Dectin-1 Acts as a Non-Classical Receptor of Ang II to Induce Cardiac Remodeling.

BACKGROUND: Cardiac remodeling in heart failure involves macrophage-mediated immune responses. Recent studies have shown that a PRR (pattern recognition receptor) called dectin-1, expressed on macrophages, mediates proinflammatory responses. Whether dectin-1 plays a role in pathological cardiac remodeling is unknown. Here, we identified a potential role of dectin-1 in this disease. METHODS: To model aberrant cardiac remodeling, we utilized mouse models of chronic Ang II (angiotensin II) infusion. In this model, we assessed the potential role of dectin-1 through using D1KO (dectin-1 knockout) mice and bone marrow transplantation chimeric mice. We then used cellular and molecular assays to discover the underlying mechanisms of dectin-1 function. RESULTS: We found that macrophage dectin-1 is elevated in mouse heart tissues following chronic Ang II administration. D1KO mice were significantly protected against Ang II-induced cardiac dysfunction, hypertrophy, fibrosis, inflammatory responses, and macrophage infiltration. Further bone marrow transplantation studies showed that dectin-1 deficiency in bone marrow-derived cells prevented Ang II-induced cardiac inflammation and dysfunction. Through detailed molecular studies, we show that Ang II binds directly to dectin-1, causing dectin-1 homodimerization and activating the downstream Syk (spleen tyrosine kinase)/NF-κB (nuclear factor kappa B) signaling pathway to induce expression of inflammatory and chemoattractant factors. Mutagenesis studies identified R184 in the C-type lectin domain to interact with Ang II. Blocking dectin-1 in macrophages suppresses Ang II-induced inflammatory mediators and subsequent intercellular cross talk with cardiomyocytes and fibroblasts. CONCLUSIONS: Our study has discovered dectin-1 as a new nonclassical receptor of Ang II and a key player in cardiac remolding and dysfunction. These studies suggest that dectin-1 may be a new target for treating hypertension-related heart failure.

Associations of lipids and lipid-modifying drug target genes with atrial fibrillation risk based on genomic data.

BACKGROUND: The causal associations of lipids and the drug target genes with atrial fibrillation (AF) risk remain obscure. We aimed to investigate the causal associations using genetic evidence. METHODS: Mendelian randomization (MR) analyses were conducted using summary-level genome-wide association studies (GWASs) in European and East Asian populations. Lipid profiles (low-density lipoprotein cholesterol, triglyceride, and lipoprotein[a]) and lipid-modifying drug target genes (3-hydroxy-3-methylglutaryl-CoA reductase, proprotein convertase subtilisin/kexin type 9, NPC1-like intracellular cholesterol transporter 1, apolipoprotein C3, angiopoietin-like 3, and lipoprotein[a]) were used as exposures. AF was used as an outcome. The inverse variance weighted method was applied as the primary method. Summary-data-based Mendelian randomization analyses were performed for further validation using expression quantitative trait loci data. Mediation analyses were conducted to explore the indirect effect of coronary heart disease. RESULTS: In the European population, MR analyses demonstrated that elevated levels of lipoprotein(a) increased AF risk. Moreover, analyses focusing on drug targets revealed that the genetically proxied target gene LPA, which simulates the effects of drug intervention by reducing lipoprotein(a), exhibited an association with AF risk. This association was validated in independent datasets. There were no consistent and significant associations observed for other traits when analyzed in different datasets. This finding was also corroborated by Summary-data-based Mendelian randomization analyses between LPA and AF. Mediation analyses revealed that coronary heart disease plays a mediating role in this association. However, in the East Asian population, no statistically significant evidence was observed to support these associations. CONCLUSIONS: This study provided genetic evidence that Lp(a) may be a causal factor for AF and that LPA may represent a promising pharmacological target for preventing AF in the European population.

Fascinating Immobilization-Free Electrochemical Immunosensing Strategy Based on the Cooperation of Buoyancy and Magnetism.

