Demand analysis of health care services for community-dwelling breast cancer survivors based on the Kano model: A cross-sectional study.

Objectives: Providing satisfactory healthcare services for breast cancer survivors can effectively reduce their burden and the pressure on medical resources. The aim of this study was to explore health care service demands for community-dwelling breast cancer survivors using the Kano model. Methods: A cross-sectional survey was conducted from January to March 2023 among breast cancer survivors discharged from a tertiary cancer hospital. Participants were asked to fill out a self-designed questionnaire involving the Kano model, which helped to categorize and prioritize the attributes of healthcare services. The questionnaire included 30 health care services. Additionally, their social demographic characteristics were collected during the survey. Results: A total of 296 valid questionnaires were collected, and demand attributes of the 30 health care services were evaluated. The findings revealed that one of 30 services was classified as "must-be attributes" (body image management), 13 as "one-dimensional attributes" (focused on medical security support, health management, and health counseling), 3 as "attractive attributes" (focused on communication needs and telehealth services), and 11 as "indifferent attributes" (mainly in the area of psycho-social services). Conclusions: Breast cancer survivors in the community have different levels of need for various health care services. It's crucial for healthcare providers to identify these needs and devise effective strategies to deliver the appropriate services. Services with must-be and one-dimensional attributes should be given priority, and efforts should be made to provide services with attractive attributes, hence improving the quality of life of breast cancer survivors.

Long Noncoding RNA Gpr137b-ps Promotes Advanced Atherosclerosis via the Regulation of Autophagy in Macrophages.

BACKGROUND: Current therapies cannot completely reverse advanced atherosclerosis. High levels of amino acids, induced by Western diet, stimulate mTORC1 (mammalian target of rapamycin complex 1)-autophagy defects in macrophages, accelerating atherosclerotic plaque progression. In addition, autophagy-lysosomal dysfunction contributes to plaque necrotic core enlargement and lipid accumulation. Therefore, it is essential to investigate the novel mechanism and molecules to reverse amino acid-mTORC1-autophagy signaling dysfunction in macrophages of patients with advanced atherosclerosis. METHODS: We observed that Gpr137b-ps (G-protein-coupled receptor 137B, pseudogene) was upregulated in advanced atherosclerotic plaques. The effect of Gpr137b-ps on the progression of atherosclerosis was studied by generating advanced plaques in ApoE-/- mice with cardiac-specific knockout of Gpr137b-ps. Bone marrow-derived macrophages and mouse mononuclear macrophage cell line RAW264.7 cells were subjected to starvation or amino acid stimulation to study amino acid-mTORC1-autophagy signaling. Using both gain- and loss-of-function approaches, we explored the mechanism of Gpr137b-ps-regulated autophagy. RESULTS: Our results demonstrated that Gpr137b-ps deficiency led to enhanced autophagy in macrophages and reduced atherosclerotic lesions, characterized by fewer necrotic cores and less lipid accumulation. Knockdown of Gpr137b-ps increased autophagy and prevented amino acid-induced mTORC1 signaling activation. As the downstream binding protein of Gpr137b-ps, HSC70 (heat shock cognate 70) rescued the impaired autophagy induced by Gpr137b-ps. Furthermore, Gpr137b-ps interfered with the HSC70 binding to G3BP (Ras GTPase-activating protein-binding protein), which tethers the TSC (tuberous sclerosis complex) complex to lysosomes and suppresses mTORC1 signaling. In addition to verifying that the NTF2 (nuclear transport factor 2) domain of G3BP binds to HSC70 by in vitro protein synthesis, we further demonstrated that HSC70 binds to the NTF2 domain of G3BP through its W90-F92 motif by using computational modeling. CONCLUSIONS: These findings reveal that Gpr137b-ps plays an essential role in the regulation of macrophage autophagy, which is crucial for the progression of advanced atherosclerosis. Gpr137b-ps impairs the interaction of HSC70 with G3BP to regulate amino acid-mTORC1-autophagy signaling, and these results provide a new potential therapeutic direction for the treatment of advanced atherosclerosis.

