USP31 Activates the Wnt/ß-catenin Signaling Pathway and Promotes Gastric Cancer Cell Proliferation, Invasion and Migration.

BACKGROUND: Gastric cancer (GC) has a poor prognosis because it is highly aggressive, yet there are currently few effective therapies available. Although protein ubiquitination has been shown to play a complex role in the development of gastric cancer, to date, no efficient ubiquitinating enzymes have been identified as treatment targets for GC. METHODS: The TCGA database was used for bioinformatic investigation of ubiquitin-specific protease 31 (USP31) expression in GC, and experimental techniques, including Western blotting, qRT-PCR, and immunohistochemistry, were used to confirm the findings. We also analyzed the relationship between USP31 expression and clinical prognosis in patients with GC. We further investigated the effects of USP31 on the proliferation, invasion, migration, and glycolysis of GC cells in vitro and in vivo by using colony formation, CCK-8 assays, Transwell chamber assays, cell scratch assays, and cell-derived xenograft. Furthermore, we examined the molecular processes by which USP31 influences the biological development of GC. RESULTS: Patients with high USP31 expression have a poor prognosis because USP31 is abundantly expressed in GC. Therefore, USP31 reduces the level of ubiquitination of the Wnt/ß-catenin pathway by binding to ß-catenin, thereby activating glycolysis, which ultimately promotes GC proliferation and aggressive metastasis. CONCLUSION: USP31 inhibits ubiquitination of ß-catenin by binding to it, stimulates the Wnt/ß-- catenin pathway, activates glycolysis, and accelerates the biology of GCs, which are all demonstrated in this work.

Exosomal let-7a-5p derived from human umbilical cord mesenchymal stem cells alleviates coxsackievirus B3-induced cardiomyocyte ferroptosis via the SMAD2/ZFP36 signal axis. / 人脐带间å 质干细胞来源的外泌体let-7a-5p通过SMAD2/ZFP36ä¿¡å·è½´å‡è½»æŸ¯è¨å¥‡ç— æ¯’B3诱导的心肌细胞铁死亡.

Viral myocarditis (VMC) is one of the most common acquired heart diseases in children and teenagers. However, its pathogenesis is still unclear, and effective treatments are lacking. This study aimed to investigate the regulatory pathway by which exosomes alleviate ferroptosis in cardiomyocytes (CMCs) induced by coxsackievirus B3 (CVB3). CVB3 was utilized for inducing the VMC mouse model and cellular model. Cardiac echocardiography, left ventricular ejection fraction (LVEF), and left ventricular fractional shortening (LVFS) were implemented to assess the cardiac function. In CVB3-induced VMC mice, cardiac insufficiency was observed, as well as the altered levels of ferroptosis-related indicators (glutathione peroxidase 4 (GPX4), glutathione (GSH), and malondialdehyde (MDA)). However, exosomes derived from human umbilical cord mesenchymal stem cells (hucMSCs-exo) could restore the changes caused by CVB3 stimulation. Let-7a-5p was enriched in hucMSCs-exo, and the inhibitory effect of hucMSCs-exolet-7a-5p mimic on CVB3-induced ferroptosis was higher than that of hucMSCs-exomimic NC (NC: negative control). Mothers against decapentaplegic homolog 2 (SMAD2) increased in the VMC group, while the expression of zinc-finger protein 36 (ZFP36) decreased. Let-7a-5p was confirmed to interact with SMAD2 messenger RNA (mRNA), and the SMAD2 protein interacted directly with the ZFP36 protein. Silencing SMAD2 and overexpressing ZFP36 inhibited the expression of ferroptosis-related indicators. Meanwhile, the levels of GPX4, solute carrier family 7, member 11 (SLC7A11), and GSH were lower in the SMAD2 overexpression plasmid (oe-SMAD2)+let-7a-5p mimic group than in the oe-NC+let-7a-5p mimic group, while those of MDA, reactive oxygen species (ROS), and Fe2+ increased. In conclusion, these data showed that ferroptosis could be regulated by mediating SMAD2 expression. Exo-let-7a-5p derived from hucMSCs could mediate SMAD2 to promote the expression of ZFP36, which further inhibited the ferroptosis of CMCs to alleviate CVB3-induced VMC.

The Future of Graphene: Preparation from Biomass Waste and Sports Applications.

