Preparation of size-tunable Fe3O4 magnetic nanoporous carbon composites by MOF pyrolysis regulation for magnetic resonance sensing of aflatoxin B1 with excellent anti-matrix effect.

Magnetic nanoporous materials represent a new emerging category of magnetic materials for construction of magnetic resonance sensors. In this study, we adopted the metal-organic framework materials, MIL-101(Fe), as the precursor to prepare series nanoporous-carbon-Fe3O4 (NPC-Fe3O4) composites. Results showed that Fe3O4 were uniformly distributed in MIL-101(Fe) and the size of MNP was precisely tuned at different pyrolysis temperatures, conferring the optimal NPC-Fe3O4-450 °C composite with dramatically improved T2 relaxivity. The NPC-Fe3O4-450 °C composite was modified with antibodies and antigens, respectively, for detection of aflatoxin B1 in various food samples with complicated matrix. Range from 0.010 ng mL-1 to 2.0 ng mL-1, extreme low detection limit of 5.0 pg mL-1, and satisfied recoveries were successfully achieved, indicating excellent anti-matrix effect. These findings offer a new dimension to engineer novel magnetic materials with improved relaxivity for simple and easy sensing of food hazards in complicated food matrix without any purification or separation procedures.

Inhibition of the lncRNA 585189 prevents podocyte injury and mitochondria dysfunction by promoting hnRNP A1 and SIRT1 in diabetic nephropathy.

Podocyte dysfunction has been identified as a crucial pathological characteristic of diabetic nephropathy (DN). However, the regulatory effects of long non-coding RNAs (lncRNAs) in this process have not been fully elucidated. Here, we performed an unbiased RNA-sequencing (RNA-seq) analysis of renal tissues and identified a significantly upregulated long non-coding RNA, ENST00000585189.1 (lncRNA 585189), in patients with DN. Furthermore, lncRNA 585189 was positively correlated with renal insufficiency and was upregulated in both DN patients and high-glucose-induced human podocytes. Gain- and loss-of-function experiments revealed that silencing lncRNA 585189 decreased the production of ROS, rescued aberrant mitochondrial morphology and membrane potential, and alleviated podocyte damage caused by high glucose. Mechanistically, bioinformatics analysis predicted an interaction between lncRNA 585189 and hnRNP A1, which was subsequently confirmed by RIP, pull-down, and EMSA assays. Further investigation revealed that lncRNA 585189 destabilizes the hnRNP A1 protein, leading to the downregulation of its expression. Conversely, hnRNP A1 promoted the expression of lncRNA 585189. Moreover, both RIP and pull-down assays demonstrated a direct interaction between hnRNP A1 and SIRT1, which enhanced SIRT1 mRNA stability. Our findings suggest that lncRNA 585189 suppresses SIRT1 through hnRNP A1, thereby hindering the recovery from mitochondrial abnormalities and podocyte damage. In summary, targeting lncRNA 585189 is a promising strategy for reversing mitochondrial dysfunction and treating DN.

Designing Multimodal ON-OFF Nanoswitches of DNA-Functionalized Nanoparticles by Stimuli-Responsive Polymers.

It is a challenging task to realize highly reversible ON-OFF nanoswitches over a wide range of temperatures, which emerge as a versatile toolbox for use in nanobiotechnology. Herein, nanoparticles (NPs) bifunctionalized by DNA strands and stimuli-responsive polymers are proposed to construct multimodal ON-OFF nanoswitches by the coarse-grained model. The successful achievement of multimodal ON-OFF nanoswitches for bifunctionalized NPs at lower temperatures is attributed to the synergistic effects of the contraction and expansion configurations of stimuli-responsive polymers, combined with the hybridization-dehybridization event of DNA strands. Importantly, our simulations isolate the conditions of programmable self-assembly of bifunctionalized NPs to realize the multimodal ON-OFF nanoswitches by the changes of temperature and chain rigidity. In addition, it is found that the bifunctionalized NPs in the ON state display anisotropic and patchy features due to an introduction of stimuli-responsive polymers. Our simulation results provide fundamental insights on qualitative predictions of ON/OFF states of DNA-based NPs, which can aid in realizing a set of ON-OFF nanoswitches by the rational design of functionalization molecules.