Nicotine exacerbates endothelial dysfunction and drives atherosclerosis via extracellular vesicle-miRNA.

AIMS: Nicotine, a major component of tobacco, is an important factor contributing to atherosclerosis. However, the molecular mechanisms underlying the link between nicotine and atherosclerosis are unclear. As extracellular vesicles (EVs) are involved in intercellular communication in atherosclerosis, we investigated whether their influence on arterial pathophysiology under nicotine stimulation. METHODS AND RESULTS: EVs from the serum of smokers (smoker-EVs) were significantly increased and exacerbated endothelial inflammation, as well as apoptosis according to functional studies. Meanwhile, inhibition of EVs blunted the nicotine-induced atherosclerosis progression, and injection of nicotine-induced EVs promoted atherosclerosis progression in ApoE-/- mice. Furthermore, quantitative reverse transcription-polymerase chain reaction analysis revealed a remarkable increase in miR-155 levels in smoker-EVs, which was correlated with carotid plaque formation in patients measured by ultrasound imaging. Moreover, CD14 levels were significantly increased in EVs from smokers (representing EVs derived from monocytes), indicating that monocytes are an important source of smoker-EVs. DNA methylation and the transcription factor HIF1α may contribute to increased miR-155 levels in monocytes, as assessed with bisulfite conversion sequencing and chromatin immunoprecipitation. Mechanistically, EVs encapsulated miR-155 induced endothelial cell dysfunction by directedly targeting BCL2, MCL1, TIMP3, BCL6, and activating NF-κB pathway, as verified in a series of molecular and biological experiments. Injecting EVs from nicotine-stimulated monocytes promoted plaque formation and triggered vascular endothelial injury in ApoE-/- mice, whereas inhibition of miR-155 weakened this effect. CONCLUSION: Our findings revealed an EV-dependent mechanism of nicotine-aggravated atherosclerosis. Accordingly, we propose an EV-based intervention strategy for atherosclerosis management.

Effective prediction of potential ferroptosis critical genes in clinical colorectal cancer.

Background: Colon cancer is common worldwide, with high morbidity and poor prognosis. Ferroptosis is a novel form of cell death driven by the accumulation of iron-dependent lipid peroxides, which differs from other programmed cell death mechanisms. Programmed cell death is a cancer hallmark, and ferroptosis is known to participate in various cancers, including colon cancer. Novel ferroptosis markers and targeted colon cancer therapies are urgently needed. To this end, we performed a preliminary exploration of ferroptosis-related genes in colon cancer to enable new treatment strategies. Methods: Ferroptosis-related genes in colon cancer were obtained by data mining and screening for differentially expressed genes (DEGs) using bioinformatics analysis tools. We normalized the data across four independent datasets and a ferroptosis-specific database. Identified genes were validated by immunohistochemical analysis of pathological and healthy clinical samples. Results: We identified DEGs in colon cancer that are involved in ferroptosis. Among these, five core genes were found: ELAVL1, GPX2, EPAS1, SLC7A5, and HMGB1. Bioinformatics analyses revealed that the expression of all five genes, except for EPAS1, was higher in tumor tissues than in healthy tissues. Conclusions: The preliminary exploration of the five core genes revealed that they are differentially expressed in colon cancer, playing an essential role in ferroptosis. This study provides a foundation for subsequent research on ferroptosis in colon cancer.

Histone Lactylation Boosts Reparative Gene Activation Post-Myocardial Infarction.

