Cardiorenal syndrome (CRS) is a complex condition characterized by the interplay between cardiac and renal dysfunction, often culminating in renal fibrosis. The role of macrophage polarization and its downstream effects in CRS-induced renal fibrosis remains an area of active investigation.

Single-cell RNA sequencing (scRNA-seq) and immune infiltration analyses were employed to identify key immune cells and genes involved in renal fibrosis in CRS. Meta-analysis and pseudo-time analysis were conducted to validate the functional relevance of these genes. Functional studies utilizing CRISPR/Cas9 gene editing and lentiviral vectors assessed macrophage polarization and epithelial-to-mesenchymal transition (EMT). In vivo, a CRS mouse model was established, and fibrosis progression was tracked using histological and imaging methods.

The PKM2/mTORC1/YME1L signaling axis was identified as a critical pathway driving renal fibrosis, mediated by HIF-1α-induced M1 macrophage polarization. Inhibition of HIF-1α significantly alleviated renal fibrosis by restricting M1 polarization and suppressing the PKM2/mTORC1/YME1L axis. Co-culture models further demonstrated the involvement of EMT and metabolic reprogramming in affected cells.

Targeting the HIF-1α signaling pathway offers a promising therapeutic strategy for renal fibrosis by modulating macrophage polarization and the PKM2/mTORC1/YME1L axis.

Fatty acids play a critical role in cerebral ischemia injury through the regulation of lipid metabolism and inflammatory signaling. Myristic acid (MA), a 14‑carbon saturated fatty acid, serves as a substrate of N-myristoyltransferase 1 (NMT1) and modulates protein function and subcellular localization via myristoylation. We show here that intraperitoneal injection of MA has no effect on the infarct volume after rat cerebral ischemia-reperfusion (I/R) injury. However, our results reveal that the level of MA within the penumbra of ischemic brain is increased and that ischemia-induced downregulation of NMT1 is responsible for the increase of MA. We further show that upregulation of MA by knockdown of NMT1 exacerbates cerebral ischemia injury, while downregulation of MA by BCtDCS (bilateral and cathodal transcranial direct current stimulation) protects against cerebral ischemia injury. Furthermore, we demonstrate that MA reduces the expression of VPS15 (phosphoinositide 3-kinase regulatory subunit 4) to exacerbate cerebral ischemia injury, and that NMT1 acts on MA to regulate VPS15 expression in the ischemic cerebral cortex. Together, this study provides the first evidence identifying NMT1/MA/VPS15 signal pathway as potential target for stroke therapy and suggests that BCtDCS may act on MA-dependent signal pathway to confer neuroprotection.

Kawasaki disease (KD) is an acute vasculitis primarily affecting children, with a potential risk of developing coronary artery aneurysms (CAAs) and cardiovascular complications. The emergence of non-coding RNAs (ncRNAs), including microRNAs (miRNAs), long non-coding RNAs (lncRNAs), and circular RNAs (circRNAs), has provided insights into Kawasaki disease pathogenesis and opened new avenues for diagnosis and therapeutic intervention. Furthermore, polymorphism analysis of ncRNA genes offers significant insights into genetic predisposition to Kawasaki disease, facilitating tailored treatment approaches and risk assessment to improve patient outcomes. Exosomal ncRNAs, which are ncRNAs encapsulated within extracellular vesicles, have garnered significant attention as potential biomarkers for Kawasaki disease and CAA due to their stability and accessibility in biological fluids. This review comprehensively discusses the biogenesis, components, and potential of exosomal and non-exosomal ncRNAs in Kawasaki disease diagnosis and prognosis prediction. It also highlights the roles of non-exosomal ncRNAs, such as miRNAs, lncRNAs, and circRNAs, in Kawasaki disease pathogenesis and their implications as therapeutic targets. Additionally, the review explores the current diagnostic and therapeutic approaches for Kawasaki disease and emphasizes the need for further research to validate these ncRNA-based biomarkers in diverse populations and clinical settings.

Serum exosomal long noncoding RNAs (lncRNAs) have not been studied extensively as biomarkers in heart failure (HF) with reduced ejection fraction (HFrEF). We compared lncRNA expression in patients with HFrEF hospitalized for acute HF with that in healthy individuals to identify differentially expressed exosomal lncRNAs. Furthermore, we explored the clinical value of exosomal KLF3-AS1 in diagnosing HF and investigated its role in cardiac hypertrophy.

Exosomes were isolated from patients with HFrEF and healthy individuals. We performed microarray analysis of differentially expressed lncRNAs and genes (DELs and DEGs, respectively) associated with HF. Protein-protein interaction (PPI), lncRNA-mRNA-KEGG pathway, and interaction networks between lncRNAs and RNA-binding proteins (RBPs) were developed. Expression patterns were verified using qRT-PCR. The diagnostic applicability of exosomal lncRNAs in HF was quantified by plotting receiver operating characteristic (ROC) curves. The size of the cardiomyocytes was evaluated using α-actinin immunostaining.