At present, the main raw material for producing graphene is graphite ore. However, researchers actively seek alternative resources due to their high cost and environmental problems. Biomass waste has attracted much attention due to its carbon-rich structure and renewability, emerging as a potential raw material for graphene production to be used in sports equipment. However, further progress is required on the quality of graphene produced from waste biomass. This paper, therefore, summarizes the properties, structures, and production processes of graphene and its derivatives, as well as the inherent advantages of biomass waste-derived graphene. Finally, this paper reviews graphene's importance and application prospects in sports since this wonder material has made sports equipment available with high-strength and lightweight quality. Moreover, its outstanding thermal and electrical conductivity is exploited to prepare wearable sensors to collect more accurate sports data, thus helping to improve athletes' training levels and competitive performance. Although the large-scale production of biomass waste-derived graphene has yet to be realized, it is expected that its application will expand to various other fields due to the associated low cost and environmental friendliness of the preparation technique.

New nurses' turnover intention and clinical belonging, based on latent class analysis (LCA).

AIM: To identify potential categories of clinical belonging among new nurses and explore the relationship between different categories and turnover intention. DESIGN: A cross sectional study. METHOD: A cross sectional study was conducted among 348 new nurses from tertiary hospitals in Hainan and Guangdong provinces. A general data questionnaire, clinical belonging scale and turnover intention scale were used for examination. Further, the potential categories were used to analyse the categories of clinical belonging, and latent class analysis was utilized to analyse the relationship between different categories of clinical belonging and turnover intention. RESULTS: The clinical sense of belonging of new nurses were divided into three groups namely C1, C2 and C3. The C1: poor clinical sense of belonging (8.7%), C2: moderate clinical sense of belonging (57.9%) and C3: rich clinical sense of belonging (33.4%). The risk of the turnover intention of new nurses with 'poor clinical sense of belonging' was 0.62 times that of new nurses with 'rich clinical sense of belonging' (OR = 0.62, p < 0.01), which was 0.24 times that of 'moderate clinical sense of belonging' (OR = 0.24, p < 0.01), the risk of the turnover intention of new nurses with 'moderate clinical sense of belonging' was 0.13 times that of new nurses with 'rich clinical sense of belonging'(OR = 0. 13, p < 0.01). CONCLUSIONS: The results of our study revealed that in order to enhance the new nurses' sense of belonging, support was most crucial when they were first encountering difficulties. To reduce turnover intention, more structured learning opportunities are also required to maximize learning for newly graduated nurses with various nursing degrees. PATIENT OR PUBLIC CONTRIBUTION: There are no patient or public contributions in this study.

An approach to complex transboundary water management in Central Asia: Evolutionary cooperation in transboundary basins under the water-energy-food-ecosystem nexus.

Water-related issues in transboundary basins are generally complicated by the challenges of climate change, the historical evolution of the basin characteristics, and the different interests of the riparian countries. Therefore, dealing with water-sharing and water cooperation problems among basin countries needs to be based on multi-factor system analysis in the context of regional water, energy, food (land) resources, and ecosystems. In the present study, the Aral Sea basin in Central Asia, where transboundary water problems are extremely prominent and complex, was selected as the research area. Firstly, the characteristics of the water-energy-food-ecosystem nexus of the Aral Sea basin are analyzed. Then, based on the game theory, a multi-objective game model is constructed, and the multi-objective evolutionary game process and evolutionary stable strategies (ESSs) of both the upstream and downstream countries are explored. Finally, the evolutionary stable strategy under the intervention of the basin commission is simulated. The results show that there are obvious reciprocal feedbacks among water, land, energy, and ecosystem in the Aral Sea basin, and the uneven distribution of natural resources, fragile ecosystems, and conflicting demands of multiple actors lead to the unstable evolution of the nexus. Driven by the maximization of upstream and downstream countries' respective interests, the optimal stabilization strategy of the system cannot be realized. Whereas, the introduction of the basin commission intervention and its restraint mechanism is conducive to promoting cooperation and maximizing the overall benefits of the basin. The incentives and penalties of the basin commission have significant effects on whether the system can reach Pareto optimality, and higher incentive coefficient and penalty coefficient help the system converge to the ideal state more quickly. The evolution of the water-energy-food-ecosystem nexus based on the perspective of the whole basin can provide theoretical support for dealing with the transboundary water conflicts, and the cooperation strategy aiming at maximizing the overall benefits of the basin can provide decision-making basis for promoting transboundary water cooperation and synergistic development of the water-energy-food-ecosystem nexus.