Statin use, survival and incidence of thrombosis among older patients with polycythemia vera and essential thrombocythemia.

BACKGROUND: Polycythemia vera (PV) and essential thrombocythemia (ET) are linked to increased risk of cardiovascular morbidity and mortality. In addition to the reduction in of arterial thrombotic events, statins may prevent venous thrombosis including among patients with cancer. As previous registry- and claims-based studies revealed that the use of statins may improve the survival of patients with various malignancies we evaluated their impact on outcomes of older adults with PV and ET. METHODS: We identified 4010 older adults (aged 66-99 years at diagnosis) with PV (n = 1809) and ET (n = 2201) in a population-based cohort study using the Surveillance, Epidemiology, and End Results-Medicare database with median follow-up of 3.92 (interquartile range: 2.58-5.75) years. Propensity score matching (PSM) and inverse probability of treatment weighting (IPTW) approaches were utilized to assess potential association between statins and overall survival. Multivariable competing risk models with death as a competing risk were used to evaluate possible relationship between statins and the incidence of thrombosis. RESULTS: 55.8% of the patients used statins within the first year after PV/ET diagnosis, and statin use was associated with a 22% reduction in all-cause mortality (PSM: hazard ratio [HR] = 0.78, 95% confidence interval [CI]: 0.63-0.98, p = 0.03; IPTW: HR = 0.79, 95% CI: 0.64-0.97, p = 0.03). Statins also reduced the risk of thrombosis in this patient population (PSM: HR = 0.63, 95% CI: 0.51-0.78, p < 0.01; IPTW: HR = 0.57, 95% CI: 0.49-0.66, p < 0.01) as well as in PV and ET subgroups. CONCLUSIONS: These findings suggest that it may be important to incorporate statins into the therapeutic strategy for older adults with PV and ET.

Hydrolysis of propyrisulfuron in water: Kinetics, influence of 34 environmental factors, transformation products identification, mechanisms and toxicities.

Propyrisulfuron is a novel sulfonylurea herbicide used for controlling annual grass and broad-leaved weeds in fields, but its fates and behaviors in environment are still unknown, which are of utmost importance for environmental protection. To reduce its potential environmental risks in agricultural production, the hydrolysis kinetics, influence of 34 environmental factors including 12 microplastics (MPs), disposable face masks (DFMs) and its different parts, 6 fertilizers, 5 ions, 3 surfactants, a co-existed herbicide of florpyrauxifen-benzy, humic acid and biochar, and the effect of MPs and DFMs on its hydrolysis mechanisms were systematically investigated. The main hydrolysis products (HPs), possible mechanisms, toxicities and potential risks to aquatic organisms were studied. Propyrisulfuron hydrolysis was an acid catalytic pyrolysis, endothermic and spontaneous process driven by the reduction of activation enthalpy, and followed the first-order kinetics. All environmental factors can accelerate propyrisulfuron hydrolysis to varying degrees except humic acid, and different hydrolysis mechanisms occurred in the presence of MPs and DFMs. In addition, 10 possible HPs and 7 possible mechanisms were identified and proposed. ECOSAR prediction and ecotoxicity testing showed that acute toxicity of propyrisulfuron and its HPs for aquatic organisms were low, but may have high chronic toxicity and pose a potential threat to aquatic ecosystems. The investigations are significantly important for elucidating the environmental fates and behaviors of propyrisulfuron, assessing the risks in environmental protection, and further providing guidance for scientific application in agro-ecosystem.

The quality of group interactions in medical problem-based learning in China: the roles of intercultural sensitivity and group ethnic composition.