In total, 138 DELs and 1132 DEGs were identified. PPI network analysis identified INS, CTNNB1, and CAT as the most prominent hub genes, whereas MDM2, MYH6, ENAH, and KLF3-AS1 were significantly enriched in the RBP interaction network. In the validation phase, patients with HFrEF exhibited a significant increase in KLF3-AS1 expression compared with healthy individuals. Exosomal KLF3-AS1 had an area under the ROC curve of 0.861. Functionally, KLF3-AS1 overexpression reduced Ang II-induced cardiac hypertrophy in vitro.

Our results elucidated the exact patterns of circulating exosomal mRNAs and lncRNA expression in patients with HFrEF hospitalized for acute HF. Moreover, the high expression of exosomal KLF3-AS1 is a potential diagnostic biomarker for HFrEF.

Despite advancements in the development of targeted approaches for the treatment of myocardial infarction (MI), there is a continuing need for improvements in treatment approaches due to the high mortality and prevalence of MI. The identification of specific therapeutic targets and the development of efficient delivery systems are essential. In this study, a nanoparticle delivery system targeting necrotic cardiomyocytes was engineered. This system effectively downregulated long noncoding RNA (lncRNA) AK156373 and reduced oxidative stress and inflammation during MI progression. Mechanistically, silencing lncRNA AK156373 enhanced the viability and mitochondrial function of hypoxic cardiomyocytes and lowered intracellular inflammatory cytokine levels and reactive oxygen species (ROS) production. In vivo, cardiac-specific lncRNA AK15673 knockout mice were generated (AK156373flox/flox, Myh6-Cre mice), and lncRNA AK156373 knockout obviously reduced the infarct size, collagen fiber deposition, and ischemia severity in MI mice, leading to improved cardiac function. Additionally, lncRNA AK156373 modulated miR-204-5p to regulate C-X-C motif chemokine receptor 2 (CXCR2) protein expression via the competing endogenous RNA (ceRNA) mechanism, exacerbating myocardial damage and accelerating MI progression. Subsequently, nanoparticles loaded with lncRNA AK156373 siRNA were synthesized. The nanoparticles significantly inhibited MI progression by modulating the miR-204-5p/CXCR2 axis to reduce oxidative stress and inflammation. Overall, these findings establish a key regulatory role for lncRNA AK156373 in MI progression and present a direct preclinical approach for MI therapy.

Colorectal cancer (CRC) is a common type of cancer that impacts the digestive tract, and current treatment options have limitations. Studies have confirmed that ferroptosis plays a key role in CRC progression. This research sought to clarify how Proline-rich acidic protein 1 (PRAP1) influences CRC advancement and ferroptosis, and to uncover the underlying mechanisms involved.

Real-time quantitative PCR (RT-qPCR) and western blot were employed to ascertain the levels of PRAP1 in CRC cells (SW480, SW620, and LOVO) and tissues. Immunofluorescence was utilized to locate PRAP1. Biological characterization of CRC cells was determined through CCK-8 assay, EdU staining, Transwell assay, TUNEL staining and Scratch-wound assay. Iron and Fe2+ content was measured using prussian blue staining and iron assay kit. A nude mouse model of xenograft was established, and the impact of PRAP1 on tumor growth was investigated by pathological staining. Expression of ferroptosis-related proteins as well as nuclear factor-erythroid factor 2-related factor 2 (Nrf2) pathway proteins was detected by Western blot.

PRAP1 levels were elevated in CRC. Overexpression PRAP1 promoted cell proliferation, inhibited apoptosis and ferroptosis. Additionally, overexpression PRAP1 can activate the Nrf2 pathway. However, silencing PRAP1 had the opposite effect. In vivo tumor xenograft experiments showed that silencing PRAP1 resulted in decreased Ki67 positivity and increased TUNEL positivity in tumor tissues, and blocked Nrf2 pathway, thereby inhibited tumor growth.

PRAP1 promotes CRC cell proliferation and inhibits ferroptosis by Nrf2 pathway. This study provides a conceptual framework for the development of novel targeted drugs.

In the cardiovascular system, different types of cardiovascular cells can secrete specific exosomes and participate in the maintenance of cardiovascular function and the occurrence and development of diseases. Exosomes carry biologically active substances such as proteins and nucleic acids from cells of origin and can be used as biomarkers for disease diagnosis and prognosis assessment. In addition, exosome-mediated intercellular communication plays a key role in the occurrence and development of cardiovascular diseases and has become a potential therapeutic target. This article emphasizes the importance of understanding the mechanism of exosomes in cardiovascular diseases and systematically details the current understanding of exosomes as regulators of intercellular communication in cardiomyocytes, providing a basis for future research and therapeutic intervention.

Depression, a major global health issue, is closely associated with imbalances in gut microbiota and altered intestinal functions. This study investigates the antidepressant potential of a composite of Geniposide (GP) and Nanocrystalline Cellulose (NCC), focusing on its effects on the gut-brain axis. Utilizing network pharmacology, GP was identified as a key compound targeting the BCL2 gene in depression management. Experimental approaches, including a chronic unpredictable mild stress (CUMS) model in mice, cellular assays, and fecal microbiota transplantation (FMT), were used to evaluate the composite's effectiveness. Results indicate that GP activates the adenosine monophosphate-activated protein kinase (AMPK) pathway by upregulating BCL2, enhancing intestinal barrier integrity, and balancing gut flora. These mechanisms contribute to its positive effects on hippocampal function and depressive-like behaviors in mice, suggesting that the GP-NCC composite could be a promising avenue for developing depression therapies that target gut health.

