Transcriptional and functional analysis of plasma exosomal microRNAs in acute viral myocarditis.

AIM: To assess the differential expression profiles of exosome-derived microRNA (miRNA) and reveal their potential functions in patients with acute viral myocarditis (AVMC). MATERIALS & METHODS: Peripheral blood samples were collected from 9 patients diagnosed with AVMC and 9 healthy controls (HC) in the Affiliated Hospital of Qingdao University from July 2021 to September 2022. The exosomal miRNA expression were tested using RNA high-throughput sequencing. We conducted the GO and KEGG functional analysis to predict the potential molecular, biological functions and related signaling pathways of miRNAs in exosomes. Target genes of exosomal miRNAs were predicted and miRNA-target gene network was mapped using gene databases. Differentially expressed exosomal miRNAs were selected and their expression levels were detected by quantitative real-time polymerase chain reaction (qRT-PCR) to verify the sequencing results. RESULTS: P < 0.05 and Fold Change>2 were considered as cut-off value to screen miRNAs that were differently expressed. This study identified 14 upregulated and 14 downregulated exosome-derived miRNAs. GO and KEGG analysis showed that differentially expressed miRNAs may be related to ß-catenin binding, DNA transcription activities, ubiquitin ligase, PI3K-Akt, FoxO, P53, MAPK, and etc.. The target genes of differentially expressed miRNAs were predicted using gene databases. Real-time PCR confirmed the upregulation of hsa-miR-548a-3p and downregulation of hsa-miR-500b-5p in AVMC. CONCLUSIONS: Hsa-miR-548a-3p and hsa-miR-500b-5p could serve as a promising biomarker of AVMC. Exosomal miRNAs may have substantial roles in the mechanisms of AVMC.

Drug-target interactions prediction via deep collaborative filtering with multiembeddings.

Drug-target interactions (DTIs) prediction research presents important significance for promoting the development of modern medicine and pharmacology. Traditional biochemical experiments for DTIs prediction confront the challenges including long time period, high cost and high failure rate, and finally leading to a low-drug productivity. Chemogenomic-based computational methods can realize high-throughput prediction. In this study, we develop a deep collaborative filtering prediction model with multiembeddings, named DCFME (deep collaborative filtering prediction model with multiembeddings), which can jointly utilize multiple feature information from multiembeddings. Two different representation learning algorithms are first employed to extract heterogeneous network features. DCFME uses the generated low-dimensional dense vectors as input, and then simulates the drug-target relationship from the perspective of both couplings and heterogeneity. In addition, the model employs focal loss that concentrates the loss on sparse and hard samples in the training process. Comparative experiments with five baseline methods show that DCFME achieves more significant performance improvement on sparse datasets. Moreover, the model has better robustness and generalization capacity under several harder prediction scenarios.

Role of gut microbiota in doxorubicin-induced cardiotoxicity: from pathogenesis to related interventions.

Doxorubicin (DOX) is a broad-spectrum and highly efficient anticancer agent, but its clinical implication is limited by lethal cardiotoxicity. Growing evidences have shown that alterations in intestinal microbial composition and function, namely dysbiosis, are closely linked to the progression of DOX-induced cardiotoxicity (DIC) through regulating the gut-microbiota-heart (GMH) axis. The role of gut microbiota and its metabolites in DIC, however, is largely unelucidated. Our review will focus on the potential mechanism between gut microbiota dysbiosis and DIC, so as to provide novel insights into the pathophysiology of DIC. Furthermore, we summarize the underlying interventions of microbial-targeted therapeutics in DIC, encompassing dietary interventions, fecal microbiota transplantation (FMT), probiotics, antibiotics, and natural phytochemicals. Given the emergence of microbial investigation in DIC, finally we aim to point out a novel direction for future research and clinical intervention of DIC, which may be helpful for the DIC patients.

The effect of probiotics supplementation on cancer-treatment complications: a critical umbrella review of interventional meta-analyses.