Rapid and accurate detection of biomolecules is of vital importance for the diagnosis of disease and for performing timely treatments. The point-of-care analysis of cancer biomarkers in the blood with low cost and easy processing is still challenging. Herein, an advanced and robust strategy, which integrates the buoyant recognition probe with the magnetic reporter probe in one solution, was first proposed for immobilization-free electrochemical immunosensing. The tumor marker of alpha fetoprotein (AFP) can be captured immune-buoyantly, and then a multifunctional magnetic reporter probe in pseudo-homogeneous solution was further captured to fulfill a sandwich-type immunoreaction. The residual magnetic reporter probe can be firmly and efficiently attracted on a magnetic glassy carbon electrode to fulfill the conversion of the target AFP amount into the residual magnetic electrochemical signal indicator. As a result, the electrochemical signal of methylene blue can accurately reflect the original level of target antigen AFP concentration. By integrating buoyancy-driven quasi-homogenous biorecognition with magnetism-mediated amplification and signal output, the proposed immobilization-free electrochemical immunosensing strategy displayed a wide range of linear response (100 fg mL-1 to 10 ng mL-1), low detection limit (14.52 fg mL-1), and good reproducibility, selectivity, and stability. The designed strategy manifests remarkable advantages including assay simplicity, rapidness, and high sensitivity owing to the in-solution instead of on-electrode biorecognition that could accelerate and improve the biorecognition efficiency. To the best of our knowledge, this is the first cooperation of buoyancy-driven biorecognition with magnetism-mediated signal output in bioanalysis, which would be attractive for rapid clinic biomedical application. Thus, this work provides a fresh perspective for convenient and favorable immobilization-free electrochemical biosensing of universal biomolecules.

PKM1 Exerts Critical Roles in Cardiac Remodeling Under Pressure Overload in the Heart.

BACKGROUND: Metabolic remodeling precedes most alterations during cardiac hypertrophic growth under hemodynamic stress. The elevation of glucose utilization has been recognized as a hallmark of metabolic remodeling. However, its role in cardiac hypertrophic growth and heart failure in response to pressure overload remains to be fully illustrated. Here, we aimed to dissect the role of cardiac PKM1 (pyruvate kinase muscle isozyme 1) in glucose metabolic regulation and cardiac response under pressure overload. METHODS: Cardiac-specific deletion of PKM1 was achieved by crossing the floxed PKM1 mouse model with the cardiomyocyte-specific Cre transgenic mouse. PKM1 transgenic mice were generated under the control of tetracycline response elements, and cardiac-specific overexpression of PKM1 was induced by doxycycline administration in adult mice. Pressure overload was triggered by transverse aortic constriction. Primary neonatal rat ventricular myocytes were used to dissect molecular mechanisms. Moreover, metabolomics and nuclear magnetic resonance spectroscopy analyses were conducted to determine cardiac metabolic flux in response to pressure overload. RESULTS: We found that PKM1 expression is reduced in failing human and mouse hearts. It is important to note that cardiomyocyte-specific deletion of PKM1 exacerbates cardiac dysfunction and fibrosis in response to pressure overload. Inducible overexpression of PKM1 in cardiomyocytes protects the heart against transverse aortic constriction-induced cardiomyopathy and heart failure. At the mechanistic level, PKM1 is required for the augmentation of glycolytic flux, mitochondrial respiration, and ATP production under pressure overload. Furthermore, deficiency of PKM1 causes a defect in cardiomyocyte growth and a decrease in pyruvate dehydrogenase complex activity at both in vitro and in vivo levels. CONCLUSIONS: These findings suggest that PKM1 plays an essential role in maintaining a homeostatic response in the heart under hemodynamic stress.

Farnesyl diphosphate synthase regulated endothelial proliferation and autophagy during rat pulmonary arterial hypertension induced by monocrotaline.

