinical outcomes in patients with intermediate stenosis remains unclear., Objectives: The aim of this study was to assess the prognostic significance of angiography-derived index of microcirculatory resistance (angio-IMR) in patients with intermediate coronary stenosis., Methods: This post hoc analysis included 1,658 patients from the FLAVOUR (Fractional Flow Reserve and Intravascular Ultrasound for Clinical Outcomes in Patients with Intermediate Stenosis) trial, with angio-IMR measured in each vessel exhibiting intermediate stenosis. The primary endpoint was a patient-oriented composite outcome (POCO), a composite of all-cause death, myocardial infarction, or revascularization over a 2-year period., Results: The median follow-up period was 24.8 months (Q1-Q3: 24.4-26.4 months). Over the 2-year follow-up period, patients with angio-IMR >25 exhibited a significantly higher POCO rate in both the percutaneous coronary intervention (PCI) group (35.06% [27 of 77] vs 7.2% [51 of 708]; P < 0.001) and the non-PCI group (17.95% [21 of 117] vs 4.23% [32 of 756]; P < 0.001). After adjusting for potentially related risk factors, angio-IMR >25 remained an independent predictor of the POCO in the PCI group (HR: 6.235; 95% CI: 3.811-10.203; P < 0.001) and the non-PCI group (HR: 5.282; 95% CI: 2.948-9.462; P < 0.001). The addition of angio-IMR demonstrated incremental prognostic value in both an angiographic risk factor model (C-index 0.710 [95% CI: 0.663-0.756] vs 0.615 [95% CI: 0.563-0.664] [P < 0.001]; net reclassification index 0.268 [95% CI: 0.191-0.362; P < 0.001]; integrated discrimination improvement 0.055 [95% CI: 0.030-0.108; P < 0.001]) and a clinical risk factor model (C-index 0.705 [95% CI: 0.658-0.751] vs 0.594 [95% CI: 0.544-0.644] [P < 0.001]; net reclassification index 0.268 [95% CI: 0.171-0.350; P < 0.001]; integrated discrimination improvement 0.057 [95% CI: 0.027-0.102; P < 0.001])., Conclusions: In individuals with intermediate coronary stenosis, elevated angio-IMR is linked to an adverse prognosis. Using angio-IMR significantly enhanced the capability to reclassify patients and accurately estimate the risk for the POCO., Competing Interests: Funding Support and Author Disclosures The FLAVOUR trial was funded by Boston Scientific. This post hoc analysis was funded by the National Natural Science Foundation of China (grant 82170332), Zhejiang Provincial Key Research and Development Plan (grant 2024C03095), and Hangzhou Leading Innovation and Entrepreneurship Team Project (grant TD2022007). Dr Hahn has received research grants from Abbott Korea, Biosensors International Group, Biotronik, Boston Scientific, and Medtronic. Dr Koo has received institutional research grants from Abbott Vascular, Boston Scientific, and Philips. Dr Xiang is principal scientist for ArteryFlow Technology. All other authors have reported that they have no relationships relevant to the contents of this paper to disclose., (Copyright © 2025 The Authors. Published by Elsevier Inc. All rights reserved.)

Background: Recent randomized clinical trials have demonstrated the benefits of intravascular imaging (IVI)-guided percutaneous coronary intervention (PCI) over angiography-guided PCI. However, the role of angiography-based physiological assessment during IVI-guided PCI remains unclear., Objectives: This study aimed to explore the discrepancies and significance of angiography-based physiological assessments in IVI-guided PCI., Methods: In the international multicenter randomized FLAVOUR (Fractional Flow Reserve and Intravascular Ultrasound for Clinical Outcomes in Patients With Intermediate Stenosis) trial, angiography-based physiological assessment was retrospectively performed using the Murray law-based quantitative flow ratio (μQFR). In this post hoc analysis, patients were categorized based on intravascular ultrasound (IVUS)-guided treatment decisions (PCI or deferral) and μQFR as follows: negative μQFR with deferral of PCI (DEFER), negative μQFR with PCI (PERFORM), and positive μQFR with PCI (REFERENCE). The primary outcome was major adverse cardiovascular events, defined as a composite of death, myocardial infarction, and target vessel revascularization at the 24-month follow-up., Results: Of the 784 patients, 34.4% (270/784), 29.3% (230/784), and 31.5% (247/784) were categorized into the DEFER, PERFORM, and REFERENCE groups, respectively. Physiological assessment led to substantial reclassification, encompassing 48.2% (230/477) of patients who underwent IVUS-guided PCI. The REFERENCE group showed a higher risk for major adverse cardiovascular events at 2 years compared with the PERFORM group (adjusted HR: 2.46; 95% CI: 1.13-5.35; P = 0.023). However, the primary outcomes in the DEFER and PERFORM groups were similar (adjusted HR: 0.88; 95% CI: 0.37-2.11; P = 0.779). The quality of life at 2 years was comparable among the 3 groups (P = 0.198)., Conclusions: Angiography-based physiological assessments can offer additional prognostic insights for patients undergoing IVI-guided PCI. IVUS-guided PCI may not be advantageous in patients with functionally insignificant lesions., Competing Interests: Funding Support and Author Disclosures The FLAVOUR trial was funded by Boston Scientific. It was also supported by grants from the Patient-Centered Clinical Research Coordinating Center (HI19C0481 and HC19C0305) funded by the Ministry of Health and Welfare and from the Ministry of Food and Drug Safety (RS-2023-00215667). The study funders had no role in trial design, data collection, analysis, and interpretation, or writing of the manuscript. Dr Joo-Yong Hahn has received research grants from Abbott Korea, Biosensors International Group, Biotronik, Boston Scientific Corporation, and Medtronic. Dr Bon-Kwon Koo has received institutional research grants from Abbott Vascular, Boston Scientific Corporation, and Philips. All other authors have reported that they have no relationships relevant to the contents of this paper to disclose., (Copyright © 2025 American College of Cardiology Foundation. Published by Elsevier Inc. All rights reserved.)