BACKGROUND: Chinese universities are increasingly recruiting foreign students, and problem-based learning (PBL) is an effective approach to integrating those students. This study focuses on the role of intercultural sensitivity and group ethnic composition on the quality of group interaction in medical problem-based learning in China. METHODS: This paper reports an investigation of the differences in three types of group interaction (exploratory questions, cumulative reasoning, and handling conflict) among 139 s-year medical undergraduates from two backgrounds (Chinese and foreign) in a PBL setting. The roles of intercultural sensitivity, group ethnic composition, and students' personal characteristics including age, gender and ethnicity on students' perceptions of the three types of interaction were quantitatively analyzed. A 35-item questionnaire and demographic survey were administered to second year medical undergraduates. RESULTS: The results indicated that group ethnic composition was a significant negative predictor while intercultural sensitivity was a strong positive predictor of group interactions involving exploratory questions and cumulative reasoning. In addition, group heterogeneity in terms of age and ethnicity were significant predictors of group interaction. CONCLUSIONS: The findings of this study provide insights for strategically designing effective multiethnic group learning environments that encourage interaction and collaboration.

Genetic structure shows the presence of small-scale management units in a relict tree species.

Identifying conservation units is crucial for the effective conservation of threatened species. Previous cases are almost exclusively based on large-scale but coarse sampling for genetic structure analyses. Significant genetic structure can occur within a small range, and thus multiple conservation units may exist in narrowly distributed plants. However, small-scale genetic structure is often overlooked in conservation planning especially for wind-pollinated and wind-dispersed trees, largely due to the absence of dense and elaborate sampling. In this study, we focused on a representative endangered relict plant, Metasequoia glyptostroboides. Using both nuclear microsatellites (nSSRs) and chloroplast DNA (cpDNA) fragments, we sampled across the narrow distribution range of this species and determined its conservation units by exploring its genetic structure and historical demography. cpDNA haplotypes were classified into two groups, but mixed in space, suggesting that the existent wild trees of M. glyptostroboides cannot be divided into different evolutionarily significant units. However, using nSSRs, we detected strong spatial genetic structure, with significant genetic differentiation and weak gene flow between the samples in the east of the species' distribution range and other samples. The divergence between the two nSSR groups was dated to the Last Glacial Maximum (c. 19.6 kya), suggesting that such spatial genetic structure has been maintained for a long term. Therefore, these two nSSR groups should be considered as different conservation units, that is, management units, to protect intergroup genetic variations, which is likely to be the outputs of local adaptation. Our findings highlight the necessity to reveal small-scale genetic structure and population demography to improve the conservation strategies of evolutionary potential of endangered plants.

Revealing mechanisms of triclosan on the removal and distribution of nitrogen and phosphorus in microalgal-bacterial symbiosis system.

Microalgal-bacterial symbiosis (MABS) system performs synergistic effect on the reduction of nutrients and carbon emissions in the water treatment process. However, antimicrobial agents are frequently detected in water, which influence the performance of MABS system. In this study, triclosan (TCS) was selected to reveal the effects and mechanisms of antimicrobial agents on MABS system. Results showed that the removal efficiencies of chemical oxygen demand, NH4+-N and total phosphorus decreased by 3.0%, 24.0% and 14.3% under TCS stress. In contrast, there were no significant decrease on the removal effect of total nitrogen. Mechanism analysis showed that both the growth rate of microorganisms and the nutrients retention capacity of extracellular polymeric substances were decreased. The intracellular accumulation for nitrogen and phosphorus was promoted due to the increased cytomembrane permeability caused by lipid peroxidation. Moreover, microalgae were dominant in MABS system with ratio between microalgae and bacteria of more than 5.49. The main genus was Parachlorella, with abundance of more than 90%. Parachlorella was highly tolerant to TCS, which might be conductive to maintain its survival. This study revealed the nutrients pathways of MABS system under TCS stress, and helped to optimize the operation of MABS system.

A novel method using a differential staining fluorescence microscopy (DSFM) to track the location of enteric pathogens within mixed-species biofilms.