BACKGROUND: Inflammation resolution and cardiac repair initiation after myocardial infarction (MI) require timely activation of reparative signals. Histone lactylation confers macrophage homeostatic gene expression signatures via transcriptional regulation. However, the role of histone lactylation in the repair response post-MI remains unclear. We aimed to investigate whether histone lactylation induces reparative gene expression in monocytes early and remotely post-MI. METHODS: Single-cell transcriptome data indicated that reparative genes were activated early and remotely in bone marrow and circulating monocytes before cardiac recruitment. Western blotting and immunofluorescence staining revealed increases in histone lactylation levels, including the previously identified histone H3K18 lactylation in monocyte-macrophages early post-MI. Through joint CUT&Tag and RNA-sequencing analyses, we identified Lrg1, Vegf-a, and IL-10 as histone H3K18 lactylation target genes. The increased modification and expression levels of these target genes post-MI were verified by chromatin immunoprecipitation-qPCR and reverse transcription-qPCR. RESULTS: We demonstrated that histone lactylation regulates the anti-inflammatory and pro-angiogenic dual activities of monocyte-macrophages by facilitating reparative gene transcription and confirmed that histone lactylation favors a reparative environment and improves cardiac function post-MI. Furthermore, we explored the potential positive role of monocyte histone lactylation in reperfused MI. Mechanistically, we provided new evidence that monocytes undergo metabolic reprogramming in the early stage of MI and demonstrated that dysregulated glycolysis and MCT1 (monocarboxylate transporter 1)-mediated lactate transport promote histone lactylation. Finally, we revealed the catalytic effect of IL (interleukin)-1ß-dependent GCN5 (general control non-depressible 5) recruitment on histone H3K18 lactylation and elucidated its potential role as an upstream regulatory element in the regulation of monocyte histone lactylation and downstream reparative gene expression post-MI. CONCLUSIONS: Histone lactylation promotes early remote activation of the reparative transcriptional response in monocytes, which is essential for the establishment of immune homeostasis and timely activation of the cardiac repair process post-MI.

Fluorophore-conjugated 4-1BB antibody enables early detection of T-cell responses in inflammatory arthritis via NIRF imaging.

PURPOSE: We first developed a 4-1BB-targeted optical probe, named IRDye-680RD-4-1BB mAb (monoclonal antibody), and evaluated its value for the detection of 4-1BB+ activated T cells in vivo as well as the diagnosis of rheumatoid arthritis (RA) in an adjuvant-induced arthritis (AIA) mouse model. METHODS: The 4-1BB expression pattern was analysed by flow cytometry and immunofluorescence (IF) staining. The 4-1BB mAb was conjugated with IRDye-680RD NHS ester, and characterized via fluorescence spectrum. A cell-binding assay was also performed to assess the interaction of this probe with activated and naïve murine T cells. Longitudinal near-infrared fluorescence (NIRF) imaging of the probe was performed at 6, 24, 48, 72, and 96 h after probe administration. RESULTS: 4-1BB expression was highly upregulated during the pathogenesis of RA. Good colocalization was also observed between CD3 and 4-1BB by IF staining and t-SNE (T-distributed stochastic neighbour embedding) analysis, which indicates that 4-1BB was mainly expressed on T cells. Compared to the control group, a significantly higher signal was observed in the right hind paw (RP) of mice with AIA at all time points. The ex vivo biodistribution study results were consistent with the in vivo NIRF imaging results, which validated the accuracy of the region of interest (ROI) measurements. The sensitivity against 100% specificity observed in the receiver operator characteristic (ROC) curve analysis could distinguish the AIA group from the control group at all time points, indicating the value of IRDye-680RD-4-1BB mAb for RA diagnosis. CONCLUSION: We successfully developed a novel optical imaging probe, named IRDye-680RD-4-1BB mAb, for tracking 4-1BB+ activated T cells in vivo, and 4-1BB NIRF imaging is a promising strategy for noninvasively detecting the pathogenesis of RA.

Mettl14 mediates the inflammatory response of macrophages in atherosclerosis through the NF-κB/IL-6 signaling pathway.