Golgi Protein 73 (GP73) is a Golgi-resident protein that is highly expressed in primary tumor tissues. Initially identified as an oncoprotein, GP73 has been shown to promote tumor development, particularly by mediating the transport of proteins related to epithelial-mesenchymal transition (EMT), thus facilitating tumor cell EMT. Though our previous review has summarized the functional roles of GP73 in intracellular signal transduction and its various mechanisms in promoting EMT, recent studies have revealed that GP73 plays a crucial role in regulating the tumor and immune microenvironment. GP73 can modulate intracellular signaling pathways to influence cytokine and chemokine networks, resulting in inflammation caused by viral and bacterial infection or immune diseases, and leading tumor microenvironment deteriorated. Additionally, extracellular GP73 can also regulate signaling pathways of target cells by binding to their cell-surface receptors or entering the acceptor cells, thereby facilitating inflammation or promoting tumor development. In this review, we aim to summarize the findings, providing insights for future investigations on GP73 and its potential as a therapeutic target in ameliorating chronic inflammation in the immune and tumor microenvironment., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2025 Feng, Hu, Zhou, Liu, Zeng and Liu.)

Peripheral artery disease (PAD), primarily caused by atherosclerosis, leads to the narrowing or blockage of arteries that supply blood to the limbs. This study explores the pro-angiogenic effects of L-theanine and its underlying mechanisms in a mouse model of hindlimb ischemia (HLI). To evaluate L-theanine's pro-angiogenic effects, human umbilical vein endothelial cells (HUVECs) were subjected to tube formation, migration, sprouting, and proliferation assays. In vivo, C57BL/6 mice with induced HLI were treated with L-theanine. Blood flow recovery was measured via Doppler ultrasound, and vascular density was analyzed using immunofluorescence staining. RNA sequencing identified neuropilin-1 (NRP1) as a key regulator, and the expression levels of NRP1 and VEGFR2 were examined through qPCR and Western blotting. L-theanine significantly enhanced angiogenesis in HUVECs, as demonstrated by improved tube formation, migration, sprouting, and proliferation. In mice, L-theanine treatment resulted in increased vessel density and improved blood flow recovery. Furthermore, L-theanine was found to activate the NRP1/VEGFR2 signaling pathway in both HUVECs and the HLI mouse model. These findings indicate that L-theanine can promote angiogenesis and activate key pathways involved in vascular repair, suggesting its potential as a therapeutic agent for treating vascular defects associated with PAD.

Background: Coronary physiology measured by fractional flow reserve (FFR) is superior to angiography for assessing the efficacy of percutaneous coronary intervention (PCI). Yet, the clinical adoption of post-PCI FFR is limited. Murray law-based quantitative flow ratio (μQFR) may represent a promising alternative, as it can quickly compute FFR from a single angiographic view., Objectives: The authors aimed to investigate the potential role of post-PCI μQFR in predicting clinical outcomes., Methods: This was a post hoc blinded analysis of the FLAVOUR trial. Patients with angiographically intermediate lesions randomized 1:1 to receive FFR or intravascular ultrasound-guided PCI were included. Post-PCI μQFR was assessed in successfully stented vessels, blinded to clinical outcomes. Suboptimal physiological outcome post-PCI was defined a priori as post-PCI μQFR <0.90. The primary endpoint was 2-year target vessel failure, including cardiac death, target vessel myocardial infarction, and target vessel revascularization. Secondary endpoints included the diagnostic concordance of pre-PCI μQFR with FFR in the FFR-guidance arm., Results: Post-PCI μQFR was successfully analyzed in 806 vessels from 777 participants (feasibility 97.0% [806 of 831]). Suboptimal physiological outcome post-PCI was identified in 24.7% (199 of 806) of vessels and post-PCI μQFR <0.90 was associated with higher risk of 2-year target vessel failure (6.1% [12 of 199] vs 2.7% [16 of 607]; HR: 2.45 [95% CI: 1.14-5.26]; P = 0.022). Pre-PCI μQFR was obtained in 877 of 919 vessels (feasibility 95.4%), showing 90% accuracy, 82% sensitivity, and 94% specificity for identifying physiologically significant stenosis defined by pre-PCI FFR ≤0.80., Conclusions: In patients with intermediate lesions who underwent PCI with contemporary imaging or physiology guidance, lower post-PCI μQFR values predict subsequent adverse events. (Fractional FLow Reserve And IVUS for Clinical OUtcomes in Patients With InteRmediate Stenosis [FLAVOUR]; NCT02673424)., Competing Interests: This work was supported by the Natural Science Foundation of China (grant number 82020108015 and 81871460) and by Shanghai Jiao Tong University (grant number YG2021ZD04) to Dr Tu, by a Science Foundation Ireland Research Professorship Award (15/RP/2765 to Dr. Wijns, which supported Dr. Ding), and by China Postdoctoral Science Foundation (grant number 2024M752017) to Dr Ding. Dr Shi is an employee of Pulse Medical. Dr Hahn has received research grants from Abbott Korea, Biosensors International Group, Biotronik, Boston Scientific Corporation, and Medtronic. Dr Wijns has received institutional research grants and past honoraria from MicroPort; is senior advisor of Rede Optimus Research; and is cofounder of Argonauts, an innovation facilitator. Dr Tu is the cofounder of Pulse Medical; and has received research grants and consultancy from Pulse Medical. All other authors have reported that they have no relationships relevant to the contents of this paper to disclose., (© 2025 The Authors.)