Biodegradable Polylactic Acid and Its Composites: Characteristics, Processing, and Sustainable Applications in Sports.

Polylactic acid (PLA) is a biodegradable polyester polymer that is produced from renewable resources, such as corn or other carbohydrate sources. However, its poor toughness limits its commercialization. PLA composites can meet the growing performance needs of various fields, but limited research has focused on their sustainable applications in sports. This paper reviews the latest research on PLA and its composites by describing the characteristics, production, degradation process, and the latest modification methods of PLA. Then, it discusses the inherent advantages of PLA composites and expounds on different biodegradable materials and their relationship with the properties of PLA composites. Finally, the importance and application prospects of PLA composites in the field of sports are emphasized. Although PLA composites mixed with natural biomass materials have not been mass produced, they are expected to be sustainable materials used in various industries because of their simple process, nontoxicity, biodegradability, and low cost.

Coupling coordination and spatiotemporal dynamic evolution of the water-energy-food-land (WEFL) nexus in the Yangtze River Economic Belt, China.

The interrelationship between regional water, energy, food, and land systems is extremely complex. Hence, accurately assessing the coupling coordination relationship and identifying the influential factors of the water-energy-food-land nexus (WEFL nexus) are of utmost importance. This study proposes a novel analytical framework and evaluation index system for exploring interactions across the WEFL nexus. The comprehensive benefit evaluation index (CBEI), coupling coordination degree (CCD) model, and obstacle factor diagnosis model are integrated to assess and analyze the coupling coordination relationship and spatiotemporal dynamic evolution of the WEFL nexus in the Yangtze River Economic Belt (YREB) from 2006 to 2020. The results indicated that (1) the CBEI and CCD generally increased from 0.23 to 0.79 and 0.45 to 0.88, respectively, revealing the upward trend of the coordination development levels of the WEFL nexus in the YREB. (2) The lower reaches achieved a relatively higher coordination development degree than the upper and middle reaches of the YREB. (3) The findings of obstacle factors reveal that agricultural non-point source pollution control, waterlogging disaster prevention, industrial solid waste efficient treatment, and urban water-saving are the essential fields that need to be improved in YREB's future development. This study helps to understand the complex interrelation of the WEFL nexus at different spatial-temporal scales and provides a novel framework that can be used as an evaluation system and policy insights for a region's integrated resources, environmental management, and green sustainable development.

Inspired by Skeletal Muscles: Study of the Physical and Electrochemical Properties of Derived Lignocellulose-Based Carbon Fibers.

Skeletal muscles exhibit excellent properties due to their well-developed microstructures. Taking inspiration from nature that thick filaments and thin filaments are linked by "cross-bridges", leading to good stability and ion transport performance of muscles. In this work, extracted poplar lignin and microcrystalline cellulose (MCC) were connected by biomimetic covalent bonds, akin to biological muscle tissue, in which isophorone diisocyanate was used as the chemical crosslinking agent. Then, poplar lignin-MCC was mixed with polyacrylonitrile to serve as the precursor for electrospinning. The results show that due to the effective covalent-bond connection, the precursor fibers possess excellent morphology, smooth surface, good thermal stability, and high flexibility and toughness (average elongation-at-break is 51.84%). Therefore, after thermal stabilization and carbonization, derived lignocellulose-based carbon fibers (CFs) with a reduced cost, complete fiber morphology with a uniform diameter (0.48 ± 0.22 µm), and high graphitization degree were obtained. Finally, the electrodes fabrication and electrochemical testing were carried out. The results of electrochemical impedance spectroscopy (EIS) indicate that the Rs and Rct values of CFs supercapacitors are 1.18 Ω and 0.14 Ω, respectively. Results of cyclic voltammetry (CV) and galvanostatic charge-discharge (GCD) suggest that these CFs demonstrate great application potential in electrochemical materials.

Green and Low-Cost Natural Lignocellulosic Biomass-Based Carbon Fibers-Processing, Properties, and Applications in Sports Equipment: A Review.