Hepatocellular carcinoma (HCC) is a deadly malignancy known for its ability to evade immune surveillance. NOP2/Sun RNA methyltransferase family member 2 (NSUN2), an RNA methyltransferase involved in carcinogenesis, has been associated with immune evasion and energy metabolism reprogramming. This study aimed to examine the molecular mechanisms underlying the involvement of NSUN2 in immune evasion and metabolic reprogramming of HCC.

Single-cell transcriptomic sequencing was applied to examine cellular composition changes, particularly immune cell dynamics, in HCC and adjacent normal tissues. Bulk RNA-seq and proteomics identified key genes and proteins. Methylation sequencing and methylated RNA immunoprecipitation (MeRIP) were carried out to characterize the role of NSUN2 in 5-methylcytosine (m5C) modification of sterol O-acyltransferase 2 (SOAT2). Clinical samples from 30 HCC patients were analyzed using reverse transcription-quantitative polymerase chain reaction and Western blotting. Gene expression was manipulated using CRISPR/Cas9 and lentiviral vectors. In vitro co-culture models and metabolomics were used to study HCC cell-T cell interactions, energy metabolism, and immune evasion. Tumor growth in an orthotopic mouse model was monitored by bioluminescence imaging, with subsequent measurements of tumor weight, volume, and immunohistochemical staining.

Single-cell transcriptomic analysis identified a marked increase in malignant cells in HCC tissues. Cell communication analysis indicated that tumor cells might promote cancer progression by evading immune clearance. Multi-omics analyses identified NSUN2 as a key regulator in HCC development. MeRIP confirmed that NSUN2 facilitated the m5C modification of SOAT2. Analysis of human HCC tissue samples demonstrated pronounced upregulation of NSUN2 and SOAT2, along with elevated m5C levels in HCC tissues. In vitro experiments uncovered that NSUN2 augmented the reprogramming of energy metabolism and repressed the activity and cytotoxicity of CD8+ T cells, contributing to immune evasion. In vivo studies further substantiated the role of NSUN2 in fostering immune evasion and tumor formation of HCC by modulating the m5C modification of SOAT2.

The findings highlight the critical role of NSUN2 in driving HCC progression through the regulation of m5C modification on SOAT2. These findings present potential molecular markers for HCC diagnosis and therapeutic targets for its treatment.

Osteoporosis, a prevalent bone disease, is characterized by the deterioration of bone tissue microstructure and imbalanced osteogenesis. The regulatory role of PPARγ m6A methylation mediated by METTL16 remains poorly elucidated. This study utilized advanced single-cell RNA sequencing (scRNA-seq) and Bulk RNA-seq techniques to explore how METTL16 influences the osteogenic differentiation of Bone Marrow-Derived Mesenchymal Stem Cells (BMSCs) and its implication in osteoporosis. The research revealed that METTL16 enhances the suppression of osteogenic differentiation in BMSCs, while PPARγ is associated with BMSC ferroptosis. Mechanistically, METTL16 facilitates the m6A modification of PPARγ transcription, thereby promoting ferroptosis in BMSCs and impeding their osteogenic differentiation. The in vivo animal experiments confirmed the pivotal role of the METTL16-PPARγ axis in osteoporosis development in mice. These findings suggest that the regulation of PPARγ m6A methylation by METTL16, leading to ferroptosis, is a critical mechanism impacting BMSC osteogenic differentiation and the pathogenesis of osteoporosis.

Cardiovascular disease (CVD) is a leading cause of human mortality worldwide, with patients often at high risk of heart failure (HF) in myocardial infarction (MI), a common form of CVD that results in cardiomyocyte death and myocardial necrosis due to inadequate myocardial perfusion. As terminally differentiated cells, cardiomyocytes possess a severely limited capacity for regeneration, and an excess of dead cardiomyocytes will further stress surviving cells, potentially exacerbating to more extensive heart disease. The article focuses on the relationship between programmed cell death (PCD) of cardiomyocytes, including different forms of apoptosis, necrosis, and autophagy, and MI, as well as the potential application of these mechanisms in the treatment of MI. By gaining a deeper understanding of the mechanisms of cardiomyocyte death, it aims to provide new insights into the prevention and treatment of MI.

Cardiovascular diseases (CVDs) are the leading cause of morbidity and mortality worldwide, posing significant challenges to healthcare systems. Despite advances in medical interventions, the molecular mechanisms underlying CVDs are not yet fully understood. For decades, protein-coding genes have been the focus of CVD research. However, recent advances in genomics have highlighted the importance of long non-coding RNAs (lncRNAs) in cardiovascular health and disease. Changes in lncRNA expression specific to tissues may result from various internal or external factors, leading to tissue damage, organ dysfunction, and disease. In this review, we provide a comprehensive discussion of the regulatory mechanisms underlying lncRNAs and their roles in the pathogenesis and progression of CVDs, such as coronary heart disease, atherosclerosis, heart failure, arrhythmias, cardiomyopathies, and diabetic cardiomyopathy, to explore their potential as therapeutic targets and diagnostic biomarkers.