Background and Aims: NAFLD comprises a spectrum of liver disorders with the initial abnormal accumulation of lipids in hepatocytes called NAFL, progressing to the more serious NASH in a subset of individuals. Our previous study revealed that global flavin-containing monooxygenase 2 (FMO2) knockout causes higher liver weight in rats. However, the role of FMO2 in NAFLD remains unclear. Herein, we aimed to determine the function and mechanism of FMO2 in liver steatosis and steatohepatitis., Approach and Results: The expression of FMO2 was significantly downregulated in patients with NAFL/NASH and mouse models. Both global and hepatocyte-specific knockout of FMO2 resulted in increased lipogenesis and severe hepatic steatosis, inflammation, and fibrosis, whereas FMO2 overexpression in mice improved NAFL/NASH. RNA sequencing showed that hepatic FMO2 deficiency is associated with impaired lipogenesis in response to metabolic challenges. Mechanistically, FMO2 directly interacts with SREBP1 at amino acids 217-296 competitively with SREBP cleavage-activating protein (SCAP) and inhibits SREBP1 translocation from the endoplasmic reticulum (ER) to the Golgi apparatus and its subsequent activation, thus suppressing de novo lipogenesis (DNL) and improving NAFL/NASH., Conclusions: In hepatocytes, FMO2 is a novel molecule that protects against the progression of NAFL/NASH independent of enzyme activity. FMO2 impairs lipogenesis in high-fat diet-induced or choline-deficient, methionine-deficient, amino acid-defined high-fat diet-induced steatosis, inflammation, and fibrosis by directly binding to SREBP1 and preventing its organelle translocation and subsequent activation. FMO2 thus is a promising molecule for targeting the activation of SREBP1 and for the treatment of NAFL/NASH., (Copyright © 2023 American Association for the Study of Liver Diseases.)

Background and Objectives: The Fractional Flow Reserve and Intravascular Ultrasound-Guided Intervention Strategy for Clinical Outcomes in Patients with Intermediate Stenosis (FLAVOUR) trial demonstrated non-inferiority of fractional flow reserve (FFR)-guided percutaneous coronary intervention (PCI) compared with intravascular ultrasound (IVUS)-guided PCI. We sought to investigate the cost-effectiveness of FFR-guided PCI compared to IVUS-guided PCI in Korea., Methods: A 2-part cost-effectiveness model, composed of a short-term decision tree model and a long-term Markov model, was developed for patients who underwent PCI to treat intermediate stenosis (40% to 70% stenosis by visual estimation on coronary angiography). The lifetime healthcare costs and quality-adjusted life-years (QALYs) were estimated from the healthcare system perspective. Transition probabilities were mainly referred from the FLAVOUR trial, and healthcare costs were mainly obtained through analysis of Korean National Health Insurance claims data. Health utilities were mainly obtained from the Seattle Angina Questionnaire responses of FLAVOUR trial participants mapped to EQ-5D., Results: From the Korean healthcare system perspective, the base-case analysis showed that FFR-guided PCI was 2,451 U.S. dollar lower in lifetime healthcare costs and 0.178 higher in QALYs compared to IVUS-guided PCI. FFR-guided PCI remained more likely to be cost-effective over a wide range of willingness-to-pay thresholds in the probabilistic sensitivity analysis., Conclusions: Based on the results from the FLAVOUR trial, FFR-guided PCI is projected to decrease lifetime healthcare costs and increase QALYs compared with IVUS-guided PCI in intermediate coronary lesion, and it is a dominant strategy in Korea., Trial Registration: ClinicalTrials.gov Identifier: NCT02673424., Competing Interests: Bon-Kwon Koo has received institutional research grants from Abbott Vascular and Philips. All other authors declare no competing interests., (Copyright © 2025. The Korean Society of Cardiology.)