At present, high-performance carbon fibers (CFs) are mainly produced from petroleum-based materials. However, the high costs and environmental problems of the production process prompted the development of new precursors from natural biopolymers. This review focuses on the latest research on the conversion of natural lignocellulosic biomass into precursor fibers and CFs. The influence of the properties, advantages, separation, and extraction of lignin and cellulose (the most abundant natural biopolymers), as well as the spinning process on the final CF performance are detailed. Recent strategies to further improve the quality of such CFs are discussed. The importance and application of CFs in sports equipment manufacturing are briefly summarized. While the large-scale production of CFs from natural lignocellulosic biomass and their applications in sports equipment have not yet been realized, CFs still provide a promising market prospect as green and low-cost materials. Further research is needed to ensure the market entry of lignocellulosic biomass-based CFs.

Investigating Acupoint Selection and Combinations of Acupuncture for Tic Disorders: An Association Rule Mining and Network Analysis Study.

Objective: Tic disorders (TDs) are common mental disorders in children and adolescents, and the clinical application of acupuncture for treating TDs is becoming increasingly widespread. However, the criteria for selecting acupoint prescriptions and combinations have not been summarized. Therefore, data mining was used herein to determine the treatment principles and the most effective acupoint selection and compatibility criteria for the treatment of TDs. Methods: Clinical studies and observations of the efficacy of acupuncture treatment for TDs were obtained from the PubMed, Cochrane Library, EMBASE, China National Knowledge Infrastructure (CNKI), Wanfang, VIP, and Chinese Biomedical (CBM) databases. The data on the acupoint prescriptions applied in these studies were collected, and network and association analyses were used to reveal the relationships between acupoints and to identify acupoint combinations. Additionally, the principles of acupuncture for TDs were determined through cluster analysis. Subgroup analysis of acupuncture prescriptions based on specific categorical diagnoses was performed to further assess the selection of acupoints. Results: Eighty-six trials were identified, and 257 groups of effective prescriptions involving 121 acupoints were extracted. Bai-hui (DU20), Feng-chi (GB20), Tai-chong (LR3), He-gu (LI4), and San-yin-jiao (SP6) were the most regularly used acupoints for treating TDs. The Governor Vessel, gallbladder, and large intestine meridians were more commonly used than other meridians. Moreover, most acupoint sites focused on the head and neck. Network analysis revealed potentially effective acupoint prescriptions for their commonly used acupoints, namely, Bai-hui (DU20), Si-shen-cong (EX-HN1), Feng-chi (GB20), Nei-guan (PC6), Shen-men (HT7), He-gu (LI4), Zu-san-li (ST36), San-yin-jiao (SP6) and Tai-chong (LR3). Association rule mining indicated that potential point combinations that should be prioritized in TD treatment are Bai-hui (DU20), Neiguan (PC6) and Sanyinjiao (SP6). Cluster analysis revealed the treatment principle of "coordinating yin and yang, tonifying qi and blood, dispelling pathogenic wind and eliminating phlegm". The core acupoint prescription of TS treatment comprised He-gu (LI4), Feng-chi (GB20), Tai-chong (LR3), Bai-hui (DU20), Yin-tang (EX-HN3), Si-shen-cong (EX-HN1), San-yin-jiao (SP6), and Nei-guan (PC6). The core group included He-gu (LI4) and Feng-chi (GB20). Proximal points were usually used in TS as an additional method of point selection. Conclusion: Using data mining analysis of published studies, this study provides valuable information regarding the selection of the most effective acupoints and point combinations for clinical acupuncture practice for treating TDs.

Recycling Carbon Fiber from Carbon Fiber-Reinforced Polymer and Its Reuse in Photocatalysis: A Review.

Driven by various environmental and economic factors, it is emerging to adopt an efficient and sustainable strategy to recycle carbon fibers (rCFs) from carbon fiber-reinforced polymer (CFRP) wastes and reuse them in high-value applications. This review summarized the latest progress of CFRP waste recycling methods (including mechanical, chemical, and thermal methods), discussed their advantages and disadvantages, influence parameters and possible environmental effects, and their potential effects on the mechanical and surface chemical properties of rCFs. In addition, the latest optimization schemes of leading recycling technologies were detailed. According to the literature, CFs are the key points in the structural support of semiconductor-based recyclable photocatalytic systems and the enhancement of performance, which means that rCFs have high reuse potential in sustainable photocatalysis. Therefore, this paper also emphasized the possibility and potential value of reusing recovered fibers for developing recyclable photocatalytic products, which may be a new way of reuse in environmental purification often ignored by researchers and decision-makers in the field of CFs.