The inflammatory response of macrophages has been reported to play a critical role in atherosclerosis. The inflammatory state of macrophages is modified by epigenetic reprogramming. m6A RNA methylation is an epigenetic modification of RNAs. However, little is known about the potential roles and underlying mechanisms of m6A modification in macrophage inflammation. Herein, we showed that the expression of the m6A modification "writer" Mettl14 was increased in coronary heart disease and LPS-stimulated THP-1 cells. Knockdown of Mettl14 promoted M2 polarization of macrophages, inhibited foam cell formation and decreased migration. Mechanistically, the expression of Myd88 and IL-6 was decreased in Mettl14 knockdown cells. Through m6A modification, Mettl14 regulated the stability of Myd88 mRNA. Furthermore, Myd88 affected the transcription of IL-6 via the distribution of p65 in nuclei rather than directly regulating the expression of IL-6 through m6A modification. In vivo, Mettl14 gene knockout significantly reduced the inflammatory response of macrophages and the development of atherosclerotic plaques. Taken together, our data demonstrate that Mettl14 plays a vital role in macrophage inflammation in atherosclerosis via the NF-κB/IL-6 signaling pathway, suggesting that Mettl14 may be a promising therapeutic target for the clinical treatment of atherosclerosis.

Cooperation between melanoma cell states promotes metastasis through heterotypic cluster formation.

Melanomas can have multiple coexisting cell states, including proliferative (PRO) versus invasive (INV) subpopulations that represent a "go or grow" trade-off; however, how these populations interact is poorly understood. Using a combination of zebrafish modeling and analysis of patient samples, we show that INV and PRO cells form spatially structured heterotypic clusters and cooperate in the seeding of metastasis, maintaining cell state heterogeneity. INV cells adhere tightly to each other and form clusters with a rim of PRO cells. Intravital imaging demonstrated cooperation in which INV cells facilitate dissemination of less metastatic PRO cells. We identified the TFAP2 neural crest transcription factor as a master regulator of clustering and PRO/INV states. Isolation of clusters from patients with metastatic melanoma revealed a subset with heterotypic PRO-INV clusters. Our data suggest a framework for the co-existence of these two divergent cell populations, in which heterotypic clusters promote metastasis via cell-cell cooperation.

A Wet Gas Metering System Based on the Extended-Throat Venturi Tube.

Although the use of a classical Venturi tube for wet gas metering has been extensively studied in the literature, the use of an extended-throat Venturi (ETV) tube has rarely been reported since its first proposal by J. R. Fincke in 1999. The structure of an ETV is very simple, but due to the complexity of multiphase flow, its theoretical model has not been fully established yet. Therefore, in this paper theoretical models have been developed for the convergent and throat sections of an ETV, and the gradients of front and rear differential pressures are derived analytically. Several flowrate algorithms have been proposed and compared with the existing ones. Among them, the iteration algorithm is found to be the best. A reasonable explanation is provided for its performance. The relationship between the differential pressure gradient and the flowrate relative error is also studied, such that the relative error distributions varying with ETV measured flowrates can be derived. The gas flowrate error of ETV increases with the liquid content whilst the liquid flowrate error of ETV decreases with the liquid content, and the relative errors of liquid flowrate are generally 2 to 3 times larger than that of the gas flowrate. Finally, the ETV tends to be more accurate than the classical Venturi tube. The ETV can be designed more compact under the same signal intensity due to its significantly higher velocity in the throat section.

CNN-Based Volume Flow Rate Prediction of Oil-Gas-Water Three-Phase Intermittent Flow from Multiple Sensors.