BACKGROUND: The proliferation ability and autophagy level of pulmonary artery endothelial cells (PAECs) play an important role in promoting the development of pulmonary artery hypertension (PAH), and there is still no effective treatment for PAH. Farnesyl diphosphate synthase (FDPS) is a key enzyme in the mevalonate pathway. The intermediate metabolites of this pathway are closely related to the activity of autophagy-associated small G proteins, including Ras-related C3 botulinum toxin substrate 1 (Rac1). Studies have shown that the mevalonate pathway affects the activation levels of different small G proteins, autophagy signaling pathways, vascular endothelial function, and so on. However, the exact relationship between them is still unclear in PAH. METHOD: In vitro, western blotting and mRFP-GFP-LC3 puncta formation assays were used to observe the expression of FDPS and the level of autophagy in PAECs treated with monocrotaline pyrrole (MCTP). In addition, cell proliferation and migration assays were used to assess the effect of FDPS on endothelial function, and Rac1 activity assays were used to evaluate the effect of Rac1 activation on PAEC autophagy via the PI3K/AKT/mTOR signaling pathway. In vivo, the right heart catheterization method, hematoxylin and eosin (H&E) staining and western blotting were used to determine the effect of FDPS on PAEC autophagy and monocrotaline (MCT)-induced PAH. RESULTS: We show that the expression of FDPS is increased in the PAH module in vitro and in vivo, concomitant with the induction of autophagy and the activation of Rac1. Our data demonstrate that inhibition of FDPS ameliorates endothelial function and decreases MCT-induced autophagy levels. Mechanistically, we found that FDPS promotes autophagy, Rac1 activity and endothelial disfunction through the PI3K/AKT/mTOR signaling pathway. CONCLUSION: Our study suggests that FDPS contributes to active small G protein-induced autophagy during MCT-induced PAH, which may serve as a potential therapeutic target against PAH.

Rosuvastatin Reverses Hypertension-Induced Changes in the Aorta Structure and Endothelium-Dependent Relaxation in Rats Through Suppression of Apoptosis and Inflammation.

Vascular remodeling is one of the most critical complications caused by hypertension. Previous studies have demonstrated that rosuvastatin has anti-inflammatory, antioxidant, and antiplatelet effects and therefore can be used to treat cardiovascular disease. In this study, we explored the beneficial effects of rosuvastatin in reversing aortic remodeling in spontaneously hypertensive rats. After treating with different doses of rosuvastatin, its antilipid, antiapoptosis, and anti-inflammatory effects were determined. We also examined whether rosuvastatin can improve the structure and function of the aorta. We found that rosuvastatin treatment of spontaneously hypertensive rats for 2 months at 2 different doses can effectively reduce the media thickness of the aorta compared with the control group. Similarly, rosuvastatin improved the vascular relaxation function of the aortic rings at a high level of acetylcholine in vitro. Mechanistically, it was found that rosuvastatin increased the expression of endothelial nitric oxide synthase and plasma nitrite/nitrate levels. Besides, rosuvastatin suppressed the apoptosis and inflammation and upregulated the expression of gap-junction complex connexin 43 both in media and endothelium. Finally, rosuvastatin inhibited the AT1R/PKCα/HSP70 signaling transduction pathway. In summary, these findings demonstrated that rosuvastatin could improve the vascular structure and function mainly by increasing endothelial nitric oxide synthase expression and preventing apoptosis and inflammation. This study provided evidence that rosuvastatin has beneficial effects in reversing the remodeling of the aorta due to hypertension.

Ginkgolide C inhibits ROS-mediated activation of NLRP3 inflammasome in chondrocytes to ameliorate osteoarthritis.