Cancer-related complications pose significant challenges in the management and treatment of patients with malignancies. Several meta-analyses have indicated improving effects of probiotics on cancer complications, while some studies have reported contentious findings. The purpose of the present study was to evaluate the efficacy of probiotics in addressing cancer complications, including diarrhea, mucositis, and infections, following chemotherapy, radiotherapy, and surgery. Relevant studies were searched in the PubMed, Scopus, Embase and Web of Science databases and Google Scholar up to September 2023. All meta-analyses addressing the effects of probiotics on all cancer treatments-induced complications including infection, diarrhea and oral mucositis were included. The pooled results were calculated using a random-effects model. Analyses of subgroups, sensitivity and publication bias were also conducted. The results revealed that the probiotics supplementation was effective on reduction of total cancer complications (OR:0.53; 95% CI: 0.44, 0.62, p < 0.001; I2=79.0%, p < 0.001), total infection rate (OR:0.47; 95%CI: 0.41, 0.52, p < 0.001; I2= 48.8%, p < 0.001); diarrhea (OR:0.50; 95%CI: 0.44, 0.57, p < 0.001; I2=44.4%, p = 0.023) and severe diarrhea (OR: 0.4; 95%CI: 0.27, 0.56, p < 0.001; I2=31.3%, p = 0.178), oral mucositis (OR: 0.76; 95%CI: 0.58, 0.94, p < 0.001; I2=95.5%, p < 0.001) and severe oral mucositis (OR:0.65, 95%CI: 0.58, 0.72 p < 0.001; I2=22.1%, p = 0.274). Multi strain probiotic (OR:0.49; 95%CI: 0.32, 0.65, p < 0.001; I2=90.7%, p < 0.001) were more efficacious than single strain (OR:0.73; 95%CI: 0.66, 0.81, p < 0.001; I2=0.00%, p = 0.786). The findings of the current umbrella meta-analysis provide strong evidence that probiotic supplementation can reduce cancer complications.

The effect of green coffee extract supplementation on obesity indices: critical umbrella review of interventional meta-analyses.

Despite a multitude of investigations assessing the impact of green coffee extract supplementation on obesity indices, there is still a great deal of heated debate regarding the benefits of this intervention in obesity management. Therefore, in order to clarify the effect of green coffee extract on waist circumference (WC), body mass index (BMI) and body weight (BW), we conducted an umbrella review of interventional meta-analyses. The Web of Science, Scopus, PubMed/Medline, and Embase databases were searched using specific keywords and word combinations. The umbrella meta-analysis was performed using the Stata software version 17 (Stata Corp. College Station, Texas, USA). We pooled effect sizes (ES) and confidence intervals (CI) for the outcomes using the random effects model (the DerSimonian and Laird method). In total, 5 eligible meta-analyses were included in the final quantitative assessment. Data pooled from 5 eligible papers revealed that green coffee extract can reduce BW (WMD: -1.22 kg, 95% CI: -1.53 to -0.92, p < 0.001), BMI (WMD: -0.48 kg/m2, 95% CI: -0.67 to -0.29, p < 0.001) and WC (WMD: -0.55 cm, 95% CI: -0.80 to -0.31, p < 0.001). Subgroup analyses highlighted that green coffee extract supplementation in dosages ≤600 mg/day and interventions lasting >7 wk are more likely to decrease BW. The present umbrella meta-analysis confirms the beneficial effects of green coffee extract in reducing WC, BMI, and BW. Thus, we may infer that green coffee extract can be used as a complementary therapy in the management of obesity.

A comprehensive review of antitumor properties of Angelica species and their antitumor-responsible constituents and the underlying molecular mechanisms involved in tumor inhibition.