In this paper, we propose a deep-learning-based method using a convolutional neural network (CNN) to predict the volume flow rates of individual phases in the oil-gas-water three-phase intermittent flow simultaneously by analyzing the measurement data from multiple sensors, including a temperature sensor, a pressure sensor, a Venturi tube and a microwave sensor. To build datasets, a series of experiments for the oil-gas-water three-phase intermittent flow in a horizontal pipe, in which gas volume fraction and water-in-liquid ratio ranges are 23.77-94.45% and 14.95-86.97%, respectively, and gas flow superficial velocity and liquid flow superficial velocity ranges are 0.66-5.23 and 0.27-2.14 m/s, respectively, have been carried out on a test loop pipeline. The preliminary results indicate that the model can provide relative prediction errors on the testing-1 dataset for the volume flow rates of oil-phase, gas-phase and water-phase within ±10% with 94.49%, 92.56% and 95.71% confidence levels, respectively. Additionally, the prediction results on the testing-2 dataset also demonstrate the generalization ability of the model. The consuming time of a prediction with one sample is 0.43 s on an Intel Xeon CPU E5-2678 v3, and 0.01 s on an NVIDIA GeForce GTX 1080 Ti GPU. Hence, the proposed CNN-based prediction model, which can fulfill the real-time application requirements in the petroleum industry, reveals the potential of using deep learning to obtain accurate results in the multiphase flow measurement field.

Methotrexate Therapy Promotes Cell Coverage and Stability in in-Stent Neointima.

PURPOSE: Anti-proliferative drugs released from drug-eluting stents delay cell coverage and vascular healing, which increases the risk of late stent thrombosis. We assessed the potential effects of systemic methotrexate (MTX) on cell coverage, vascular healing and inflammation activation in vivo and in vitro. METHODS: We applied MTX in the right common carotid artery in a rabbit stenting model to determine the impact on cell coverage and inflammation activation using a serial optical coherence tomography (OCT) analysis and elucidated the molecular mechanism of MTX in human umbilical vein endothelial cells (HUVECs). RESULTS: Low-dose MTX promoted the development of cell coverage and vascular healing, which was associated with fewer uncovered struts (%) and cross-sections with any uncovered struts (%) at 4 weeks of stenting. The MTX group also exhibited lower rates of heterogeneity, microvessels and per-strut low-signal-intensity layers, indicating neointimal instability at 12 weeks of stenting. In vitro, low-dose MTX strongly inhibited HUVEC apoptosis, promoted proliferation and inhibited inflammatory activation by targeting the phosphoinositide 3-kinase (PI3K)/AKT signalling pathway. CONCLUSION: Low-dose MTX may be a key means of promoting early cell coverage via the inhibition of the inflammatory response and stability of neointima by targeting inflammatory pathways after stent implantation.

Feasibility and effect of a guided self-disclosure intervention designed to facilitate benefit finding in breast cancer patients: A pilot study.

PURPOSE: This pilot study aimed to evaluate the feasibility and effect of a guided self-disclosure intervention (GSDI) promoting benefit finding (BF) for breast cancer patients. METHODS: A total of 40 women with breast cancer were randomized either to a GSDI group, which included a 6-session face-to-face self-disclosure intervention, or to a control group. The Benefit Finding Scale (BFS) was used to measure BF, the Distress Disclosure Index (DDI) was used to measure self-disclosure, and the Impact of Event Scale-Revised (IES-R) was used to measure cognitive reappraisal. The outcomes were evaluated at baseline and the 3rd and 6th months. RESULTS: The GSDI group had more satisfaction (t = 2.35, P = .02) than the control group and had significant group effects of higher BF (t = 2.214, P = .03) and a lower avoidance of the IES-R (t = -2.353, P = .024) at the 3rd month. There was a significant difference of BF (t = 2.036, P = .049) between the two groups at the 6th month, and other outcomes were not significant (P > .05). Intention-to treat (ITT) analysis showed significant time effects for all outcomes (P < .05); there were slightly significant time × group effects for BF (F = 4.15, P = .052) and disclosure (F = 2.719, P = .090). There were no time × group effects for the other outcomes (all P > .05). CONCLUSION: This study suggests that the GSDI intervention may be feasible in the clinic and might improve BF for breast cancer patients. However, future research needs to further refine the intervention and expand the sample to carry out a full-scale randomized controlled trial.

Revisiting Tumors and the Cardiovascular System: Mechanistic Intersections and Divergences in Ferroptosis.