ETHNOPHARMACOLOGICAL RELEVANCE: Ginkgo biloba, as the most widely available medicinal plant worldwide, has been frequently utilized for treat cardiovascular, cerebrovascular, diabetic and other diseases. Due to its distinct pharmacological effects, it has been broadly applications in pharmaceuticals, health products, dietary supplements, and so on. Ginkgolide C (GC), a prominent extract of Ginkgo biloba, possesses potential in anti-inflammatory and anti-oxidant efficacy. AIMS OF THE STUDY: To determine whether GC mitigated the progressive degeneration of articular cartilage in a Monosodium Iodoacetate (MIA)-induced osteoarthritis (OA) rat model by inhibiting the activation of the NLRP3 inflammasome, and the specific underlying mechanisms. MATERIALS AND METHODS: In vivo, an OA rat model was established by intra-articular injection of MIA. The protective effect of GC (10 mg/kg) on articular cartilage was evaluated. Application of ATDC5 cells to elucidate the mechanism of the protective effect of GC on articular cartilage. Specifically, the expression levels of molecules associated with cartilage ECM degrading enzymes, OS, ERS, and NLRP3 inflammasome activation were analyzed. RESULTS: In vivo, GC ameliorated MIA-induced OA rat joint pain, and exhibited remarkable anti-inflammatory and anti- ECM degradation effects via inhibition of the activation of NLRP3 inflammasome, the release of inflammatory factors, and the expression of matrix-degrading enzymes in cartilage. Mechanically, GC inhibited the activation of NLRP3 inflammasome by restraining ROS-mediated p-IRE1α and activating Nrf2/NQO1 signal path, thereby alleviating OA. The ROS scavenger NAC was as effective as GC in reducing ROS production and inhibiting the activation of NLRP3 inflammasome. CONCLUSIONS: GC have exerted chondroprotective effects by inhibiting the activation of NLRP3 inflammasome.

Andrographolide protects against atrial fibrillation by alleviating oxidative stress injury and promoting impaired mitochondrial bioenergetics. / ç©¿å¿ƒèŽ²å† é ¯é€šè¿‡ç¼“è§£æ°§åŒ–åº”æ¿€å’Œä¿ƒè¿›çº¿ç²’ä½“èƒ½é‡åˆæˆå¯¹å¿ƒæˆ¿é¢¤åŠ¨å‘æŒ¥é¢„é˜²ä½œç”¨.

Atrial fibrillation (AF) is the most prevalent cardiac arrhythmia seen in clinical settings, which has been associated with substantial rates of mortality and morbidity. However, clinically available drugs have limited efficacy and adverse effects. We aimed to investigate the mechanisms of action of andrographolide (Andr) with respect to AF. We used network pharmacology approaches to investigate the possible therapeutic effect of Andr. To define the role of Andr in AF, HL-1 cells were pro-treated with Andr for 1 h before rapid electronic stimulation (RES) and rabbits were pro-treated for 1 d before rapid atrial pacing (RAP). Apoptosis, myofibril degradation, oxidative stress, and inflammation were determined. RNA sequencing (RNA-seq) was performed to investigate the relevant mechanism. Andr treatment attenuated RAP-induced atrial electrophysiological changes, inflammation, oxidative damage, and apoptosis both in vivo and in vitro. RNA-seq indicated that oxidative phosphorylation played an important role. Transmission electron microscopy and adenosine triphosphate (ATP) content assay respectively validated the morphological and functional changes in mitochondria. The translocation of nuclear factor erythroid 2-related factor 2 (Nrf2) to the nucleus and the molecular docking suggested that Andr might exert a therapeutic effect by influencing the Keap1-Nrf2 complex. In conclusions, this study revealed that Andr is a potential preventive therapeutic drug toward AF via activating the translocation of Nrf2 to the nucleus and the upregulation of heme oxygenase-1 (HO-1) to promote mitochondrial bioenergetics.

Cardiomyocyte IL-1R2 protects heart from ischemia/reperfusion injury by attenuating IL-17RA-mediated cardiomyocyte apoptosis.