This study developed a new tool, differential staining fluorescence microscopy (DSFM), to measure the biovolume and track the location of enteric pathogens in mixed-species biofilms which can pose a risk to food safety in beef processing facilities. DSFM was employed to examine the impact of pathogenic bacteria, Escherichia coli O157:H7 and three different Salmonella enterica strains on mixed-species biofilms of beef processing facilities. Fourteen floor drain biofilm samples from three beef processing plants were incubated with overnight BacLight stained enteric pathogens at 7 °C for 5 days on stainless steel surface then counter-stained with FM-1-43 biofilm stain and analyzed using fluorescence microscopy. Notable variations in biovolume of biofilms were observed across the fourteen samples. The introduction of E. coli O157:H7 and S. enterica strains resulted in diverse alterations of biofilm biovolume, suggesting distinct impacts on mixed-species biofilms by different enteric pathogens which were revealed to be located in the upper layer of the mixed-species biofilms. Pathogen strain growth curve comparisons and verification of BacLight Red Stain staining effectiveness were validated. The findings of this study show that the DSFM method is a promising approach to studying the location of enteric pathogens within mixed-species biofilms recovered from processing facilities. Understanding how foodborne pathogens interact with biofilms will allow for improved targeted antimicrobial interventions.

LncRNA PTTG3P promotes tumorigenesis and metastasis of NSCLC by binding with ILF3 to maintain mRNA stability and form a positive feedback loop with E2F1.

Non-small cell lung cancer (NSCLC) is a highly lethal disease worldwide. We found the pseudogene-derived lncRNA PTTG3P is upregulated in NSCLC and associated with larger tumor size, advanced staging, and poor prognosis. This study investigated the oncogenic roles and mechanisms of PTTG3P in NSCLC. We demonstrate that PTTG3P promoted NSCLC cell proliferation, migration, tumorigenesis, and metastasis while inhibiting apoptosis in vitro and in vivo. Mechanistically, PTTG3P formed an RNA-protein complex with ILF3 to maintain MAP2K6 and E2F1 mRNA stability, two oncogenic factors involved in NSCLC progression. RNA-seq revealed MAP2K6 and E2F1 were downregulated upon PTTG3P knockdown. RIP and RNA stability assays showed PTTG3P/ILF3 interaction stabilized MAP2K6 and E2F1 transcripts. Interestingly, E2F1 transcriptionally upregulated PTTG3P by binding its promoter, forming a positive feedback loop. Knockdown of E2F1 or PTTG3P attenuated their mutual regulatory effects on cell growth and migration. Thus, a PTTG3P/ILF3/E2F1 axis enhances oncogene expression to promote NSCLC pathogenesis. Our study reveals PTTG3P exerts oncogenic functions in NSCLC via mRNA stabilization and a feedback loop, highlighting its potential as a prognostic biomarker and therapeutic target.

Effect of roxadustat on red blood cell lifespan in patients with long-term haemodialysis: a single-centre, prospective, single-arm study.

Background: Reduced survival of red blood cells (RBCs) in patients with chronic kidney disease (CKD) is thought to contribute to renal anaemia. Although renal anaemia improved greatly because of the wide use of erythropoiesis-stimulating agents (ESAs) and the advancement of dialysis techniques, RBC longevity seems not to be obviously ameliorated. Methods: In this single-centre, single-arm trial, patients who had been undergoing haemodialysis and ESA therapy with epoetin alfa for at least 12 weeks changed their anti-anaemia drugs from epoetin alfa to oral roxadustat three times per week for 24 weeks. The primary endpoint was the change in RBC lifespan from baseline at week 24. The change in the circulating percentage of eryptotic RBCs, RBC deformability and RBC oxygen transport ability were also assessed. Results: A total of 27 patients were enrolled, with 26 completing the full course of intervention. At baseline, the average RBC lifespan was 60.1 days [standard deviation (SD) 14.4; n = 27]. At the end of the study period, 26 patients had an RBC lifespan measurement (83.9 days on average; SD 21.9). The RBC lifespan increased by 22.8 days on average [95% confidence interval (CI) 15.5-30.0, P < .001]. This equated to an average RBC lifespan increase of 39.2% (95% CI 27.8-50.6). The percentage of circulating eryptotic RBCs, erythrocyte filtration index and the pressure at which haemoglobin is 50% saturated decreased significantly from baseline to week 24 (1.39 ± 0.44% versus 0.89 ± 0.25%, P < .0001; 0.29 ± 0.12 versus 0.16 ± 0.08, P < .0001 and 32.54 ± 4.83 versus 28.40 ± 2.29, P < .001, respectively). Conclusion: Roxadustat prolonged RBC lifespan in patients with long-term haemodialysis.