Ferroptosis was recently identified as an iron-dependent regulatory necrosis process mediated by polyunsaturated fatty acid (PUFA) peroxidation. The pivotal events related to oxidative stress in ferroptosis include direct or indirect glutathione peroxidase 4 (GPX4) inhibition, ferrous iron overload, and lipid peroxidation. The links between ferroptosis and multiple pathological processes including tumor and cardiovascular system disease have become increasingly apparent, and the mechanisms and compounds involved in ferroptosis, such as reduction of coenzyme Q10 (ubiquinone/CoQ10), are gradually emerging. Current reports have revealed crossroads between ferroptosis and other multiple responses. This overview of the current research illuminates the mechanisms involving ferroptosis-related compounds and emphasizes the crosstalk between ferroptosis and other responses, including mitochondrial damage, endoplasmic reticulum stress (ER stress), autophagy, and the release of damage-associated molecular patterns (DAMPs), to reveal the intersections of regulatory mechanisms. This review also outlines the discovery, characterization, and pathological relevance of ferroptosis and notes controversial elements in ferroptosis-related mechanisms, such as nuclear factor E2-related factor 2 (Nrf2), sequestosome 1 (p62/SQSTM1), and heat shock protein family A member 5 (HSPA5). We hope our inferences will supply a partial reference for disorder prevention and treatment.

Circular RNA circSnx5 Controls Immunogenicity of Dendritic Cells through the miR-544/SOCS1 Axis and PU.1 Activity Regulation.

Dendritic cells (DCs) can orchestrate either immunogenic or tolerogenic responses to relay information on the functional state. Emerging studies indicate that circular RNAs (circRNAs) are involved in immunity; however, it remains unclear whether they govern DC development and function at the transcriptional level. In this study, we identified a central role for a novel circRNA, circSnx5, in modulating DC-driven immunity and tolerance. Ectopic circSnx5 suppresses DC activation and promotes the development of tolerogenic functions of DCs, while circSnx5 knockdown promotes their activation and inflammatory phenotype. Mechanistically, circSnx5 can act as a miR-544 sponge to attenuate miRNA-mediated target depression on suppressor of cytokine signaling 1 (SOCS1) and inhibit nuclear translocation of PU.1, regulating DC activation and function. Furthermore, the main splicing factors (SFs) were identified in DCs, of which heterogeneous nuclear ribonucleoprotein (hnRNP) C was essential for circSnx5 generation. Moreover, our data demonstrated that vaccination with circSnx5-conditioned DCs prolonged cardiac allograft survival in mice and alleviated experimental autoimmune myocarditis. Taken together, our results revealed circSnx5 as a key modulator to fine-tune DC function, suggesting that circSnx5 may serve as a potential therapeutic avenue for immune-related diseases.

Comprehensive analysis of the SLC16A gene family in pancreatic cancer via integrated bioinformatics.

SLC16A family members play crucial roles in tumorigenesis and tumor progression. However, the exact role of distinct members in the SLC16A family in human pancreatic cancer remains unclear. Integrated bioinformatics analysis for the identification of therapeutic targets for certain cancers based on transcriptomics, proteomics and high-throughput sequencing could help us obtain novel information and understand potential underlying molecular mechanisms. In the present study, we investigated SLC16A family members in pancreatic cancer through accumulated data from GEO (Gene Expression Omnibus), TCGA (The Cancer Genome Atlas) and other available databases. The expression profile, clinical application significance and prognostic value of the SLC16A family for patients with pancreatic cancer were explored. SLC16A1, SLC16A3 and SLC16A13 exhibited biomarker potential for prognosis, and we further identified their related genes and regulatory networks, revealing core molecular pathways that require further investigation for pancreatic cancer.

Macrophage-Enriched lncRNA RAPIA: A Novel Therapeutic Target for Atherosclerosis.

