Objective Energy metabolism plays a crucial role in the improvement of heart dysfunction as well as the development of heart failure (HF). The current study is designed to identify energy metabolism-related diagnostic biomarkers for predicting the risk of HF due to myocardial infarction. Methods Transcriptome sequencing data of HF patients and non-heart failure (NF) people (GSE66360 and GSE59867) were obtained from gene expression omnibus (GEO) database. Energy metabolism-related differentially expressed genes (DEGs) were screened between HF and NF samples. The subtyping consistency analysis was performed to enable the samples to be grouped. The immune infiltration level among subtypes was assessed by single sample gene set enrichment analysis (ssGSEA). Random forest algorithm (RF) and support vector machine (SVM) were applied to identify diagnostic biomarkers, and the receiver operating characteristic curves (ROC) was plotted to validate the accuracy. Predictive nomogram was constructed and validated based on the result of the RF. Drug screening and gene-miRNA network were analyzed to predict the energy metabolism-related drugs and potential molecular mechanism. Results A total of 22 energy metabolism-related DEGs were identified between HF and NF patients. The clustering analysis showed that HF patients could be classified into two subtypes based on the energy metabolism-related genes, and functional analyses demonstrated that the identified DEGs among two clusters were mainly involved in immune response regulating signaling pathway and lipid and atherosclerosis. ssGSEA analysis revealed that there were significant differences in the infiltration levels of immune cells between two subtypes of HF patients. Random-forest and support vector machine algorithm eventually identified ten diagnostic markers (MEF2D, RXRA, PPARA, FOXO1, PPARD, PPP3CB, MAPK14, CREB1, MEF2A, PRMT1) for risk prediction of HF patients, and the proposed nomogram resulted in good predictive performance (GSE66360, AUC = 0.91; GSE59867, AUC = 0.84) and the clinical usefulness in HF patients. More importantly, 10 drugs and 15 miRNA were predicted as drug target and hub miRNA that associated with energy metabolism-related genes, providing further information on clinical HF treatment. Conclusion This study identified ten energy metabolism-related diagnostic markers using random forest algorithm, which may help optimize risk stratification and clinical treatment in HF patients.

https://www.frontiersin.org/articles/10.3389/fcvm.2022.993142/pdf

Identification of energy metabolism-related biomarkers for risk prediction of heart failure patients using random forest algorithm

Cancer is a highly heterogeneous disease that poses a serious threat to human health worldwide. Despite significant advances in the diagnosis and treatment of cancer, the prognosis and survival rate of cancer remain poor due to late diagnosis, drug resistance, and adverse reactions. Therefore, it is very necessary to study the development mechanism of cancer and formulate effective therapeutic interventions. As widely available bioactive substances, natural products have shown obvious anticancer potential, especially by targeting abnormal epigenetic changes. The main active part of garlic is organic sulfur compounds, of which diallyl trisulfide (DATS) content is the highest, accounting for more than 40% of the total composition. The garlic-derived compounds have been recognized as an antioxidant for cancer prevention and treatment. However, the molecular mechanism of the antitumor effect of garlic-derived compounds remains unclear. Recent studies have identified garlic-derived compound DATS that plays critical roles in enhancing CpG demethylation or promoting histone acetylation as an epigenetic inhibitor. Here, we review the therapeutic progress of garlic-derived compounds against cancer through epigenetic pathways.

Garlic-derived compounds: Epigenetic modulators and their antitumor effects.

Cytoplasmic lipid droplets (LDs), which are remarkably dynamic, neutral lipid storage organelles, play fundamental roles in lipid metabolism and energy homeostasis. Both the dynamic remodeling of LDs and LD-mitochondrion interactions in adipocytes are effective mechanisms to ameliorate obesity and related comorbidities. Zeaxanthin (ZEA) is a natural carotenoid and has beneficial effects on anti-obesity. However, the underlying mechanisms of ZEA on LD modulation are still unclear. In the present study, ZEA efficiently inhibited LD accumulation and attenuated adipocyte proliferation by arresting the cell cycle. ZEA drove transcriptional alterations to reprogram a lipid oxidative metabolism phenotype in mature 3T3-L1 adipocytes. ZEA significantly decreased the TAG and FA content and modulated the dynamic alterations of LDs by upregulating the expression of lipases and the LD-mitochondrion contact site protein, perilipin 5 (PLIN5), and downregulating the LD fusion protein, fat-specific protein 27 (FSP27). Mechanistically, ZEA stimulated LD remodeling and ameliorated mitochondrial defects caused by large and unilocular LD accumulation by activating β3-adrenergic receptor (β3-AR) signaling. Furthermore, the knockdown of PLIN5 impaired the LD-mitochondrion interactions, thereby disrupting the role of ZEA in promoting mitochondrial fatty acid oxidation and respiratory chain operation. Collectively, the present study demonstrates that ZEA induces LD structural and metabolic remodeling by activating β3-AR signaling and enhances PLIN5-mediated LD-mitochondrion interactions in hypertrophic white adipocytes, thereby enhancing oxidative capacity, and has the potential as a nutritional intervention for the prevention and treatment of obesity and associated metabolic syndrome.

