Macrophage-Related Genes Biomarkers in Left Ventricular Remodeling Induced by Heart Failure.

BACKGROUND: Elevated left ventricular mass index contributes to morbidity and mortality induced by heart failure and M2 macrophages play a critical role in left ventricular remodeling. Here, our aim was to investigate the roles of M2 macrophage-related genes in heart failure. METHODS: GSE10161 was downloaded and the abundance of immune cells were estimated utilizing the CIBERSORT algorithm. Using the limma test and correlation analysis, differentially expressed plasm B cells and M2 macrophages-related genes (DEBRGs and DEMRGs) were documented. Functional pathways and the protein-protein interaction network were analyzed and the hub DEMRGs were obtained. The hub DEMRGs and their interactions were analyzed using NetworkAnalyst 3.0 and for validation, the hub DEMRGs expressions were analyzed using the GSE135055, GSE116250 and GSE74144 datasets. RESULTS: 103 differentially expressed genes were correlated with the abundance of M2 Macrophages and were identified as DEMRGs (PCC >0.4), which were mainly enriched in extracellular matrix organization, cell adhesion molecule binding and postsynaptic membrane. After screening out, 5 hub DEMRGs were obtained, including FN1 (degree = 21), COL3A1 (degree = 13), COL1A2 (degree = 13), FBN1 (degree = 12), and MMP2 (degree = 11). However, no hub DEBRGs were obtained in the network. The expression patterns of the screened DEMRGs were further validated in the patients with heart failure, dilated cardiomyopathy, ischemic cardiomyopathy or hypertension. CONCLUSIONS: The results can improve our understanding of the macrophages-associated molecular mechanisms in heart failure induced by dilated cardiomyopathy, ischemic cardiomyopathy or hypertension and 5 hub DEMRGs may help prevent the adverse left ventricular remodeling to decrease mortality and morbidity.

Myocardial Infarction-Induced INSL6 Decrease Contributes to Breast Cancer Progression.

Myocardial infarction (MI) induces early-stage breast cancer progression and increases breast cancer patients' mortality and morbidity. Insulin-like peptide 6 (INSL6) overexpression can impede cardiotoxin-induced injury through myofiber regeneration, playing a significant role in MI progression. To investigate the diverse significance of INSL6 in a variety of malignant tumors, we explored INSL6 through MI GEO dataset and multiple omics data integrative analysis, such as gene expression level, enriched pathway analysis, protein-protein interaction (PPI) analysis, and immune subtypes as well as diagnostic value and prognostic value in pancancer. INSL6 expression was downregulated in the MI group, and overall survival analysis demonstrated that INSL6 could be the prognostic biomarkers in the overall survival of breast cancer (BRCA). INSL6 expression differs significantly not only in most cancers but also in different molecular and immune subtypes of cancers. INSL6 might be a potential diagnostic and prognostic biomarker of cancers due to the high accuracy in diagnostic and prognostic value. Furthermore, we focused on BRCA and further investigated INSL6 from the perspective of the correlations with clinical characteristics, prognosis in different clinical subgroups, coexpression genes, and differentially expressed genes (DEGs) and PPI analysis. Overall survival and disease-specific survival analysis of subgroups in BRCA demonstrated that lower INSL6 expression had a worse prognosis. Therefore, INSL6 aberrant expression is associated with the progression and immune cell infiltration of the tumor, especially in KIRP and BRCA. Therefore, INSL6 may serve as a potential prognostic biomarker and the crosstalk between MI and tumor progression.

ACT001 inhibited CD133 transcription by targeting and inducing Olig2 ubiquitination degradation.

Lung cancer is the most lethal malignancies with high aggressive and poor prognosis. Until now, the five-year survival rate has not been improved which brings serious challenge to human health. Lung cancer stem cells (LCSCs) serve as the root of cancer occurrence, progression, recurrence, and drug resistance. Therefore, effective anti-cancer agents and molecular mechanisms which could specifically eliminate LCSCs are urgently needed for drug design. In this article, we discovered Olig2 was overexpressed in clinical lung cancer tissues and acted as a transcription factor to regulate cancer stemness by regulating CD133 gene transcription. The results suggested Olig2 could be a promising target in anti-LCSCs therapy and new drugs targeted Olig2 may exhibit excellent clinical results. Furthermore, we verified ACT001, a guaianolide sesquiterpene lactone in phase II clinical trial with excellent glioma remission, inhibited cancer stemness by directly binding to Olig2 protein, inducing Olig2 ubiquitination degradation and inhibiting CD133 gene transcription. All these results suggested that Olig2 could be an excellent druggable target in anti-LCSCs therapy and lay a foundation for the further application of ACT001 in the treatment of lung cancer in clinical.

Ferroptosis and Autophagy-Related Genes in the Pathogenesis of Ischemic Cardiomyopathy.