OBJECTIVE: Despite the current antiatherosclerotic and antithrombotic therapies, the incidence of advanced atherosclerosis-associated clinical events remains high. Whether long noncoding RNAs (lncRNAs) affect the progression of atherosclerosis and whether they are potential targets for the treatment of advanced atherosclerosis are poorly understood. Approach and Results: The progression of atherosclerotic lesions was accompanied by dynamic alterations in lncRNA expression, as revealed by RNA sequencing and quantitative polymerase chain reaction. Among the dynamically changing lncRNAs, we identified a novel lncRNA, lncRNA Associated with the Progression and Intervention of Atherosclerosis (RAPIA), that was highly expressed in advanced atherosclerotic lesions and in macrophages. Inhibition of RAPIA in vivo not only repressed the progression of atherosclerosis but also exerted atheroprotective effects similar to those of atorvastatin on advanced atherosclerotic plaques that had already formed. In vitro assays demonstrated that RAPIA promoted proliferation and reduced apoptosis of macrophages. A molecular sponge interaction between RAPIA and microRNA-183-5p was demonstrated by dual-luciferase reporter and RNA immunoprecipitation assays. Rescue assays indicated that RAPIA functioned at least in part by targeting the microRNA-183-5p/ITGB1 (integrin ß1) pathway in macrophages. In addition, the transcription factor FoxO1 (forkhead box O1) could bind to the RAPIA promoter region and facilitate the expression of RAPIA. CONCLUSIONS: The progression of atherosclerotic lesions was accompanied by dynamic changes in the expression of lncRNAs. Inhibition of the pivotal lncRNA RAPIA may be a novel preventive and therapeutic strategy for advanced atherosclerosis, especially in patients resistant or intolerant to statins.

Exercise enhances cardiac function by improving mitochondrial dysfunction and maintaining energy homoeostasis in the development of diabetic cardiomyopathy.

Diabetic cardiomyopathy (DCM) is a major cause of morbidity and mortality in diabetic patients. Reactive oxygen species (ROS) produced by oxidative stress play an important role in the development of DCM. DCM involves abnormal energy metabolism, thereby reducing energy production. Exercise has been reported to be effective in protecting the heart against ROS accumulation during the development of DCM. We hypothesize that the AMPK/PGC-1α axis may play a crucial role in exercise-induced bioenergetic metabolism and aerobic respiration on oxidative stress parameters in the development of diabetic cardiomyopathy. Using a streptozotocin/high-fat diet mouse to generate a diabetic model, our aim was to evaluate the effects of exercise on the cardiac function, mitochondrial oxidative capacity, mitochondrial function, and cardiac expression of PGC-1α. Mice fed a high-fat diet were given MO-siPGC-1α or treated with AMPK inhibitor. Mitochondrial structure and effects of switching between the Warburg effect and aerobic respiration were analysed. Exercise improved blood pressure and systolic dysfunction in diabetic mouse hearts. The beneficial effects of exercise were also observed in a mitochondrial function study, as reflected by an enhanced oxidative phosphorylation level, increased membrane potential, and decreased ROS level and oxygen consumption. On the other hand, depletion of PGC-1α attenuated the effects of exercise on the enhancement of mitochondrial function. In addition, PGC-1α may be responsible for reversing the Warburg effect to aerobic respiration, thus enhancing mitochondrial metabolism and energy homoeostasis. In this study, we demonstrate the protective effects of exercise on shifting energy metabolism from fatty acid oxidation to glucose oxidation in an established diabetic stage. These data suggest that exercise is effective at ameliorating diabetic cardiomyopathy by improving mitochondrial function and reducing metabolic disturbances.

MicroRNA-124: An emerging therapeutic target in cancer.

MicroRNAs (miRNAs) are noncoding single-stranded RNAs, approximately 20-24 nucleotides in length, known as powerful posttranscriptional regulators. miRNAs play important regulatory roles in cellular processes by changing messenger RNA expression and are widely involved in human diseases, including tumors. It has been reported in the literature that miRNAs have a precise role in cell proliferation, programmed cell death, differentiation, and expression of coding genes. MicroRNA-124 (miR-124) has reduced exparession in various human neoplasms and is believed to be related to the occurrence, development, and prognosis of malignant tumors. In our review, we focus on the specific molecular functions of miR-124 and the downstream gene targets in major cancers, which provide preclinical evidence for the treatment of human cancer. Although some obstacles exist, miR-124 is still attracting intensive research focus as a promising and effective anticancer weapon.