Atrial fibrillation (AF) is a prevalent and chronic cardiovascular disorder associated with various pathophysiological alterations, including atrial electrical and structural remodeling, disrupted calcium handling, autonomic nervous system dysfunction, aberrant energy metabolism, and immune dysregulation. Emerging evidence suggests that long non-coding RNAs (lncRNAs) play a significant role in the pathogenesis of AF.

This discussion aims to elucidate the involvement of AF-related lncRNAs, with a specific focus on their role as miRNA sponges that modulate crucial signaling pathways, contributing to the progression of AF. We also address current limitations in AF-related lncRNA research and explore potential future directions in this field. Additionally, we summarize feasible strategies and promising delivery systems for targeting lncRNAs in AF therapy.

In conclusion, targeting AF-related lncRNAs holds substantial promise for future investigations and represents a potential therapeutic avenue for managing AF.

Osteosarcoma (OS) chemoresistance presents a significant clinical challenge. This study aims to investigate the potential of using tumor vascular-targeting peptide NGR-modified cancer-associated fibroblasts (CAFs)-derived exosomes (exos) to deliver circ_0004872-encoded small peptides promoting autophagy-dependent ferroptosis to reverse chemoresistance in OS. Through combined single-cell transcriptome analysis and high-throughput sequencing, it identified circ_0004872 associated with chemoresistance. Subsequent experiments demonstrated that the small peptide encoded by this Circular RNA (circRNA) can effectively reverse chemoresistance by enhancing OS cell sensitivity to chemotherapy via the mechanism of promoting autophagy-dependent ferroptosis. Moreover, in vitro and in vivo results confirmed the efficient delivery of NGR-modified CAFs-derived exo-packaged circ_0004872-109aa to tumor cells, thereby improving targeted therapy efficacy. This study not only offers a novel strategy to overcome chemoresistance in OS but also highlights the potential application value of utilizing exos for drug delivery.

Viral myocarditis (VMC) is characterized by severe cardiac inflammation and is a major cause of congestive heart failure and sudden cardiac death in healthy young people. The lncRNA XIST plays an important regulatory role in myocardial injury, but its role in VMC caused by coxsackievirus B3 (CVB3) infection is unclear. In this study, we evaluated the effects of the lncRNA XIST on a CVB3-induced VMC mouse model and on pyroptosis in CVB3-exposed Treg cells. The results showed that in CVB3-infected VMC and Treg cells, the expression level of the lncRNA XIST was increased, whereas miR-195-5p expression was decreased. In CVB3-induced VMC mice, inflammation was elevated, whereas the Treg/Th17 ratio was reduced. Knocking down the lncRNA XIST suppressed pyroptosis in Treg cells caused by CVB3 infection and inhibited VMC progression in vivo. Studies on downstream mechanisms have shown that the lncRNA XIST targets miR-195-5p, induces caspase-1 expression through the inhibition of miR-195-5p, promotes the expression of the inflammatory factors IL-1β and IL-18 associated with pyroptosis, inhibits the secretion of the anti-inflammatory factors IL-10 and TGF-β1, and ultimately promotes pyroptosis in Treg cells. In conclusion, knocking down the lncRNA XIST inhibits CVB3-induced pyroptosis of Treg cells and VMC progression in mice induced by CVB3 infection. These findings provide a potential theoretical basis for the treatment of VMC.

In this study, the influence of glycoproteomic changes, specifically MUC16, on NK cell-mediated immunotherapy response in ovarian cancer is explored. Analysis of glycoprotein data from the CPTAC database identified significant upregulation of MUC16 in ovarian cancer tissues, associated with tumor invasiveness and immune evasion. Experimental findings showed that MUC16 knockdown increased NK cell cytotoxicity, decreased invasiveness, and boosted NK cell activation, while MUC16 overexpression resulted in the opposite effects. In vivo experiments demonstrated that MUC16 knockdown suppressed tumor growth, enhanced NK cell infiltration, and bolstered NK cell activation, underscoring the potential of MUC16 as a target for novel immunotherapy approaches in ovarian cancer treatment.

Cardiovascular diseases (CVD) are widely recognized as a leading cause of death worldwide; however, early diagnosis and disease progression monitoring play a crucial role in their clinical management. The common diagnostic and prognostic biomarkers have represented a revolutionary tool for studying CVD; however, their applications are limited to invasive irreversible heart diseases, such as drug-induced myocardial injury. In light of this information, a growing number of studies are currently investigating the diagnostic and prognostic potential of novel CVD biomarkers. Examples of this are long non-coding RNA (lncRNA) and other RNAs that are specifically expressed at the early stages of heart disease. These RNAs have been reported to be involved in the development of CVD via activating or inhibiting inflammatory mediators and angiogenesis-related factors, as well as endothelial cell proliferation, migration and phenotypic transformation. This review collectively summarizes the recent studies' results concerning exosomal lncRNA biogenesis, characterization, and function, as well as its role as a novel biomarker in a variety of CVD.