Angelica species have been traditionally used for their medicinal properties. Recent studies have suggested their potential use as anticancer agents, making them an area of interest for further research. The review aims to summarize the current understanding of the potential anticancer effects of Angelica species and to provide insights for further research in this area. We searched for "Angelica" related information on Google Scholar, PubMed, ScienceDirect, Wiley, Science Citation Index Finder, and Springer link by searching keywords such as "Angelica," "Angelica phytochemical," "Angelica antitumor effect," "Angelica molecular mechanisms," and "Angelica clinical application." Included articles focused on the Angelica plant's anticancer properties and clinical studies, while non-cancer-related biological or phytochemical investigations were excluded. We conducted a comprehensive search of books, journals, and databases published between 2001 and 2023, identifying 186 articles for this narrative review. The articles were analyzed for their potential anticancer properties and therapeutic applications. Active compounds in the Angelica genus, such as coumarins, furanocoumarins, phthalides, and polysaccharides, exhibit anticancer properties through various mechanisms. Specific species, like A. archangelica, Angelica sinensis, A. gigas, and A. ksiekie, have the potential as anticancer agents by targeting cellular pathways, generating reactive oxygen species, and inducing apoptotic cell death. Further research into the properties of the Angelica genus is needed for developing new treatments for cancer. Phytochemicals from Angelica species possess potential as anticancer agents, requiring further research for the development of effective, low-cost, and low-toxicity cancer treatments compared to synthetic antitumor drugs.

Assessment of the Binding of Pseudallecin A to Human Serum Albumin with Multi-Spectroscopic Analysis, Molecular Docking and Molecular Dynamic Simulation.

The binding of pseudallecin A (PA), a potential antibiotic with strong inhibitory activities against Gram-positive Escherichia coli and Gram-negative Staphylococcus aureus, to human serum albumin (HSA) was explored. The interaction between them was assessed by multi-spectroscopic analysis, binding site competitive analysis, molecular docking and molecular dynamic simulation, showing the results as follows: PA effectively quenched the innate fluorescence of HSA by a static quenching process, formed a complex at a molar ratio of approximately 1 : 1 and performed an effective non-radiative energy transfer; the binding of PA to HSA was a spontaneous exothermic reaction driven by enthalpy with strong affinity and had a slight effect on the conformation of HSA; PA bound at site III of HSA and hydrogen bonds were the major binding forces to maintain the stability of the PA-HSA complex. Molecular dynamic simulation was performed to calculate the root mean square deviation (RMSD), root mean square fluctuation (RMSF) and radius of gyration (Rg) for this complex and effectively supported the spectroscopic outcome. These results meant that the delivery and distribution of PA as a water-insoluble molecule can be efficiently accomplished via HSA in human blood and, it has a good potential for future drug application and pharmacological development.

Heart-targeting exosomes from human cardiosphere-derived cells improve the therapeutic effect on cardiac hypertrophy.

Exosomes of human cardiosphere-derived cells (CDCs) are very promising for treating cardiovascular disorders. However, the current challenge is inconvenient delivery methods of exosomes for clinical application. The present study aims to explore the potential to enhance the therapeutic effect of exosome (EXO) from human CDCs to myocardial hypertrophy. A heart homing peptide (HHP) was displayed on the surface of exosomes derived from CDCs that were forced to express the HHP fused on the N-terminus of the lysosomal-associated membrane protein 2b (LAMP2b). The cardiomyocyte-targeting capability of exosomes were analyzed and their therapeutic effects were evaluated in a mouse model of myocardial hypertrophy induced by transverse aorta constriction (TAC). The molecular mechanisms of the therapeutic effects were dissected in angiotensin II-induced neonatal rat cardiomyocyte (NRCMs) hypertrophy model using a combination of biochemistry, immunohistochemistry and molecular biology techniques. We found that HHP-exosomes (HHP-EXO) accumulated more in mouse hearts after intravenous delivery and in cultured NRCMs than control exosomes (CON-EXO). Cardiac function of TAC mice was significantly improved with intravenous HHP-EXO administration. Left ventricular hypertrophy was reduced more by HHP-EXO than CON-EXO via inhibition of ß-MHC, BNP, GP130, p-STAT3, p-ERK1/2, and p-AKT. Similar results were obtained in angiotensin II-induced hypertrophy of NRCMs, in which the beneficial effects of HHP-EXO were abolished by miRNA-148a inhibition. Our results indicate that HHP-EXO preferentially target the heart and improve the therapeutic effect of CDCs-exosomes on cardiac hypertrophy. The beneficial therapeutic effect is most likely attributed to miRNA-148a-mediated suppression of GP130, which in turn inhibits STAT3/ERK1/2/AKT signaling pathway, leading to improved cardiac function and remodeling.

Acacetin alleviates myocardial ischaemia/reperfusion injury by inhibiting oxidative stress and apoptosis via the Nrf-2/HO-1 pathway.