Myocardial ischemia reperfusion (I/R) injury is a complex process with intense inflammatory response and cardiomyocyte apoptosis. As a decoy receptor of IL-1ß, Interleukin-1 receptor type 2 (IL-1R2) inhibits IL-1ß signaling. However, its role in I/R injury remains unknown. Here we found that the serum levels of IL-1R2 were significantly increased in patients with acute myocardial infarction (AMI) following interventional therapy. Similarly, after myocardial I/R surgery, IL-1R2 expression was significantly increased in heart of wild-type mice. In addition, IL-1R2-deficient mice heart showed enlarged infarct size, increased cardiomyocyte apoptosis together with reduced cardiac systolic function. Following exposure to hypoxia and reoxygenation (H/R), neonatal rat ventricular myocytes (NRVM) significantly increased IL-1R2 expression relying on NF-κB activation. Consistently, IL-1R2-deficient mice increased immune cells infiltrating into heart after surgery, which was relevant with cardiac damage. Additionally, IL-1R2 overexpression in cardiomyocyte protected cardiomyocyte against apoptosis through reducing the IL-17RA expression both in vivo and in vitro. Our results indicate that IL-1R2 protects cardiomyocytes from apoptosis, which provides a therapeutic approach to turn down myocardial I/R injury.

Appraising the Causal Association between Systemic Iron Status and Heart Failure Risk: A Mendelian Randomisation Study.

Although observational studies have shown that abnormal systemic iron status is associated with an increased risk of heart failure (HF), it remains unclear whether this relationship represents true causality. We aimed to explore the causal relationship between iron status and HF risk. Two-sample Mendelian randomisation (MR) was applied to obtain a causal estimate. Genetic summary statistical data for the associations (p < 5 × 10−8) between single nucleotide polymorphisms (SNPs) and four iron status parameters were obtained from the Genetics of Iron Status Consortium in genome-wide association studies involving 48,972 subjects. Statistical data on the association of SNPs with HF were extracted from the UK biobank consortium (including 1088 HF cases and 360,106 controls). The results were further tested using MR based on the Bayesian model averaging (MR-BMA) and multivariate MR (MVMR). Of the twelve SNPs considered to be valid instrumental variables, three SNPs (rs1800562, rs855791, and rs1799945) were associated with all four iron biomarkers. Genetically predicted iron status biomarkers were not causally associated with HF risk (all p > 0.05). Sensitivity analysis did not show evidence of potential heterogeneity and horizontal pleiotropy. Convincing evidence to support a causal relationship between iron status and HF risk was not found. The strong relationship between abnormal iron status and HF risk may be explained by an indirect mechanism.

Ultrastructural and proteomic profiling of mitochondria-associated endoplasmic reticulum membranes reveal aging signatures in striated muscle.

Aging is a major risk for developing cardiac and skeletal muscle dysfunction, yet the underlying mechanism remains elusive. Here we demonstrated that the mitochondria-associated endoplasmic reticulum membranes (MAMs) in the rat heart and skeletal muscle were disrupted during aging. Using quantitative morphological analysis, we showed that the mitochondria-endoplasmic reticulum contacts (MERCs) were reduced by half over the lifespan with an early onset of accelerated thickening in the clefts. The ultrastructural changes were further validated by proteomic profiling of the MAM fractions. A combination of subcellular fractionation and quantitative mass spectrometry identified 1306 MAM-enriched proteins in both heart and skeletal muscle, with a catalog of proteins dysregulated with aging. Functional mapping of the MAM proteome suggested several aging signatures to be closely associated with the ER-mitochondria crosstalk, including local metabolic rewiring, calcium homeostasis imbalance, and impaired organelle dynamics and autophagy. Moreover, we identified a subset of highly interconnected proteins in an ER-mitochondria organization network, which were consistently down-regulated with aging. These decreased proteins, including VDAC1, SAMM50, MTX1 and MIC60, were considered as potential contributors to the age-related MAM dysfunction. This study highlights the perturbation in MAM integrity during the striated muscle aging process, and provides a framework for understanding aging biology from the perspective of organelle interactions.

Mitochondria-associated membrane-modulated Ca2+ transfer: A potential treatment target in cardiac ischemia reperfusion injury and heart failure.