Fusaricide is a Novel Iron Chelator that Induces Apoptosis through Activating Caspase-3.

Nonsmall cell lung cancer (NSCLC) has been a fatal and refractory disease worldwide. Novel therapeutic developments based on fundamental investigations of anticancer mechanisms underlie substantial foundations to win the fight against cancer diseases. In this study, we isolated a natural product fusaricide (FCD) from an endophytic fungus of Lycium barbarum, identified as Epicoccum sp. For the first time, we discovered that FCD potently inhibited proliferation in a variety of human NSCLC cell lines, with relatively less toxicity to normal cells. Our study exhibited that FCD induced apoptosis, caused DNA damage and cell cycle arrest in G0/G1 phase, and activated caspase-3 as well as other apoptosis-related factors in human NSCLC NCI-H460 cells. FCD was proven to be an iron chelator that actively decreased levels of cellular labile iron pool in NCI-H460 cells in our study. FeCl3 supplement reversed FCD-induced apoptosis. The upregulation of transferrin receptor 1 (TfR1) and downregulation of ferritin heavy chain (FTH) expression were observed after FCD treatment. In summary, our study highlighted the potential anticancer effects of FCD against human NSCLCs and demonstrated that the FCD-mediated apoptosis depended on binding to intracellular iron.

Risk sources quantitative appointment of ecological environment and human health in farmland soils: a case study on Jiuyuan District in China.

Heavy metals (HMs) in farmland soils lead to adverse influences on ecosystem and human health. Despite that, data on quantitative risk from different sources are still scarce. In this study, 100 farmland soil samples in Jiuyuan District were collected and analyzed for selected HMs (As, Cd, Co, Cr, Cu, Mn, Ni, Pb, V and Zn) content characteristics and pollution statuses. The positive matrix factorization (PMF) model combined with the Nemerow integrated risk index (NIRI) and human health risk assessment (HHRA) was used to quantitatively identify the primary risk sources. The results indicated that the mean contents or median values (mg/kg) of 10 HMs were all higher than the background values. The contamination factor (CF) and pollution load index (PLI) revealed that the soil was severely polluted. Based on PMF, the main source of HM pollution was anthropogenic activities, accounting for 78.91%. Sewage irrigation represented the biggest input but was not associated with the highest risk. The results of PMF-based NIRI and PMF-based HHRA showed that the chemical fertilizers and pesticides were the largest and priority risk sources with contribution rates of 38.10% to ecological risk and 34.61 and 32.82% to non-carcinogenic and carcinogenic risk, respectively. In addition, non-carcinogenic risk of children was higher than that of adults, while the carcinogenic risk was the opposite. The integrated approaches were beneficial for priority risk quantification from different sources and can provide direct risk information and effective policy recommendations for management and control of key risk sources.

The Efficacy of Everolimus for Facial Angiofibromas in Tuberous Sclerosis Complex Patients Treated for Renal Angiomyolipoma/Subependymal Giant Cell Astrocytoma.

BACKGROUND: Facial angiofibromas may be present since early childhood in individuals with tuberous sclerosis complex (TSC), causing substantial cosmetic disfigurement. Current therapies are partially effective, but they are uncomfortable, produce scarring, and are especially expensive. OBJECTIVE: The aim of the present study was to evaluate the efficacy of oral everolimus for TSC-associated angiofibromas. METHODS: This retrospective study included TSC patients being treated with oral everolimus for subependymal giant cell astrocytomas (SEGAs) and angiomyolipomas (AMLs). We recorded the changes in facial angiofibromas. Changes in the Angiofibroma Grading Scale (AGS) indicators were recorded according to erythema, average lesion size, lesion density, and percent involvement on the forehead, nose, cheeks, and chin. The scores were recorded before and after the administration of oral everolimus. RESULTS: Twenty-one patients being treated with oral everolimus were enrolled in this study. The mean age was 20.5 years (range 11-44 years, 4 males, and 17 females). The mean dose of oral everolimus was 3.6 mg/day. Clinically meaningful and statistically significant improvement was observed in erythema (p = 0.001), average lesion size (p < 0.001), lesion density (p < 0.001), and percent involvement (p < 0.001). Changes in the AGS findings were statistically significant on the forehead (p = 0.001), nose (p < 0.001) cheeks (p < 0.001), and chin (p = 0.004). CONCLUSION: Everolimus shows evident improvement and is approved for TSC-associated SEGAs and AMLs. The current study demonstrated the efficacy of oral everolimus in reducing facial angiofibromas, showing the parallel benefits of the treatment protocol for TSC.