Metabolic reprogramming orchestrates CD4+ T-cell immunological status and restores cardiac dysfunction in autoimmune induced-dilated cardiomyopathy mice.

Cellular autoimmune responses, especially those mediated by T-cells, play vital roles in the immunopathogenesis of dilated cardiomyopathy (DCM). Metabolic reprogramming directly controls T-cell function, imprinting distinct functional fates. However, its contribution to T-cell dysfunction and the immunopathogenesis of DCM is unknown. Here, we found that in DCM patients, CD4+ T-cells exhibited immune dysfunction and glycolytic metabolic reprogramming based on extracellular acidification and oxygen consumption rates. Similar results were observed in splenic and cardiac CD4+ T-cells from autoimmune-induced DCM mice. In vitro, the glycolysis inhibitor 2-deoxy-d-glucose (2-DG) reversed T-cell dysfunction; thus, heightened metabolic activity directly controls CD4+ T-cell immunological status. Adoptive transfer of CD4+ T-cells from DCM mice to normal recipients induced cardiac remodeling and cardiac T-cell dysfunction. Strikingly, these effects were abolished by preconditioning cells with 2-DG, indicating that CD4+ T-cell dysfunction partially induced by metabolic reprogramming contributes to cardiac remodeling. Moreover, the microRNA let-7i modulated the metabolism and function of T-cells from DCM mice by directly targeting Myc. Collectively, our results show that metabolic reprogramming occurs in T-cells of autoimmune-induced DCM mice and patients. Further, our findings highlight that glycolytic metabolism is a critical contributor to T-cell dysfunction and DCM immunopathogenesis. Our data position the modulation of the metabolism as a central integrator for T-cell function, representing a promising strategy against autoimmune-mediated DCM progression.

Knockdown of NEAT1 induces tolerogenic phenotype in dendritic cells by inhibiting activation of NLRP3 inflammasome.

Rationale: Tolerogenic dendritic cells (tol-DCs) play essential roles in immune-related diseases and induce immune tolerance by shaping T-cell responses. Accumulating evidence suggests that long noncoding RNAs (lncRNAs) play important regulatory roles in the immune system. However, the potential roles and underlying mechanisms of lncRNAs in tol-DCs remain unclear. Methods: RNA in-situ hybridization, histochemistry, and qRT-PCR were performed to determine the distribution and expression of NEAT1 in DCs. Flow cytometry was used to analyze the tolerogenic function of DCs. Small sequencing, followed by bioinformatic analysis, was performed to determine the target genes of NEAT1. The mechanism of NEAT1 was explored using a luciferase reporter, chromatin immunoprecipitation assays, and Immunofluorescence. In-vivo experiments were used to investigate the induction of immune tolerance via NEAT1-knockdown DCs. Results: Our results show that lncRNA NEAT1 can induce tolerogenic phenotype in DCs. Mechanistically, small RNA-seq analysis revealed that NEAT1 knockdown preferentially affected the expression of miR-3076-3p. Furthermore, NEAT1 used the NLRP3 inflammasome as a molecular decoy for miR-3076-3p, thus facilitating the expression of tolerogenic phenotype in DCs. Moreover, the transcription factor E2F1 acted as a repressor of NEAT1 transcription via activity of H3K27ac. Our results also indicate that NEAT1 knockdown in DCs can induce immune tolerance in models of experimental autoimmune myocarditis and heart transplantation. Conclusions: Taken together, our study shows the mechanism used by NEAT1 in inducing tol-DCs and highlights the therapeutic potential of targeting NEAT1 for the treatment of immune-related diseases.