CONTEXT: Acacetin is a natural source of flavonoids with anti-inflammatory and antioxidant effects. OBJECTIVE: This study determines acacetin's protective effect and mechanism on myocardial ischaemia/reperfusion (I/R) injury. MATERIALS AND METHODS: Sprague-Dawley rats were divided into sham and I/R injury and treatment with acacetin. Acacetin (10 mg/kg) was subcutaneously injected for 7 days. ECG and echocardiography were conducted to determine arrhythmia and heart function. The pathological characters of the heart were determined with triphenyl tetrazolium chloride staining, Haematoxylin & Eosin staining, and Masson staining. Expression of proteins in infarct tissues was examined with western blots. RESULTS: Administrated with acacetin in I/R rats significantly reduced the arrhythmia score from 4.90 to 2.50 and the reperfusion arrhythmia score from 3.79 to 1.82 in the vehicle or the acacetin group, respectively. LVEF was improved from 33.5% in the I/R group to 43.7% in the acacetin group, LVFS was increased from 16.4% to 24.5%, LVIDs was decreased from 6.5 to 5.3 mm. The inflammatory cell infiltration, myocardial fibrosis, and collagen 1 and 3 were reduced by acacetin. Acacetin promoted SOD and decreased MDA. In myocardial tissues, the expression level of TLR4 and IL-6 were restrained, and IL-10 was promoted. Apoptotic protein Bax was suppressed, and anti-apoptotic protein Bcl-2 was promoted in the acacetin group. Interestingly, the transcription factor Nrf-2/HO-1 pathway was also reversed by acacetin. DISCUSSION AND CONCLUSION: Our findings indicated that acacetin has a potential therapeutic effect in clinical application on treating I/R-induced heart injury.

Machine Learning for Drug-Target Interaction Prediction.

Identifying drug-target interactions will greatly narrow down the scope of search of candidate medications, and thus can serve as the vital first step in drug discovery. Considering that in vitro experiments are extremely costly and time-consuming, high efficiency computational prediction methods could serve as promising strategies for drug-target interaction (DTI) prediction. In this review, our goal is to focus on machine learning approaches and provide a comprehensive overview. First, we summarize a brief list of databases frequently used in drug discovery. Next, we adopt a hierarchical classification scheme and introduce several representative methods of each category, especially the recent state-of-the-art methods. In addition, we compare the advantages and limitations of methods in each category. Lastly, we discuss the remaining challenges and future outlook of machine learning in DTI prediction. This article may provide a reference and tutorial insights on machine learning-based DTI prediction for future researchers.

[Comparison of levator ani muscles in three-dimensional MRI-based models in women with and without pelvic organ prolapse at rest].

OBJECTIVE: Comparison of the levator ani muscles in three-dimensional (3D) MRI-based models in women with and without pelvic organ prolapse at rest to analyze the morphological characteristics of levator ani muscles in women with POP. METHODS: Twenty-five women with POP and 22 women with normal pelvic support were selected from Nanfang Hospital of Southern Medical University. Axial, sagittal, and coronal T2-weighted pelvic magnetic resonance scans were obtained with the women in the supine position.The 3D models were reconstructed from the source images. Morphological changes was compared within the two groups of levator ani muscles, and the 3D models were measured to determine the levator ani muscle volume (LVOL), levator plate angle (LPA), levator hiatus width (LH-W) and length (LH-L), distance between symphysis and levator sling muscle (LSG). RESULTS: There were no puborectalis avulsions in control, in POP, 3 cases of avulsions just in left, 3 cases of avulsions just in right, 7 cases in bilateral. The shape of iliococcygeus were all dome-shaped in control, 11 cases were U-shaped and 14 cases were dome-shaped in POP. The shape of levator hiatus were 7 cases of U-shape, 12 cases of V-shape, 3 cases of irregular in control; 5 cases of U-shape, 4 cases of V-shape, 16 cases of irregular in POP. POP versus control: LH-L: (68.0 ± 8.9) versus (61.6 ± 7.2) mm (P < 0.05); LH-W: (41.4 ± 3.9) versus (38.0 ± 3.2) mm (P < 0.05); LSG-L: (29.6 ± 7.4) versus (24.6 ± 3.7) mm (P < 0.05); LSG-R: (28.4 ± 6.8) versus (23.9 ± 3.2) mm (P < 0.05); LPA: (51.0 ± 11.3)° versus (40.6 ± 6.3)° (P < 0.05); LVOL: (23.7 ± 5.8) versus (24.6 ± 5.0) cm³ (P > 0.05). CONCLUSIONS: It is possible to assess the morphologic changes of levator ani by using 3D MRI models objectively, our 3D data demonstrate larger in LVOL, LPA, LH-W, LH-L, LSG, and the changes in shape. It is helpful to diagnose and assess the specific situation of patients POP in clinic.