Zeaxanthin remodels cytoplasmic lipid droplets via β3-adrenergic receptor signaling and enhances perilipin 5-mediated lipid droplet-mitochondrion interactions in adipocytes.

Exosomes, a subset of small extracellular vesicles that play a crucial role in intercellular communication, have garnered significant attention for their potential applications in the diagnosis and treatment of cardiomyopathies. Cardiomyopathies, which encompass a spectrum of heart muscle disorders, present complex challenges in diagnosis and management. Understanding the role of exosomes in the etiology of cardiomyopathies such as dilated cardiomyopathy (DCM), restrictive cardiomyopathy (RCM), arrhythmogenic cardiomyopathy (AC), and hypertrophic cardiomyopathy (HCM) may open new possibilities for therapeutic intervention and diagnosis. Exosomes have indeed demonstrated promise as diagnostic biomarkers, particularly in identifying cardiac conditions such as atrial fibrillation (AF) and in the timely classification of high-risk patients with different forms of cardiomyopathy. In DCM, exosomes have been implicated in mediating pathological responses in cardiomyocytes, potentially exacerbating disease progression. Moreover, in RCM, AC, and HCM, exosomes present significant potential as diagnostic biomarkers and therapeutic targets, offering insights into disease pathogenesis and potential avenues for intervention. Understanding the influence of exosomes on disease progression and identifying the specific molecular pathways involved in cardiomyopathy pathogenesis may significantly advance diagnostic and treatment strategies. While key findings highlight the multifaceted role of exosomes in cardiomyopathy, they also emphasize the need for further research to elucidate molecular mechanisms and translate findings into clinical practice. This review highlights the evolving landscape of exosome research in cardiomyopathies and underscores the importance of ongoing investigations to harness the full potential of exosomes in improving patient outcomes. 

Exploring the role of exosomes in the pathogenesis and treatment of cardiomyopathies: A comprehensive literature review

Maternal obesity (MO) causes maternal and fetal oxidative stress (OS) and metabolic dysfunction. We investigated whether supplementing obese mothers with resveratrol improves maternal metabolic alterations and reduces OS in the placenta and maternal and fetal liver. From weaning through pregnancy female Wistar rats ate chow (C) or a high-fat diet (MO). One month before mating until 19 days’ gestation (dG), half the rats received 20 mg resveratrol/kg/d orally (Cres and MOres). At 19dG, maternal body weight, retroperitoneal fat adipocyte size, metabolic parameters, and OS biomarkers in the placenta and liver were determined. MO mothers showed higher body weight, triglycerides and leptin serum concentrations, insulin resistance (IR), decreased small and increased large adipocytes, liver fat accumulation, and hepatic upregulation of genes related to IR and inflammatory processes. Placenta, maternal and fetal liver OS biomarkers were augmented in MO. MOres mothers showed more small and fewer large adipocytes, lower triglycerides serum concentrations, IR and liver fat accumulation, downregulation of genes related to IR and inflammatory processes, and lowered OS in mothers, placentas, and female fetal liver. Maternal resveratrol supplementation in obese rats improves maternal metabolism and reduces placental and liver OS of mothers and fetuses in a sex-dependent manner.

/pdf/resveratrol-supplementation-in-obese-pregnant-rats-improves-15uklyx2.pdf

Resveratrol Supplementation in Obese Pregnant Rats Improves Maternal Metabolism and Prevents Increased Placental Oxidative Stress

ABSTRACT Obesity is emerging as an epidemiological issue, being associated with the onset and progress of various metabolism-related disorders. Obesity is characterized by the white adipose expansion, which encounters white adipocyte hypertrophy and hyperplasia. White adipocyte hyperplasia is defined as adipogenesis with the increase in the number of the white adipocytes from the preadipocytes. Adipogenesis contributes to distributing excess triglycerides among the smaller newly formed adipocytes, reducing the number of hypertrophic adipocytes and secreting anti-inflammatory factor. Therefore, adipogenesis is emerging as a new therapeutic target for the treatment of obesity. In the present study, for a better understanding of the contribution of the alteration of the omental differentiated white adipocytes to the systemic metabolic disorders, we downloaded the mRNA expression profiles from GEO database GSE1657, 328 differentially expressed genes (DEGs) were screened between the undifferentiated preadipocytes (UNDIF) and omental differentiated white adipocytes (DIF). The contributions of the upregulated and downregulated DEGs to the system were performed via the Gene Ontology (GO) analysis, the Kyoto Encyclopedia of Genes and Genomes (KEGG) pathway analysis and Protein–Protein Interaction (PPI) network, respectively. The potential contribution of the whole altered genes in the differentiated white adipocytes was explored with the performance of Gene Set Enrichment Analysis (GSEA), especially on the GO analysis, KEGG analysis, hallmark analysis, oncogenic analysis and related miRNA analysis. The output of the current study will shed light on the new targets for the treatment of obesity and obesity-related disorders.