Background: Obesity plays an important role in type 2 diabetes mellitus (T2DM) and myocardial infarction (MI). Ferroptosis and ferritinophagy are related to metabolic pathways, such as fatty acid metabolism and mitochondrial respiration. We aimed to investigate the ferroptosis- and autophagy-related differentially expressed genes (DEGs) that might be potential targets for MI progression. Methods: GSE116250 was analyzed to obtain DEGs. A Venn diagram was used to obtain the overlapping ferroptosis- and autophagy-related DEGs. The enrichment pathway analysis was performed and the hub genes were obtained. Pivotal miRNAs, transcription factors, and drugs with the hub genes interactions were also predicted. The MI mice model was constructed, and qPCR analysis and single-cell sequencing were used to validate the hub genes. Results: Utilizing the limma package and the Venn diagram, 26 ferroptosis-related and 29 autophagy-related DEGs were obtained. The list of ferroptosis-related DEGs was analyzed, which were involved in the cellular response to a toxic substance, cellular oxidant detoxification, and the IL-17 signaling pathway. The list of autophagy-related DEGs was involved in the regulation of autophagy, the regulation of JAK-STAT signaling pathway, and the regulation of MAPK cascade. In the protein-protein interaction network, the hub DEGs, such as IL-6, PTGS2, JUN, NQO1, NOS3, LEPR, NAMPT, CDKN2A, CDKN1A, and Snai1, were obtained. After validation using qPCR analysis in the MI mice model and single-cell sequencing, the 10 hub genes can be the potential targets for MI deterioration. Conclusion: The screened hub genes, IL-6, PTGS2, JUN, NQO1, NOS3, LEPR, NAMPT, CDKN2A, CDKN1A, and Snai1, may be therapeutic targets for patients with MI and may prevent adverse cardiovascular events.

Macrophages-Related Genes Biomarkers in the Deterioration of Atherosclerosis.

Background: The macrophages are involved in all stages of cardiovascular diseases, demonstrating the correlation between inflammation, atherosclerosis, and myocardial infarction (MI). Here, we aim to investigate macrophages-related genes in the deterioration of atherosclerosis. Methods: GSE41571 was downloaded and the abundance of immune cells was estimated by utilizing the xCell. By utilizing the limma test and correlation analysis, differentially expressed macrophages-related genes (DEMRGs) were documented. The functional pathways and the protein-protein interaction (PPI) network were analyzed and the hub DEMRGs were obtained. The hub DEMRGs and their interactions were analyzed using NetworkAnalyst 3.0 and for validation, the expressions of hub DEMRGs were analyzed using the GSE135055 and GSE116250 datasets as well as atherosclerosis and MI mice model. Results: A total of 509 differentially expressed genes (DEGs) were correlated with the abundance of macrophages and were identified as DEMRGs (Pearson correlation coefficients (PCC) > 0.6), which were mainly enriched in extracellular structure organization, lysosomal membrane, MHC protein complex binding, and so on. After screening out, 28 hub DEMRGs were obtained with degrees ≥20, including GNAI1 (degree = 113), MRPS2 (degree = 56), HCK (degree = 45), SOCS3 (degree = 40), NET1 (degree = 28), and so on. After validating using Gene Expression Omnibus (GEO) datasets and the atherosclerosis and MI mice model, eight proteins were validated using ApoE-/- and C57 mice. The expression levels of proteins, including SYNJ2, NET1, FZD7, LCP2, HCK, GNB2, and PPP4C were positively correlated to left ventricular ejection fraction (LVEF), while that of EIF4EBP1 was negatively correlated to LVEF. Conclusion: The screened hub DEMRGs, SYNJ2, NET1, FZD7, LCP2, HCK, GNB2, EIF4EBP1, and PPP4C, may be therapeutic targets for treatment and prediction in the patients with plaque progression and MI recurrent events. The kit of the eight hub DEMRGs may test plaque progression and MI recurrent events and help in the diagnosis and treatment of MI-induced heart failure (HF), thus decreasing mortality and morbidity.

Alpha-lipoic acid impedes myocardial ischemia-reperfusion injury, myocardial apoptosis, and oxidative stress by regulating HMGB1 expression.

BACKGROUND: Inflammation, oxidative stress, and apoptosis contribute to myocardial ischemia/reperfusion injury (I/RI). Alpha-lipoic acid (ALA) plays a critical role in I/RI by impeding apoptosis and inflammation. Here, we aimed to explore the underlying mechanisms of ALA after I/RI. METHODS: The left anterior descending coronary artery (LAD) was ligated, and H9c2 cells were exposed to hypoxia/reoxygenation (H/R) to establish an I/RI model. Prior to this, H9c2 cells and rats were treated using an appropriate amount of ALA. The cardiac function, inflammatory factors, and myocardial pathology were assessed in vitro. We detected cell viability, apoptosis, and oxidative stress-related factors in vivo. Moreover, proteins of the HMGB1/TLR4/NF-κB signaling pathway were detected both in vivo and in vitro. RESULTS: We observed that ALA increased cell viability in vitro and decreased apoptosis in vitro and in vivo. ALA inhibited reactive oxygen species production, decreased malondialdehyde, and increased superoxide dismutase activity to resist oxidative stress in vitro. ALA also reduced the expression of inflammatory cytokines (IL-6, IL-1ß, and TNF-α) in vivo. ALA also suppressed the levels of the apoptotic protein, Bax, and increased the expression of the anti-apoptotic protein Bcl-2, in vitro and in vivo. Moreover, we observed that ALA significantly inhibited the cytoplasmic localization of HMGB1, which might attenuate MI/RI or H/R via HMGB1/TLR4/NF-κB pathway. CONCLUSION: ALA regulates HMGB1 translocation and attenuates I/R via the HMGB1/TLR4/NF-κB signaling pathway, thus impeding apoptosis, oxidation, and inflammation, and might be a potential target for myocardial ischemia/reperfusion injury.