[Significance of digital three-dimensional reconstruction techniques in the diagnosis of pelvic mass].

OBJECTIVE: To explore the significance of digital three-dimensional reconstruction techniques in the diagnosis of female pelvic mass. METHODS: Original computed tomographic angiography (CTA) datasets of 72 patients with pelvic mass who were hospitalized in Southern Hospital of Southern Medical University from October 2009 to October 2012 were collected. All cases were undergone the B-mode ultrasound and CTA examination, the datasets were input into the Mimics Version 10.01 software respectively to construct digital three-dimensional models of pelvic, arterial blood network, pelvic mass and organs.On the basis of without knowing the diagnosis of the disease on CTA, two gynecologists gave the final diagnosis of the disease after observing and analyzing the supply blood vessels and the relationship between the adjacent organs of pelvic mass through rotate the three-dimensional model by single-blind method. Define the postoperative pathological diagnosis as the standard, and compare the coincidence rate between the postoperative pathological diagnosis with diagnosis results on different inspections (including B ultrasound results, CTA results or the diagnosis on the three-dimensional model of pelvic mass). RESULTS: We successfully reconstructed 72 patients' three-dimensional model which could clearly display anatomic structure of pelvic bone, abdomen and pelvic arterial branches at different levels and the anatomic relationship between the mass and main organs in the pelvis. In all cases, 56 of them preoperative B-mode ultrasound examination were consistency with the postoperative pathological diagnosis, the coincidence rate was 78%, the preoperative CTA inspection results of 58 patients were consistency with the postoperative pathological diagnosis, the coincidence rate was 81%. While the diagnosis rate of 66 patients on the basis of digital three-dimensional model were consistency with that of the postoperative pathological diagnosis, the coincidence rate was 92%. Compared the compliance rate between diagnosis of pelvic mass based on the digital three-dimensional model and preoperative B-mode ultrasound, there were significant difference(P = 0.021).While compared with the preoperative CTA examination, there was not significant difference (P = 0.054). CONCLUSION: The pelvic three-dimensional models in vivo constructed by the digital three-dimensional reconstruction technique could visually display the source of the blood supply and the relationship between the pelvic organs, and guide to diagnosis and assess preoperatively.

Comprehensive bioinformatics analysis and systems biology approaches to identify the interplay between COVID-19 and pericarditis.

Background: Increasing evidence indicating that coronavirus disease 2019 (COVID-19) increased the incidence and related risks of pericarditis and whether COVID-19 vaccine is related to pericarditis has triggered research and discussion. However, mechanisms behind the link between COVID-19 and pericarditis are still unknown. The objective of this study was to further elucidate the molecular mechanisms of COVID-19 with pericarditis at the gene level using bioinformatics analysis. Methods: Genes associated with COVID-19 and pericarditis were collected from databases using limited screening criteria and intersected to identify the common genes of COVID-19 and pericarditis. Subsequently, gene ontology, pathway enrichment, protein-protein interaction, and immune infiltration analyses were conducted. Finally, TF-gene, gene-miRNA, gene-disease, protein-chemical, and protein-drug interaction networks were constructed based on hub gene identification. Results: A total of 313 common genes were selected, and enrichment analyses were performed to determine their biological functions and signaling pathways. Eight hub genes (IL-1ß, CD8A, IL-10, CD4, IL-6, TLR4, CCL2, and PTPRC) were identified using the protein-protein interaction network, and immune infiltration analysis was then carried out to examine the functional relationship between the eight hub genes and immune cells as well as changes in immune cells in disease. Transcription factors, miRNAs, diseases, chemicals, and drugs with high correlation with hub genes were predicted using bioinformatics analysis. Conclusions: This study revealed a common gene interaction network between COVID-19 and pericarditis. The screened functional pathways, hub genes, potential compounds, and drugs provided new insights for further research on COVID-19 associated with pericarditis.