Mediator subunit MED1 deficiency prevents carbon tetrachloride induced hepatic fibrosis in mice.

Mediator subunit MED1 mediates ligand-dependent binding of the Mediator coactivator complex to various nuclear receptors and plays critical role in embryonic development, lipid and glucose metabolism, liver regeneration and tumorigenesis. However, the precise role of MED1 in the development of liver fibrosis has been unclear. Here, we showed that MED1 expression was increased in livers from nonalcoholic steatohepatitis (NASH) patients and mice, and positively correlated with TGF-ß signaling and pro-fibrotic factors. Upon with CCl4 treatment,hepatic fibrosis was much lesser in liver specific MED1 deletion (MED1ΔLiv) mice than in MED1fl/fl littermates. TGF-ß/Smad2/3 signaling pathway was inhibited, and gene expression of fibrotic markers, including α-smooth muscle actin (α-SMA), collagen type 1 alpha 1 (Col1a1), matrix metalloproteinase-2 (Mmp2), and metallopeptidase inhibitor 1 (Timp1) were decreased in livers of MED1ΔLiv mice with CCl4 injection. Transcriptomic analysis revealed that the differentially expressed genes in livers of CCl4-adminstered MED1ΔLiv mice were enriched in pathway of oxidoreductase activity, following with robustly reduced oxidoreductase activity related genes, such as Gm4756, Txnrd3, and Etfbkmt. More importantly, we found that reduction of reactive oxygen species (ROS) in MED1knockdown hepatocytes blocked the activation of TGF-ß/Smad2/3 pathway and the expression of fibrotic genes in LX2 cells. These results indicate that MED1 is a positive regulator for hepatic fibrogenesis and MED1 may be considered as a potential therapeutic target for the regression of liver fibrosis.

Dissecting the tumour immune microenvironment in merkel cell carcinoma based on a machine learning framework.

Merkel cell carcinoma (MCC) is a primary cutaneous neoplasm of neuroendocrine carcinoma of the skin, which is characterized by molecular heterogeneity with diverse tumour microenvironment (TME). However, we are still lack knowledge of the cellular states and ecosystems in MCC. Here, we systematically identified and characterized the landscape of cellular states and ecotypes in MCC based on a machine learning framework. We obtained 30 distinct cellular states from 9 immune cell types and investigated the B cell, CD8 T cell, fibroblast, and monocytes/macrophage cellular states in detail. The functional profiling of cellular states were investigated and found the genes highly expressed in cellular states were significantly enriched in immune- and cancer hallmark-related pathways. In addition, four ecotypes were further identified which were with different patient compositions. Transcriptional regulation analysis revealed the critical transcription factors (i.e. E2F1, E2F3 and E2F7), which play important roles in regulating the TME of MCC. In summary, the findings of this study may provide rich knowledge to understand the intrinsic subtypes of MCCs and the pathways involved in distinct subtype oncogenesis, and will further advance the knowledge in developing a specific therapeutic strategy for these MCC subtypes.

Graph Joint Representation Clustering via Penalized Graph Contrastive Learning.

Graph clustering based on graph contrastive learning (GCL) is one of the dominant paradigms in the current graph clustering research field. However, those GCL-based methods often yield false negative samples, which can distort the learned representations and limit clustering performance. In order to alleviate this issue, we propose the idea of maintaining mutual information (MI) between the representations and the inputs to mitigate the loss of semantic information of false negative samples. We demonstrate the validity of this proposal through relevant experiments. Since maximizing MI can be approximately replaced by minimizing reconstruction error, we further propose a graph clustering method based on GCL penalized by reconstruction error, in which our carefully designed reconstruction decoder, as well as reconstruction error term, improve the clustering performance. In addition, we use a pseudo-label-guided strategy to improve the GCL process and further alleviate the problem of false negative samples. Our experiment results demonstrate the superiority and great potential of our proposed graph clustering method compared with state-of-the-art algorithms.