Construction of a meroterpenoid-like compound collection by precursor-assisted biosynthesis.

Natural products (NPs) and their derivatives play a pivotal role in drug discovery due to their complexity and diversity. The strategies to rapidly generate NP-like compounds offer unique opportunities to access bioactive compounds. Here we present a new approach, precursor-assisted biosynthesis (PAB), for the creation of NP-like compounds by combination of artificial supplementation of common precursors and divergent post-modifications of precursor-deficient fungi. This method was applied to construct a meroterpenoid-like compound collection containing 43 compounds with diverse molecular scaffolds. Extensive bioactive screening of the collection revealed novel STING (stimulator of interferon genes) inhibitors, cytotoxic and antifungal compounds. This result indicates that PAB is an effective methodology for producing compound collections for the purpose of drug discovery.

The Association Between Usage of Colchicine and Pneumonia: A Nationwide, Population-Based Cohort Study.

Objectives: A previous study suggested that colchicine may cause leukopenia and increase the risk of infection, such as pneumonia. Thus, we investigated the potential relationship between colchicine use and risk of developing pneumonia. Methods: Data were collected from Taiwan's National Health Insurance Research Database (NHIRD), a nationwide, population-based database. A 13-year retrospective cohort study was conducted, and all investigated subjects were identified by International Classification of Disease, Ninth Revision, Clinical Modification, codes between 2000 and 2012. Propensity score matching was applied to adjust for potential confounding variables, and then Cox proportional hazard model was used to evaluate the hazard ratio (HR) of pneumonia in gout patients and its associations with colchicine use, colchicine dosage, and days of colchicine use. Results: A total of 24,410 gout patients were enrolled in this study, including 12,205 cases who were treated with colchicine (colchicine group) and 12,205 cases who did not receive colchicine (non-colchicine group). The overall incidence rates of pneumonia in the colchicine group and non-colchicine group were 18.6 and 12.6 per 1,000 person-years, respectively. The colchicine group had a higher risk of pneumonia as compared with the non-colchicine group [adjusted HR, 1.42; 95% confidence interval (CI), 1.32 to 1.53; P < 0.05]. High cumulative dose and days of colchicine use notably increased the risk of contracting pneumonia. Conclusion: This nationwide population-based cohort study reveals that gout patients taking colchicine are at increased risk of developing pneumonia compared with gout patients who do not use colchicine. Therefore, it is crucial that gout patients being treated with colchicine be given the minimally effective dosage for the shortest possible duration to minimize their risk of pneumonia.

Efficacy and safety of clopidogrel only vs. clopidogrel added proton pump inhibitors in the treatment of patients with coronary heart disease after percutaneous coronary intervention: A systematic review and meta-analysis.

BACKGROUND: Controversy still exists that whether clopidogrel should add proton pump inhibitors (PPIs) in patients with coronary heart disease after percutaneous coronary intervention (PCI). The aim of this study was to evaluate the efficacy and safety of clopidogrel added proton pump inhibitors (PPIs) vs. clopidogrel for the treatment of patients with coronary heart disease after percutaneous coronary intervention (PCI). METHODS AND RESULTS: We systematically searched PubMed, EMBASE, Web of Science, the Chinese Biomedical Medical Literature database, and the Cochrane Library for all clinical trials that were published on this topic through October 2018. We specifically selected the clinical trials that evaluated the efficacy and safety of clopidogrel added proton pump inhibitors vs. clopidogrel in the treatment of patients with coronary heart disease after PCI. RevMan 5.0 software was used for quantitative data analyses.15 randomized controlled trials including 50,366 patients were included. The meta-analysis results showed that compared with the clopidogrel added PPI group, the non-PPI group had significantly less risk of MACE[RR = 0.82,95%CI:0.77-0.88], myocardial infarction recurrence[RR = 0.72,95%CI:0.57-0.90], stent thrombosis[RR = 0.71,95%CI:0.56-0.92], Target vessel revascularization (TVR)[RR = 0.77,95%CI:0.63-0.93] and stroke [RR = 0.72,95%CI:0.67-0.76]. The risks of all cause death [RR = 1.14,95%CI:0.85-1.51], cardiovascular death [RR = 1.14, 95% CI: 0.85-1.52], bleedings events [RR = 1.60,95%CI:0.53-4.81] were similar in the two groups. CONCLUSIONS: The patients in the non-PPI group were observed to be associated with less risk of MACE, myocardial infarction recurrence, stent thrombosis, target vessel revascularization (TVR) and stroke. And the two groups had similar all cause death, cardiovascular death, bleedings events.