Analysis and Validation of Critical Signatures and Immune Cell Infiltration Characteristics in Doxorubicin-Induced Cardiotoxicity by Integrating Bioinformatics and Machine Learning.

Purpose: Doxorubicin-induced cardiotoxicity (DIC) is a severe side reaction in cancer chemotherapy that greatly impacts the well-being of cancer patients. Currently, there is still an insufficiency of effective and reliable biomarkers in the field of clinical practice for the early detection of DIC. This study aimed to determine and validate the potential diagnostic and predictive values of critical signatures in DIC. Methods: We obtained high-throughput sequencing data from the GEO database and performed data analysis and visualization using R software, GO, KEGG and Cytoscape. Machine learning methods and weighted gene coexpression network (WGCNA) were used to identify key genes for diagnostic model construction. Receiver operating characteristic (ROC) analysis and a nomogram were used to assess their diagnostic values. A multiregulatory network was built to reveal the possible regulatory relationships of critical signatures. Cell-type identification by estimating relative subsets of RNA transcript (CIBERSORT) analysis was used to investigate differential immune cell infiltration. Additionally, a cell and animal model were constructed to investigate the relationship between the identified genes and DIC. Results: Among the 3713 differentially expressed genes, three key genes (CSGALNACT1, ZNF296 and FANCB) were identified. A nomogram and ROC curves based on three key genes showed excellent diagnostic predictive performance. The regulatory network analysis showed that the TFs CREB1, EP300, FLI1, FOXA1, MAX, and MAZ modulated three key genes. An analysis of immune cell infiltration indicated that many immune cells (activated NK cells, M0 macrophages, activated dendritic cells and neutrophils) might be related to the progression of DIC. Furthermore, there may be various degrees of correlation between the three critical signatures and immune cells. RT‒qPCR demonstrated that the mRNA expression of CSGALNACT1 and ZNF296 was significantly upregulated, while FANCB was significantly downregulated in DOX-treated cardiomyocytes in vitro and in vivo. Conclusion: Our study suggested that the differential expression of CSGALNACT1, ZNF296 and FANCB is associated with cardiotoxicity and is also involved in immune cell infiltration in DIC. They might be potential biomarkers for the early occurrence of DIC.

The Transcriptome Analysis of Circular RNAs Between the Doxorubicin- Induced Cardiomyocytes and Bone Marrow Mesenchymal Stem Cells- Derived Exosomes Treated Ones.

AIM: To analyze the sequencing results of circular RNAs (circRNAs) in cardiomyocytes between the doxorubicin (DOX)-injured group and exosomes treatment group. Moreover, to offer potential circRNAs possibly secreted by exosomes mediating the therapeutic effect on DOX-induced cardiotoxicity for further study. METHODS: The DOX-injured group (DOX group) of cardiomyocytes was treated with DOX, while an exosomes-treated group of injured cardiomyocytes were cocultured with bone marrow mesenchymal stem cells (BMSC)-derived exosomes (BEC group). The high-throughput sequencing of circRNAs was conducted after the extraction of RNA from cardiomyocytes. The differential expression of circRNA was analyzed after identifying the number, expression, and conservative of circRNAs. Then, the target genes of differentially expressed circRNAs were predicted based on the targetscan and Miranda database. Next, the GO and KEGG enrichment analyses of target genes of circRNAs were performed. The crucial signaling pathways participating in the therapeutic process were identified. Finally, a real-time quantitative polymerase chain reaction experiment was conducted to verify the results obtained by sequencing. RESULTS: Thirty-two circRNAs are differentially expressed between the two groups, of which twenty-three circRNAs were elevated in the exosomes-treated group (BEC group). The GO analysis shows that target genes of differentially expressed circRNAs are mainly enriched in the intracellular signalactivity, regulation of nucleic acid-templated transcription, Golgi-related activity, and GTPase activator activity. The KEGG analysis displays that they were involved in the autophagy biological process and NOD-like receptor signaling pathway. The verification experiment suggested that mmu_circ_0000425 (ID: 116324210) was both decreased in the DOX group and elevated in BEC group, which was consistent with the result of sequencing. CONCLUSION: mmu_circ_0000425 in exosomes derived from bone marrow mesenchymal stem cells (BMSC) may have a therapeutic role in alleviating doxorubicin-induced cardiotoxicity (DIC).