Discrete and Balanced Spectral Clustering with Scalability.

Spectral Clustering (SC) has been the main subject of intensive research due to its remarkable clustering performance. Despite its successes, most existing SC methods suffer from several critical issues. Firstly, they typically involve two independent stages, i.e., learning the continuous relaxation matrix followed by the discretization of the cluster indicator matrix. This two-stage approach can result in suboptimal solutions that negatively impact the clustering performance. Secondly, these methods are hard to maintain the balance property of clusters inherent in many real-world data, which restricts their practical applicability. Finally, these methods are computationally expensive and hence unable to handle large-scale datasets. In light of these limitations, we present a novel Discrete and Balanced Spectral Clustering with Scalability (DBSC) model that integrates the learning the continuous relaxation matrix and the discrete cluster indicator matrix into a single step. Moreover, the proposed model also maintains the size of each cluster approximately equal, thereby achieving soft-balanced clustering. What's more, the DBSC model incorporates an anchor-based strategy to improve its scalability to large-scale datasets. The experimental results demonstrate that our proposed model outperforms existing methods in terms of both clustering performance and balance performance. Specifically, the clustering accuracy of DBSC on CMUPIE data achieved a 17.93% improvement compared with that of the SOTA methods (LABIN, EBSC, etc.).

In vitro bloodbrain barrier permeability study of four main active ingredients from Alpiniae oxyphyllae fructus.

The fruits of Alpinia oxyphylla Miq., a broadly utilized traditional Chinese medicine, have a number of effects on the central nervous system (CNS). The main active constituents of Alpiniae oxyphyllae fructus (AOF) were nootkatone, tectochrysin, chrysin and protocatechuic acid. An immortalized human brain microvascular endothelial cell (hCMEC/D3) and astrocyte (HA1800) coculture model was used to investigate the permeability of the blood-brain barrier (BBB). The validation of ultrahigh-performance liquid chromatography-tandem mass spectrometry (UHPLC-MS/MS) methods for the four compounds was conducted following industry guidelines. Calibration curves were generated with mean coefficients (R2) better than 0.99. The inter-day and intra-day precisions were less than 8.53% and 7.12%, respectively. The accuracies were lower than ± 11.57%, and recoveries were greater than 86.07%. The samples of the transport experiment were examined, and the apparent permeability coefficients (Papp) were calculated. The efflux ratios of the four compounds are all less than 2. The Papp values of protocatechuic acid, chrysin, nootkatone, tectochrysin were at the level of 10-5, 10-6, 10-6, and 10-7 cm/s, respectively. All four compounds crossed the BBB by passive diffusion, with protocatechuic acid having high permeability, and tectochrysin having poor permeability. This research indicated the permeability of protocatechuic acid, chrysin, nootkatone and tectochrysin through the BBB and offered a foundation for related research on AOF in the treatment of CNS illnesses.

Effect of web-implemented exercise interventions on depression and anxiety in patients with neurological disorders: a systematic review and meta-analysis.