Analysis of the different characteristics between omental preadipocytes and differentiated white adipocytes using bioinformatics methods

It has been demonstrated that APPL1 (adaptor protein, phosphotyrosine interacting with PH domain and leucine zipper 1) is involved in the regulation of several growth-related signaling pathways and thus closely associated with the development and progression of some cancers. Diallyl trisulfide (DAT), a garlic-derived bioactive compound, exerts selective cytotoxicity to various human cancer cells through interfering with pro-survival signaling pathways. However, whether and how DAT affects survival of human hepatocellular carcinoma (HCC) cells remain unclear. Herein, we tested the hypothesis of the involvement of APPL1 in DAT-induced cytotoxicity in HCC HepG2 cells. We found that Lys 63 (K63)-linked polyubiquitination of APPL1 was significantly decreased whereas phosphorylation of APPL1 at serine residues remained unchanged in DAT-treated HepG2 cells. Compared with wild-type APPL1, overexpression of APPL1 K63R mutant dramatically increased cell apoptosis and mitigated cell survival, along with a reduction of phosphorylation of STAT3, Akt, and Erk1/2. In addition, DAT administration markedly reduced protein levels of intracellular TNF receptor-associated factor 6 (TRAF6). Genetic inhibition of TRAF6 decreased K63-linked polyubiquitination of APPL1. Moreover, the cytotoxicity impacts of DAT on HepG2 cells were greatly attenuated by overexpression of wild-type APPL1. Taken together, these results suggest that APPL1 polyubiquitination probably mediates the inhibitory effects of DAT on survival of HepG2 cells by modulating STAT3, Akt, and Erk1/2 pathways.

https://www.kjpp.net/journal/download_pdf.php?doi=10.4196/kjpp.2022.26.6.457

Involvement of adaptor protein, phosphotyrosine interacting with PH domain and leucine zipper 1 in diallyl trisulfide-induced cytotoxicity in hepatocellular carcinoma cells

Iron overload has been demonstrated to be associated with insulin resistance, iron overload cardiomyopathy (IOC). Brown adipose tissue (BAT) is emerging as a novel therapeutic target for the treatment of various diseases, not only because of its capacity for dissipating excess energy via nonshivering thermogenesis, but also because of its implication in the physiologic and pathophysiologic processes. However, little attention has been devoted to the precise alterations and impacts of iron overload-BAT. We conducted RNA-Seq analysis on BAT samples obtained from mice subjected to a high iron diet (HID) or a normal chow diet (CON), respectively. The RNA-seq transcriptomic analysis revealed that 1289 differentially expressed RNAs (DEGs) were identified, with a higher number of the downregulated genes (910 genes) compared to the upregulated genes (379 genes). The results of Gene Ontology (GO) and The Kyoto Encyclopedia of Genes and Genomes (KEGG) analysis indicated that the downregulated DEGs were primarily involved in hypertrophic cardiomyopathy, dilated cardiomyopathy, which were defined as IOC under the iron overload condition. The association between iron overload-BAT with cardiomyopathy was further investigated using exosome coculture technology. Our results demonstrated that the exosomes derived from ferric citrate treated-mature HIB 1B brown adipocytes, could be internalized by HL-1 cardiomyocytes, and contributed to the dysfunction in these cells. The present study has revealed the alteration and impact of iron overload-BAT, particularly on the onset of IOC via not only RNA-seq but also exosomes coculture technology. The outputs might shed light on the novel therapeutic strategies for the treatment of IOC. 

Revealing the Contribution of Iron Overload-Brown Adipocytes to Iron Overload Cardiomyopathy: Insights from RNA-seq and Exosomes Coculture Technology.

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Analysis of the different characteristics between omental preadipocytes and differentiated white adipocytes using bioinformatics methods

Involvement of adaptor protein, phosphotyrosine interacting with PH domain and leucine zipper 1 in diallyl trisulfide-induced cytotoxicity in hepatocellular carcinoma cells

Revealing the Contribution of Iron Overload-Brown Adipocytes to Iron Overload Cardiomyopathy: Insights from RNA-seq and Exosomes Coculture Technology.