The gut microbiotas with metabolites regulate the protective role of miR-30a-5p in myocardial infarction.

INTRODUCTION: Gut microbial homeostasis is closely associated with myocardial infarction (MI). However, little is known about how gut microbiota influences miRNAs-regulated MI. OBJECTIVES: This study aims to elucidate the connections between miR-30a-5p, MI, gut microbiota, and gut microbial metabolite-related pathways, to explore potential strategy for preventing and treating MI. METHODS: We evaluated the effects of knocking out (KO) or overexpressing (OE) miR-30a-5p on MI by assessing cardiac structure and function, myocardial enzyme levels, and apoptosis. Then, we applied 16S rDNA sequencing and metabolomics to explore how intestinal microecology and its microorganisms affect miR-30a-5p-regulated MI. RESULTS: The results showed that KO exacerbated MI, whereas OE improved MI damage, compared to the wild-type (WT) mice. KO exacerbated intestinal barrier structure deterioration and further downregulated the expression of Cloudin-1, Occludin, and ZO-1 in MI mice. 16S rDNA sequencing-analyzed gut microbiome of KO and WT mice found that KO mainly reduced g_Lactobacillus. Transplanting fecal microorganisms from KO mice aggravated MI damage in WT mice. However, administering probiotics (mainly containing lactobacilli) helped neutralize these damages. Intriguingly, fecal microbiota transplantation from OE mice reduced MI damage. Analysis of intestinal microbial metabolites in KO and WT mice found that KO may mainly affect ABC transporters. ABCC1 was identified as the target of KO-aggravated MI. Furthermore, fecal transplantation microorganisms of MI patients aggravated MI injury in mice and miR-30a-5p and ABCC1 were involved in the process. CONCLUSIONS: Our findings demonstrate that miR-30a-5p regulates MI by affecting intestinal microbiota homeostasis and targeting ABCC1. This highlights the critical importance of maintaining a healthy gut microbiota homeostasis in MI management.

Integrated metabolomics and network pharmacology to reveal the mechanisms of Shexiang Baoxin pill against atherosclerosis.

BACKGROUND: Atherosclerosis is a disease marked by the development of lipid lesions within the endothelium and continues to be a prominent contributor to global mortality. Shexiang Baoxin pill (SBP) has been employed in the management of numerous cardiovascular diseases, but the complex mechanisms by which it operates remain obscure. This research was conducted to determine the potential impact of SBP on atherosclerosis and the underlying regulatory mechanism involved. METHOD: Network pharmacology was utilized to predict the key drug-disease targets, and a nontargeted metabolomic assay was applied to identify the key metabolites and metabolic pathways. A mouse atherosclerosis model was constructed to clarify the protective effect of SBP on atherosclerosis, and in vivo and in vitro tests were performed to verify the analysis results and clarify the mechanism through which SBP affects atherosclerosis. RESULTS: The results show that SBP can exert a protective effect in vivo by decreasing lipid levels, plaque formation and endothelial damage. Network pharmacology and metabolomics revealed that MAPK3, AKT1 and STAT3 were the hub targets and that trimethylamine n-oxide (TMAO) was the pivotal metabolite. Due to the atherogenic effect of TMAO, the corresponding protective effect of SBP was investigated in vitro. SBP inhibited TMAO-induced endothelial cell apoptosis and oxidative stress and counteracted the upregulation of MAPK3, AKT1, and STAT3 expression. Molecular docking and enzymatic inhibition suggested that the active components of SBP could bind stably to key target proteins. CONCLUSION: Taken together, based on the integrated metabolomics and network pharmacology, our findings suggest that SBP may be implicated in TMAO-induced atherosclerosis by affecting endothelial function and bile acid synthesis. We observed that SBP may ameliorate atherosclerosis by regulating TMAO levels through multiple pathways, which may provide a novel direction and insight for SBP involved in cardiovascular protection by mediating the gut-heart axis.