Leptin enhances glycolysis via OPA1-mediated mitochondrial fusion to promote mesenchymal stem cell survival.

Transplantation of mesenchymal stem cells (MSCs) is emerging as a potential therapy for cardiovascular diseases. However, the poor survival of transplanted MSCs is a major obstacle to improving their clinical efficacy. Accumulating evidence indicates that hypoxic preconditioning (HPC) can improve the survival of MSCs. It has been previously reported that leptin plays a critical role in HPC­enhanced MSC survival through increasing optic atrophy 1 (OPA1)­dependent mitochondrial fusion. Survival of MSCs mainly relies on glycolysis as an energy source. The close relationship between leptin and glucose homeostasis has attracted intense scientific interest. Furthermore, emerging evidence indicates that mitochondrial dynamics (fusion and fission) are associated with alterations in glycolysis. The aim of the present study was to investigate whether leptin increases MSC survival through metabolic regulation. Leptin­modulated increased OPA1 expression was found to be associated with increased glycolysis. However, the glycolytic efficacy of leptin was abrogated after silencing OPA1 using a selective siRNA, suggesting that OPA1 directly regulates glycolysis. Furthermore, the activation of sodium­glucose symporter 1 (SGLT1) was markedly induced by leptin. However, leptin­induced glycolysis was primarily blocked by SGLT1 inhibitor treatment. Thus, leptin regulates OPA1­dependent glycolysis to improve MSC survival primarily through SGLT1 activation. We therefore identified a pivotal leptin/OPA1/SGLT1 signaling pathway for mitochondrial dynamic­mediated glycolysis, which may optimize the therapeutic efficiency of MSCs.

Promotion of HeLa cells apoptosis by cynaropicrin involving inhibition of thioredoxin reductase and induction of oxidative stress.

Cancer is considered as one of the highly mortal diseases globally. This is largely due to the lack of efficacious medicines for tumors, and thus development of potent anticancer agents is urgently needed. The thioredoxin (Trx) system is crucial to the survival ability of cells and its expression is up-regulated in many human tumors. Recently, increasing evidence has been established that mammalian thioredoxin reductase (TrxR), a selenocysteine-containing protein and the core component of the thioredoxin system, is a promising therapeutic target. The sesquiterpene lactone compound cynaropicrin (CYN), a major component of Cynara scolymus L., has shown multiple pharmacological functions, especially the anticancer effect, in many experimental models. Most of these functions are concomitant with the production of reactive oxygen species (ROS). Nevertheless, the target of this promising natural anticancer product in redox control has rarely been explored. In this study, we showed that CYN induces apoptosis of Hela cells. Mechanistic studies demonstrated that CYN impinges on the thioredoxin system via inhibition of TrxR, which leads to Trx oxidation and ROS accumulation in HeLa cells. Particularly, the cytotoxicity of CYN is enhanced through the genetic knockdown of TrxR, supporting the pharmacological effect of CYN is relevant to its inhibition of TrxR. Together, our studies reveal an unprecedented mechanism accounting for the anticancer effect of CYN and identify a promising therapeutic agent worthy of further development for cancer therapy.

Targeting Thioredoxin Reductase by Ibrutinib Promotes Apoptosis of SMMC-7721 Cells.

Ibrutinib (IBT), the first-in-class inhibitor of Bruton's tyrosine kinase (BTK), has demonstrated clinical activity against various B-cell malignancies. Aside from its therapeutic mechanism through BTK inhibition, IBT has other target sites reported for cancer therapy, leading us to investigate whether IBT has unreported targets. Our study revealed that IBT can inhibit SMMC-7721 cells through irreversible inhibition of mammalian thioredoxin reductase enzymes. Further study demonstrated that IBT can cause cellular reactive oxygen species elevation and induce cancer cell apoptosis. The discovery of a new target of IBT sheds light on better understanding its anticancer mechanisms and provides a theoretical foundation for its further use in clinical therapy.