The Key Genes Underlying Pathophysiology Association between Plaque Instability and Progression of Myocardial Infarction.

Young patients with type 2 diabetes and myocardial infarction (MI) have higher long-term all-cause and cardiovascular mortality. In addition, the observed increased, mildly abnormal baseline lipid levels, but not lipid variability, are associated with an increased risk of atherosclerotic cardiovascular disease events, particularly MI. This study investigated differentially expressed genes (DEGs), which might be potential targets for young patients with MI and a high-fat diet (HFD). GSE114695 and GSE69187 were downloaded and processed using the limma package. A Venn diagram was applied to identify the same DEGs, and further pathway analysis was performed using Metascape. Protein-protein interaction (PPI) network analysis was then applied, and the hub genes were screened out. Pivotal miRNAs were predicted and validated using the miRNA dataset in GSE114695. To investigate the cardiac function of the screened genes, an MI mouse model, echocardiogram, and ELISA of hub genes were applied, and a correlation analysis was also performed. From aged mice fed HFD, 138 DEGs were extracted. From aged mice fed with chow, 227 DEGs were extracted. Pathway enrichment analysis revealed that DEGs in aging mice fed HFD were enriched in lipid transport and lipid biosynthetic process 1 d after MI and in the MAPK signaling pathway at 1 w after MI, suggesting that HFD has less effect on aging with MI. A total of 148 DEGs were extracted from the intersection between plaques fed with HFD and chow in young mice and MI_1d, respectively, which demonstrated increased inflammatory and adaptive immune responses, in addition to myeloid leukocyte activation. A total of 183 DEGs were screened out between plaques fed with HFD vs. chow in young mice and MI_1w, respectively, which were mainly enriched in inflammatory response, cytokine production, and myeloid leukocyte activation. After validation, PAK3, CD44, CD5, SOCS3, VAV1, and PIK3CD were demonstrated to be negatively correlated with LVEF; however, P2RY1 was demonstrated to be positively correlated. This study demonstrated that the screened hub genes may be therapeutic targets for treating STEMI patients and preventing MI recurrence, especially in young MI patients with HFD or diabetes.

PIK3R1, SPNB2, and CRYAB as Potential Biomarkers for Patients with Diabetes and Developing Acute Myocardial Infarction.

BACKGROUND: Young patients with type 2 diabetes mellitus (DM) and acute myocardial infarction (AMI) have high long-term all-cause and cardiovascular mortality rates. We aimed to investigate the differentially expressed genes (DEGs) that might be potential targets for DM patients with AMI. METHODS: Gene datasets GSE775, GSE19322, and GSE97494 were meta-analyzed to obtain DEGs of the left ventricle myocardium in infarcted mice. Gene datasets including GSE3313, GSE10617, and GSE136948 were meta-analyzed to identify DEGs in diabetes mice. A Venn diagram was used to obtain the overlapping DEGs. KEGG and GO pathway analyses were performed, and hub genes were obtained. Pivotal miRNAs were predicted and validated using the miRNA dataset in GSE114695. To investigate the cardiac function of the screened genes, a MI mouse model was constructed; echocardiogram, qPCR, and ELISA of hub genes were performed; ELISA of hub genes in human blood samples was also utilized. RESULTS: A total of 67 DEGs were identified, which may be potential biomarkers for patients with DM and AMI. GO and KEGG pathway analyses were performed, which were mainly enriched in response to organic cyclic compound and PI3K-Akt signaling pathway. The expression of PIK3R1 and SPNB2 increased in the MI group and was negatively correlated to left ventricular ejection fraction (LVEF), whereas that of CRYAB decreased and was positively correlated to LVEF. Patients with high CRYAB expression demonstrated a short hospital stay and the area under the curves of the three protein levels before and after treatment were 0.964, 0.982, and 0.918, suggesting that PIK3R1, SPNB2, and CRYAB may be diagnostic and prognostic biomarkers for the diabetes patients with AMI. CONCLUSION: The screened hub genes, PIK3R1, SPNB2, and CRYAB, were validated as credible molecular biomarkers and may provide a novel therapy for diabetic cardiac diseases with increased proteotoxic stress.