Extracellular vesicles (EVs) are cell-secreted heterogeneous vesicles that play crucial roles in intercellular communication and disease pathogenesis. Due to their non-tumorigenicity, low immunogenicity, and therapeutic potential, EVs are increasingly used in cardiac repair as cell-free therapy. There exist multiple steps for the design of EV therapies, and each step offers many choices to tune EV properties. Factors such as EV source, cargo, loading methods, routes of administration, surface modification, and biomaterials are comprehensively considered to achieve specific goals. PubMed and Google Scholar were searched in this review, 89 articles related to EV-based cardiac therapy over the past five years (2019 Jan - 2023 Dec) were included, and their key steps in designing EV therapies were counted and analyzed. We aim to provide a comprehensive overview that can serve as a reference guide for researchers to design EV-based cardiac therapies.

This study aims to investigate how the E3 ubiquitin ligase LITAF influences mitochondrial autophagy by modulating MCL-1 ubiquitination, and its role in the development of epilepsy.

Employing single-cell RNA sequencing (scRNA-seq) to analyze brain tissue from epilepsy patients, along with high-throughput transcriptomics, we identified changes in gene expression. This was complemented by in vivo and in vitro experiments, including protein-protein interaction (PPI) network analysis, western blotting, and behavioral assessments in mouse models.

Neuronal cells in epilepsy patients exhibited significant gene expression alterations, with increased activity in apoptosis-related pathways and decreased activity in neurotransmitter-related pathways. LITAF was identified as a key upregulated factor, inhibiting mitochondrial autophagy by promoting MCL-1 ubiquitination, leading to increased neuronal damage. Knockdown experiments in mouse models further confirmed that LITAF facilitates MCL-1 ubiquitination, aggravating neuronal injury.

Our findings demonstrate that LITAF regulates MCL-1 ubiquitination, significantly impacting mitochondrial autophagy and contributing to neuronal damage in epilepsy. Targeting LITAF and its downstream mechanisms may offer a promising therapeutic strategy for managing epilepsy.

Tissue repair is an extremely crucial part of clinical treatment. During the course of disease treatment, surgery, chemotherapy, and radiotherapy cause tissue damage. On the other hand, Normal tissue from accidental or therapeutic exposure to high-dose radiation can cause severe tissue damage. There is an urgent need for developing medical countermeasures against radiation injury for tissue repair. Tissue repair involves the regeneration, proliferation, differentiation, and migration of tissue cells; imbalance of local tissue homeostasis, progressive chronic inflammation; decreased cell activity and stem cell function; and wound healing. Although many clinical treatments are currently available for tissue repair, they are expensive. The long recovery time and some unavoidable complications such as cell damage and the inflammatory reaction caused by radiotherapy have led to unsatisfactory results. Extracellular vesicles (EVs) derived from mesenchymal stem cells (MSCs) have similar tissue repair functions as MSCs. In tissue damage, EVs can be used as an alternative to stem cell therapy, thereby avoiding related complications such as immunological rejection. EVs play a major role in regulating tissue damage, anti-inflammation, pro-proliferation, and immune response, thus providing a diversified and efficient solution for the repair of disease- and radiotherapy-induced tissue damage. This article reviews the research progress of mesenchymal stem cell-derived EVs in promoting the repair of tissue including heart, lung, liver, intestine, skin, blood system, central nervous system, and tissue damage caused by radiotherapy, thereby aiming to offer new directions and ideas for the radiotherapy and regenerative applications.

Osteosarcoma (OS) is a highly malignant tumor, and chemotherapy resistance is a major challenge in the treatment of this disease. This study aims to explore the role of the CLTC-VMP1 gene fusion in the mechanism of chemotherapy resistance in OS and investigate its molecular mechanisms in mediating energy metabolism reprogramming by regulating autophagy and apoptosis balance. Using single-cell transcriptome analysis, the heterogeneity of OS cells and their correlation with resistance to platinum drugs were revealed. Cisplatin-resistant cell lines were established in human OS cell lines for subsequent experiments. Based on transcriptomic analysis, the importance of VMP1 in chemotherapy resistance was confirmed. Lentiviral vectors overexpressing or interfering with VMP1 were used, and it was observed that inhibiting VMP1 could reverse cisplatin resistance, promote cell apoptosis, and inhibit autophagy, and mitochondrial respiration and glycolysis. Furthermore, the presence of CLTC-VMP1 gene fusion was validated, and its ability to regulate autophagy and apoptosis balance, promote mitochondrial respiration, and glycolysis was demonstrated. Mouse model experiments further confirmed the promoting effect of CLTC-VMP1 on tumor growth and chemotherapy resistance. In summary, the CLTC-VMP1 gene fusion mediates energy metabolism reprogramming by regulating autophagy and apoptosis balance, which promotes chemotherapy resistance in OS.NEW & NOTEWORTHY This study identifies the CLTC-VMP1 gene fusion as a key driver of chemotherapy resistance in osteosarcoma by regulating autophagy and reprogramming cellular energy metabolism. Through single-cell transcriptomics, the research reveals the heterogeneity of tumor cells and the role of VMP1 in promoting resistance to cisplatin. The findings suggest that targeting the CLTC-VMP1 fusion gene may offer new therapeutic strategies to overcome chemotherapy resistance in osteosarcoma.