MINOCA biomarkers: Non-atherosclerotic aspects.

Myocardial infarction in the absence of obstructive coronary artery disease (MINOCA) is an important subtype of myocardial infarction. Although comprising less than 50% stenosis in the main epicardial coronary arteries, it constitutes a severe health risk. A variety of approaches have been recommended, but definitive diagnosis remains elusive. In addition, the lack of a comprehensive understanding of underlying pathophysiology makes clinical management difficult and unpredictable. This review highlights ongoing efforts to identify relevant biomarkers in MINOCA to improve diagnosis, individualize treatment and better predict outcomes.

Bradykinin-pretreated Human cardiac-specific c-kit+ Cells Enhance Exosomal miR-3059-5p and Promote Angiogenesis Against Hindlimb Ischemia in mice.

BACKGROUND: Protection of cardiac function following myocardial infarction was largely enhanced by bradykinin-pretreated cardiac-specific c-kit+ (BK-c-kit+) cells, even without significant engraftment, indicating that paracrine actions of BK-c-kit+ cells play a pivotal role in angiogenesis. Nevertheless, the active components of the paracrine actions of BK-c-kit+ cells and the underlying mechanisms remain unknown. This study aimed to define the active components of exosomes from BK-c-kit+ cells and elucidate their underlying protective mechanisms. METHODS: Matrigel tube formation assay, cell cycle, and mobility in human umbilical vein endothelial cells (HUVECs) and hindlimb ischemia (HLI) in mice were applied to determine the angiogenic effect of condition medium (CM) and exosomes. Proteome profiler, microRNA sponge, Due-luciferase assay, microRNA-sequencing, qRT-PCR, and Western blot were used to determine the underlying mechanism of the angiogenic effect of exosomes from BK-c-kit+. RESULTS: As a result, BK-c-kit+ CM and exosomes promoted tube formation in HUVECs and the repair of HLI in mice. Angiogenesis-related proteomic profiling and microRNA sequencing revealed highly enriched miR-3059-5p as a key angiogenic component of BK-c-kit+ exosomes. Meanwhile, loss- and gain-of-function experiments revealed that the promotion of angiogenesis by miR-3059-5p was mainly through suppression of TNFSF15-inhibited effects on vascular tube formation, cell proliferation and cell migration. Moreover, enhanced angiogenesis of miR-3059-5p-inhibited TNFSF15 has been associated with Akt/Erk1/2/Smad2/3-modulated signaling pathway. CONCLUSION: Our results demonstrated a novel finding that BK-c-kit+ cells enrich exosomal miR-3059-5p to suppress TNFSF15 and promote angiogenesis against hindlimb ischemia in mice.

Specific subsets of urothelial bladder carcinoma infiltrating T cells associated with poor prognosis.

Comprehensive investigation of tumor-infiltrating lymphocytes in cancer is crucial to explore the effective immunotherapies, but the composition of infiltrating T cells in urothelial bladder carcinoma (UBC) remains elusive. Here, single-cell RNA sequencing (scRNA-seq) were performed on total 30,905 T cells derived from peripheral blood, adjacent normal and tumor tissues from two UBC patients. We identified 18 distinct T cell subsets based on molecular profiles and functional properties. Specifically, exhausted T (TEx) cells, exhausted NKT (NKTEx) cells, Ki67+ T cells and B cell-like T (B-T) cells were exclusively enriched in UBC. Additionally, the gene signatures of TEx, NKTEx, Ki67+ T and B-T cells were significantly associated with poor survival in patients with BC and various tumor types. Finally, IKZF3 and TRGC2 are the potential biomarkers of TEx cells. Overall, our study demonstrated an exhausted context of T cells in UBC, which layed a theoretical foundation for the development of effective tumor immunotherapies.