Effective Ca2+ dependent mitochondrial energy supply is imperative for proper cardiac contractile activity, while disruption of Ca2+ homeostasis participates in the pathogenesis of multiple human diseases. This phenomenon is particularly prominent in cardiac ischemia and reperfusion (I/R) and heart failure, both of which require strict clinical intervention. The interface between endoplasmic reticula (ER) and mitochondria, designated the mitochondria-associated membrane (MAM), is now regarded as a crucial mediator of Ca2+ transportation. Thus, interventions targeting this physical and functional coupling between mitochondria and the ER are highly desirable. Increasing evidence supports the notion that restoration, and maintenance, of the physiological contact between these two organelles can improve mitochondrial function, while inhibiting cell death, thereby sufficiently ameliorating I/R injury and heart failure development. A better understanding regarding the underlying mechanism of MAM-mediated transport will pave the way for identification of novel treatment approaches for heart disease. Therefore, in this review, we summarize the crucial functions and potential mechanisms of MAMs in the pathogenesis of I/R and heart failure.

Downregulation of activating transcription factor 4 attenuates lysophosphatidycholine-induced inflammation via the NF-κB pathway.

Lysophosphatidycholine (LPC) is the main active component in oxidized low-density lipoprotein (ox-LDL). The pathological function of ox-LDL has been broadly studied in atherosclerosis. However, the specific relationship between LPC-induced unfolded protein response (UPR) and inflammation in human umbilical vein endothelial cells (HUVECs) remains elusive. In this study, we found elevated serum levels of LPC in atherosclerotic patients. LPC stimulation resulted in elevated secretion of interleukin (IL)-6 and IL-8 in HUVECs, accompanied with the activation of ER stress and NF-κB pathway. Additionally, suppression of ER stress by 4-phenylbutric acid (4-PBA), an ER stress inhibitor, alleviated the activation of the NF-κB pathway and secretion of inflammatory factors. Moreover, activating transcription factor 4 (ATF4) silencing inhibited the transcription and secretion of IL-6 and IL-8, and suppressed the adhesion of THP-1 cells to HUVECs. Activation of the NF-κB pathway and expression of its upstream factors, including Toll like receptor 4 and cellular inhibitor of apoptosis, were also inhibited by ATF4 silencing. The present findings suggest that suppression of UPR alleviates LPC-induced HUVECs inflammation by inhibition of NF-κB pathway, and indicate ATF4 as a potential target for the treatment of atherosclerosis.

iPLA2ß Contributes to ER Stress-Induced Apoptosis during Myocardial Ischemia/Reperfusion Injury.

Both calcium-independent phospholipase A2 beta (iPLA2ß) and endoplasmic reticulum (ER) stress regulate important pathophysiological processes including inflammation, calcium homeostasis and apoptosis. However, their roles in ischemic heart disease are poorly understood. Here, we show that the expression of iPLA2ß is increased during myocardial ischemia/reperfusion (I/R) injury, concomitant with the induction of ER stress and the upregulation of cell death. We further show that the levels of iPLA2ß in serum collected from acute myocardial infarction (AMI) patients and in samples collected from both in vivo and in vitro I/R injury models are significantly elevated. Further, iPLA2ß knockout mice and siRNA mediated iPLA2ß knockdown are employed to evaluate the ER stress and cell apoptosis during I/R injury. Additionally, cell surface protein biotinylation and immunofluorescence assays are used to trace and locate iPLA2ß. Our data demonstrate the increase of iPLA2ß augments ER stress and enhances cardiomyocyte apoptosis during I/R injury in vitro and in vivo. Inhibition of iPLA2ß ameliorates ER stress and decreases cell death. Mechanistically, iPLA2ß promotes ER stress and apoptosis by translocating to ER upon myocardial I/R injury. Together, our study suggests iPLA2ß contributes to ER stress-induced apoptosis during myocardial I/R injury, which may serve as a potential therapeutic target against ischemic heart disease.

Identification of Underlying Hub Genes Associated with Hypertrophic Cardiomyopathy by Integrated Bioinformatics Analysis.