The prevalence of breast cancer (BRCA) is notable in the female population, being a commonly diagnosed malignancy, where the management of copper levels is crucial for treatment success. This research aims to explore the influence of copper homeostasis on BRCA therapy, with a specific focus on the role of Cyclin-Dependent Kinase 1 (CDK1) and its relationship to copper regulation. A novel thermosensitive hydrogel incorporating nanoparticles (NPs) was engineered to synergize with the chemotherapy drug vincristine (VCR) in inhibiting tumor growth and metastasis. Through a comprehensive approach involving bioinformatics analyses, in vitro experiments, and in vivo models, the study identified CDK1 as a significant factor in BRCA progression under copper homeostasis. MBVP-Gel, a novel thermosensitive hydrogel incorporating NPs, was developed to enhance the delivery of chemotherapy drugs and regulate copper homeostasis in breast cancer treatment. The MBVP-Gel, formulated with copper chelation and VCR NPs, effectively suppressed CDK1 expression, thereby restraining BRCA cell growth and metastasis while enhancing the therapeutic impact of VCR. This investigation offers fresh insights and experimental validation on the interaction between copper homeostasis and BRCA, providing a valuable foundation for refining future treatment strategies. These findings underscore the potential advantages of targeting copper homeostasis and CDK1 in enhancing BRCA therapy, setting the stage for individualized interventions and improved patient consequences.

Hepatocellular carcinoma is one of the most prevalent types of liver malignancy and poses a severe threat to global health. Despite recent improvements in therapeutic approaches, treatment options for patients with advanced or recurrent HCC are still limited.

Our study analyzed miRNA differential expression using data from hepatocellular carcinoma patients in the Cancer Genome Atlas. Pyroptosis-related genes were identified from gene cards. Differential expression of miRNAs was analyzed using DESeq2 and visualized using ggplot2 and pheatmap. A prognostic risk model for pyroptosis-associated miRNAs was constructed using LASSO regression and validated by principal component analysis, Kaplan-Meier survival and ROC curve analysis. We also performed gene and pathway enrichment analysis. Immune cell infiltration and function in HCC were assessed using single-sample genomic enrichment analysis, and correlations with immune cells and function were explored. Also, CCK-8 assay as well as migration and invasion assays were performed after knockdown of miR-6844.

We have established and validated a prognostic risk model based on ten DEmiRNAs, which is important for the survival of HCC patients. Significant changes in immune cell infiltration and immune function were also found in high-risk patients. It also demonstrated that knockdown of miR-6844 inhibited HCC cell proliferation, migration and invasion, highlighting its role in HCC progression.

Our study reveals the implications of pyroptosis-associated differential miRNAs on the prognosis of patients with hepatocellular carcinoma and provides a foundation for novel HCC therapies, especially immunotherapy.

Cardiovascular diseases (CVDs) are the leading cause of death worldwide, and effectively repairing the heart following myocardial injuries remains a significant challenge. Research has increasingly shown that exosomes derived from mesenchymal stem cells (MSC-Exo) can ameliorate myocardial injuries and improve outcomes after such injuries. The therapeutic benefits of MSC-Exo are largely due to their capacity to deliver specific cargo, including microRNAs and proteins. MSC-Exo can modulate various signaling pathways and provide several beneficial effects, including cytoprotection, inflammation modulation, and angiogenesis promotion to help repair the damaged myocardium. In this review, we summarize the cardioprotective effects of MSC-Exo in myocardial injury, the underlying molecular mechanism involved in the process, and various approaches studied to enhance their efficacy based on recent findings.

This study aimed to investigate the influence of sperm miRNAs on fertilization rates (FR) in in vitro fertilization (IVF) and to explore potential regulatory mechanisms in sperm-mediated fertilization and embryo development. Through high-throughput sequencing, we identified differentially expressed miRNAs in sperm, with miR-133a-3p significantly upregulated in samples associated with low FR and available embryo rate (AER). Key regulatory circRNAs and mRNAs were further identified via the Starbase database, intersected with differentially expressed RNA, and analyzed through GO, KEGG, and PPI analyses. The circMYH9/miR-133a-3p/CXCR4 axis emerged as a critical regulatory network. In vitro assays using the GC-2 spd mouse spermatogenic cell line revealed that miR-133a-3p inhibited cell growth and proliferation while promoting apoptosis. circMYH9, acting as a competing endogenous RNA (ceRNA) for miR-133a-3p, modulated CXCR4 expression, enhancing GC-2 spd cell growth and inhibiting apoptosis through the miR-133a-3p/CXCR4 axis. In vivo experiments using a mouse model confirmed that circMYH9 overexpression increased IVF success rates and promoted embryo development via this axis. Mechanistically, miR-133a-3p suppresses sperm fertilization and embryo development by targeting the circMYH9/miR-133a-3p/CXCR4 axis. These findings suggest that this regulatory network could serve as a novel biomarker for assessing fertilization potential and embryo quality in clinical settings and as a potential therapeutic target to improve IVF outcomes and address infertility. This study provides valuable insights into the molecular mechanisms governing sperm function and early embryonic development.