Introduction: Web-implemented exercise intervention is the latest and innovative method to improve people's mental health. Currently, many studies have proven that web-implemented interventions are effective to improve depression and anxiety in adults. However, the influence of different web-implemented exercise interventions on depression and anxiety in patients with neurological disorders is still unclear. Objective: The study aims to systematically summarize the type and content of web-implemented exercise interventions and quantify the effect of different web-implemented exercise interventions on depression and anxiety in patients with neurological disorders. Methods: Four literature databases (PubMed, Web of Science, China National Knowledge Infrastructure, and WanFang data) were searched. The literature search considered studies published in English or Chinese before October 13, 2022. Randomized controlled trials (RCTs) that participants accepted web-implemented interventions were included. Two authors independently extracted data and assessed the risk of bias for included studies. Standardized mean differences (SMD) with 95% CI were used to integrate the effect size. Results: 16 RCTs (a total of 963 participants) were included. The results showed that web-implemented exercise intervention had a significant effect on depression (SMD = -0.80; 95% CI, -1.09 to -0.52; I2 = 75%; P < 0.00001) and anxiety (SMD = -0.80; 95% CI, -1.23 to -0.36; I2 = 75%; P = 0.0003) in patients with a neurological disorder. The subgroup analysis showed that the effectiveness of the web-implemented exercise intervention was influenced by several factors, such as web-implemented exercise intervention type, component, and intervention duration. Conclusion: Web-implemented exercise intervention has a relieving effect on depression and anxiety symptoms in patients with neurological disorders. Additionally, the intervention type, intervention duration, and component can influence the effect size. Systematic review registration: https://www.crd.york.ac.uk/PROSPERO/#recordDetails, identifier: CRD42023409538.

Kinsenoside mitigates myocardial ischemia/reperfusion-induced ferroptosis via activation of the Akt/Nrf2/HO-1 pathway.

Ischemia-induced myocardial infarction is regarded as one of the major killers of humans worldwide. Kinsenoside (KD), a primary active ingredient derived from Anoectochilus roxburghii, shows antioxidant and vascular protective properties. Myocardial ischemia/reperfusion (I/R) injury is associated with oxidative damage and could be regulated by KD. However, its targets and the exact mechanism by which it operates remains unclear. The aim of this study was to investigate the role of KD in myocardial I/R injury and to define the mechanism by which it works. We established both myocardial I/R model in vivo and hypoxia/reoxygenation (H/R) cardiomyocyte model in vitro in this study. KD can attenuate I/R-induced myocardial injury in vivo and inhibit H/R-induced injury in vitro in a dose-dependent manner. KD increased mitochondrial membrane potential, SOD activity, and GSH activity in cardiomyocytes, whereas MDA accumulation, iron accumulation, and Mito-ROS production were decreased. We intersected differentially expressed genes (DEGs) from RNA-seq results with ferroptosis-related genes, and found KD significantly downregulated COX2 expression and upregulated GPX4 expression. These findings were further confirmed by Western blot analysis. Additionally, KD increased AKT phosphorylation and Nrf2 translocation into the nucleus, as well as HO-1 expression. When Akt or Nrf2 were inhibited in the KD group, the anti-ferroptosis properties of KD were nullified. Thus, Kinsenoside may exert anti-ferroptosis effect in myocardial I/R injury by decreasing mitochondrial dysfunction and increasing anti-oxidation through the Akt/Nrf2/HO-1 signaling pathway, suggesting it could be used as a potential therapeutic agent for myocardial reperfusion injury.

Narciclasine, a novel topoisomerase I inhibitor, exhibited potent anti-cancer activity against cancer cells.

DNA topoisomerases are essential nuclear enzymes in correcting topological DNA errors and maintaining DNA integrity. Topoisomerase inhibitors are a significant class of cancer chemotherapeutics with a definite curative effect. Natural products are a rich source of lead compounds for drug discovery, including anti-tumor drugs. In this study, we found that narciclasine (NCS), an amaryllidaceae alkaloid, is a novel inhibitor of topoisomerase I (topo I). Our data demonstrated that NCS inhibited topo I activity and reversed its unwinding effect on p-HOT DNA substrate. However, it had no obvious effect on topo II activity. The molecular mechanism of NCS inhibited topo I showed that NCS did not stabilize topo-DNA covalent complexes in cells, indicating that NCS is not a topo I poison. A blind docking result showed that NCS could bind to topo I, suggesting that NCS might be a topo I suppressor. Additionally, NCS exhibited a potent anti-proliferation effect in various cancer cells. NCS arrested the cell cycle at G2/M phase and induced cell apoptosis. Our study reveals the antitumor mechanisms of NCS and provides a good foundation for the development of anti-cancer drugs based on topo I inhibition.