BACKGROUND: Considered as one of the major reasons of sudden cardiac death, hypertrophic cardiomyopathy (HCM) is a common inherited cardiovascular disease. However, effective treatment for HCM is still lacking. Identification of hub gene may be a powerful tool for discovering potential therapeutic targets and candidate biomarkers. METHODS: We analysed three gene expression datasets for HCM from the Gene Expression Omnibus. Two of them were merged by "sva" package. The merged dataset was used for analysis while the other dataset was used for validation. Following this, a weighted gene coexpression network analysis (WGCNA) was performed, and the key module most related to HCM was identified. Based on the intramodular connectivity, we identified the potential hub genes. Then, a receiver operating characteristic curve analysis was performed to verify the diagnostic values of hub genes. Finally, we validated changes of hub genes, for genetic transcription and protein expression levels, in datasets of HCM patients and myocardium of transverse aortic constriction (TAC) mice. RESULTS: In the merged dataset, a total of 455 differentially expressed genes (DEGs) were identified from normal and hypertrophic myocardium. In WGCNA, the blue module was identified as the key module and the genes in this module showed a high positive correlation with HCM. Functional enrichment analysis of DEGs and key module revealed that the extracellular matrix, fibrosis, and neurohormone pathways played important roles in HCM. FRZB, COL14A1, CRISPLD1, LUM, and sFRP4 were identified as hub genes in the key module. These genes showed a good predictive value for HCM and were significantly up-regulated in HCM patients and TAC mice. We also found protein expression of LUM and sFRP4 increased in myocardium of TAC mice. CONCLUSION: This study revealed that five hub genes are involved in the occurrence and development of HCM, and they are potentially to be used as therapeutic targets and biomarkers for HCM.

The multiple function of long noncoding RNAs in osteosarcoma progression, drug resistance and prognosis.

Osteosarcoma is a bone tumor prevalent in children and young adults. LncRNAs are a family of non-protein-coding transcripts longer than 200 nucleotides. The tumor-related pathological functions of lncRNAs include proliferation, migration, and chemotherapy resistance, all of which have been widely acknowledged in research on osteosarcoma. In addition, compelling evidence suggests that lncRNAs could serve as diagnostic indicators, prognostic biomarkers, and targets for disease treatment. In this review, we systematically summarize how lncRNAs regulate tumorigenesis, invasion and therapeutic resistance. By deepening our knowledge of the relationship between lncRNAs and osteosarcoma, we hope to translate research findings into clinical applications as soon as possible.

Weighted gene co-expression network analysis identified underlying hub genes and mechanisms in the occurrence and development of viral myocarditis.

BACKGROUND: Myocarditis is an inflammatory myocardial disease, which may lead to heart failure and sudden death. Despite extensive research into the pathogenesis of myocarditis, effective treatments for this condition remain elusive. This study aimed to explore the potential pathogenesis and hub genes for viral myocarditis. METHODS: A weighted gene co-expression network analysis (WGCNA) was performed based on the gene expression profiles derived from mouse models at different stages of viral myocarditis (GSE35182). Functional annotation was executed within the key modules. Potential hub genes were predicted based on the intramodular connectivity (IC). Finally, potential microRNAs that regulate gene expression were predicted by miRNet analysis. RESULTS: Three gene co-expression modules showed the strongest correlation with the acute or chronic disease stage. A significant positive correlation was detected between the acute disease stage and the turquoise module, the genes of which were mainly enriched in antiviral response and immune-inflammatory activation. Furthermore, a significant positive correlation and a negative correlation were identified between the chronic disease stage and the brown and yellow modules, respectively. These modules were mainly associated with the cytoskeleton, phosphorylation, cellular catabolic process, and autophagy. Subsequently, we predicted the underlying hub genes and microRNAs in the three modules. CONCLUSIONS: This study revealed the main biological processes in different stages of viral myocarditis and predicted hub genes in both the acute and chronic disease stages. Our results may be helpful for developing new therapeutic targets for viral myocarditis in future research.