Bone marrow mesenchymal stem cells (BMSCs) derived exosomes have demonstrated potential therapeutic efficacy on myocardial ischemia/reperfusion injury (MI/RI). This study has explored the underlying mechanisms of Danshen decoction (DSD) pretreated BMSCs-exosomes to treat MI/RI in vivo and in vitro.

Extracellular vesicles extracted from BMSCs were identified, miRNA sequencing was performed to screen the effects of DSD, and verified to target TXNIP in vivo. After MI/RI modeling, rats were treated with BMSCs-exosomes pretreated with DSD or miRNA inhibitor. BMSCs-exosomes, DSD-pretreated BMSCs-exosomes, and miRNA inhibitor/anti-miRNA-pretreated BMSCs-exosomes were used to treat H9c2 cells or MI/RI rats. CCK-8, Tunnel staining, and flow cytometry were performed to measure cell viability. LDH, CK, CK-MB were detected to evaluate cell injury. MDA, SOD, and ROS were used to confirm oxidative stress. Furthermore, IL-1β, IL-18, cleaved-caspase-1, pro-caspase-1, NLRP3, TXNIP, and GSDMD were quantified for the TXNIP/NLRP3/Caspase-1 signaling activation. In addition, echocardiography was used to observe the heart function, and H&E stain was performed to detect pathological injury.

Following DSD pretreatment, there was a marked elevation in the expression levels of miR-93-5p, miR-16-5p, and miR-15b-5p, with miR-93-5p exhibiting the highest baseMean value. The administration of a miR-93-5p inhibitor yielded effects counteractive to those observed with DSD treatment, leading to reduced cell proliferation, heightened oxidative stress (as indicated by increased levels of SOD and ROS, alongside a decrease in MDA), and enhanced cell apoptosis. Furthermore, DSD effectively mitigated the miR-93-5p-induced upregulation of key inflammatory and apoptotic markers, including IL-1β, IL-18, caspase-1, NLRP3, TXNIP, and GSDMD. Notably, exosomes derived from DSD-pretreated BMSCs demonstrated a capacity to alleviate cardiac damage.

DSD may target miR-93-5p within BMSC-derived exosomes to confer protection against cardiac damage by inhibiting the activation of the TXNIP/NLRP3/Caspase-1 signaling pathway, thereby mitigating cardiomyocyte pyroptosis. This study provides a theoretical foundation for the application of DSD in the treatment of MI/RI.

Cardiovascular disease (CVD) has been the leading cause of death worldwide for many years. In recent years, exosomes have gained extensive attention in the cardiovascular system due to their excellent biocompatibility. Studies have extensively researched miRNAs in exosomes and found that they play critical roles in various physiological and pathological processes in the cardiovascular system. These processes include promoting or inhibiting inflammatory responses, promoting angiogenesis, participating in cell proliferation and migration, and promoting pathological progression such as fibrosis.

This systematic review examines the role of exosomes in various cardiovascular diseases such as atherosclerosis, myocardial infarction, ischemia-reperfusion injury, heart failure and cardiomyopathy. It also presents the latest treatment and prevention methods utilizing exosomes. The study aims to provide new insights and approaches for preventing and treating cardiovascular diseases by exploring the relationship between exosomes and these conditions. Furthermore, the review emphasizes the potential clinical use of exosomes as biomarkers for diagnosing cardiovascular diseases.

Exosomes are nanoscale vesicles surrounded by lipid bilayers that are secreted by most cells in the body. They are heterogeneous, varying in size and composition, with a diameter typically ranging from 40 to 160 nm. Exosomes serve as a means of information communication between cells, carrying various biologically active substances, including lipids, proteins, and small RNAs such as miRNAs and lncRNAs. As a result, they participate in both physiological and pathological processes within the body.

Stroke remains the 3rd leading cause of long-term disability globally. Over the past decade, mesenchymal stem cell (MSC) transplantation has been proven as an effective therapy for ischemic stroke. However, the mechanism of MSC-derived exosomal lncRNAs during cerebral ischemia/reperfusion (I/R) remains ambiguous. The oxygen-glucose deprivation/reoxygenation (OGD/R) and middle cerebral artery occlusion (MCAO) rat model were generated. MSCs were isolated and characterized by flow cytometry and histochemical staining, and MSC exosomes were purified and characterized by transmission electron microscopy, flow cytometry and Western blot. Western blot, RT-qPCR and ELISA assay were employed to examine the expression or secretion of key molecules. CCK-8 and TUNEL assays were used to assess cell viability and apoptosis. RNA immunoprecipitation and RNA pull-down were used to investigate the direct association between krüppel-like factor 3 antisense RNA 1 (KLF3-AS1) and musashi-1(MSI1). Yin Yang 1 (YY1)-mediated transcriptional regulation was assessed by chromatin immunoprecipitation and luciferase assays. The histological changes and immunoreactivity of key molecules in brain tissues were examined by H&E and immunohistochemistry. MSCs were successfully isolated and exhibited directionally differential potentials. MSC exosomal KLF3-AS1 alleviated OGD/R-induced inflammation in SK-N-SH and SH-SY5Y cells via modulating Sphk1. Mechanistical studies showed that MSI1 positively regulated KLF3-AS1 expression through its direct binding to KLF3-AS1. YY1 was identified as a transcription activator of MSI1 in MSCs. Functionally, YY1/MSI1 axis regulated the release of MSC exosomal KLF3-AS1 to modulate sphingosine kinase 1 (Sphk1)/NF-κB pathway, thereby ameliorating OGD/R- or cerebral I/R-induced injury. MSCs promote the release of exosomal KLF3-AS1 to regulate Sphk1 through YY1/MSI axis and improve cerebral I/R injury.

Myocarditis, which can be triggered by immune checkpoint inhibitor (ICI) treatment, represents a critical and severe adverse effect observed in cancer therapy. Thus, elucidating the underlying mechanism and developing effective strategies to mitigate its harmful impact is of utmost importance. The objective of this study is to investigate the potential role and regulatory mechanism of exosomes derived from human bone marrow mesenchymal stem cells (hBMSC-Exos) in providing protection against myocardial injury induced by ICIs. We observed that the administration of programmed death 1/programmed death-ligand 1 (PD-1/PD-L1) inhibitor BMS-1 in tumor-bearing mice led to evident cardiac dysfunction and myocardial injury, which were closely associated with M1 macrophage polarization and cardiac pyroptosis. Remarkably, these adverse effects were significantly alleviated through tail-vein injection of hBMSC-Exos. Moreover, either BMS-1 or hBMSC-Exos alone demonstrated the ability to reduce tumor size, while the combination of hBMSC-Exos with BMS-1 treatment not only effectively improved the probability of tumor inhibition but also alleviated cardiac anomalies induced by BMS-1.

Myocardial infarction (MI), a major global cause of mortality and morbidity, continues to pose a significant burden on public health. Despite advances in understanding its pathogenesis, there remains a need to elucidate the intricate molecular mechanisms underlying MI progression. Long non-coding RNAs (lncRNAs) have emerged as key regulators in diverse biological processes, yet their specific roles in MI pathophysiology remain elusive. Conducting a thorough review of literature using PubMed and Google Scholar databases, we investigated the involvement of lncRNAs in MI, focusing on their regulatory functions and downstream signaling pathways. Our analysis revealed extensive dysregulation of lncRNAs in MI, impacting various biological processes through diverse mechanisms. Notably, lncRNAs act as crucial modulators of gene expression and signaling cascades, functioning as decoys, regulators, and scaffolds. Furthermore, studies identified the multifaceted roles of lncRNAs in modulating inflammation, apoptosis, autophagy, necrosis, fibrosis, remodeling, and ischemia-reperfusion injury during MI progression. Recent research highlights the pivotal contribution of lncRNAs to MI pathogenesis, offering novel insights into potential therapeutic interventions. Moreover, the identification of circulating lncRNA signatures holds promise for the development of non-invasive diagnostic biomarkers. In summary, findings underscore the significance of lncRNAs in MI pathophysiology, emphasizing their potential as therapeutic targets and diagnostic tools for improved patient management and outcomes.

Dysregulated circular RNAs (circRNAs) are involved in osteoarthritis (OA) progression.

We aimed to explore the effect of hsa_circ_0044719 (circTRIM25) on the ferroptosis of chondrocytes.

Chondrocytes were treated with interleukin (IL)-1β to generate cell model. Cellular behaviours were measured using cell counting kit-8, enzyme-linked immunosorbent assay, relevant kits, propidium iodide staining, and immunofluorescence assay. Quantitative real-time polymerase chain reaction was performed to examine the expression of circTRIM25, miR-138-5p, and cAMP responsive element binding protein 1 (CREB1), and their interactions were assessed using luciferase reporter analysis and RNA pull-down assay.

CircTRIM25 was upregulated in OA tissues and IL-1β-stimulated chondrocytes. Knockdown of circTRIM25 facilitated the viability and suppressed ferroptosis and inflammation of IL-1β-induced cells. CircTRIM25 served as a sponge of miR-138-5p, which directly targets CREB1. Downregulation of miR-138-5p abrogated the effect induced by knockdown of circTRIM25. Furthermore, enforced CREB1 reversed the miR-138-5p induced effect. Moreover, knockdown of circTRIM25 attenuated cartilage injury in vivo.

Silencing of circTRIM25 inhibited ferroptosis of chondrocytes via the miR-138-5p/CREB axis and thus attenuated OA progression.

Brain injury after cardiac arrest (CA) and cardiopulmonary resuscitation (CPR) is the leading cause of neurological dysfunction and death. This study aimed to explore the mechanism of histone deacetylase 6 (HDAC6) in neurofunctional recovery following CA/CPR in rats. A rat model was established by CA/CPR treatment. Adenovirus-packaged sh-HDAC6 was injected into the tail vein. To evaluate the neurofunction of rats, survival time, neurofunctional scores, serum NSE/S100B, and brain water content were measured and Morris water maze test was performed. HDAC6, microRNA (miR)-138-5p, Nod-like receptor protein 3 (NLRP3), and pyroptotic factor levels were determined by real-time quantitative polymerase chain reaction or Western blot assay. HDAC6 and H3K9ac enrichment on miR-138-5p promoter were examined by chromatin immunoprecipitation. miR-138-5p-NLRP3 binding was analyzed by dual-luciferase reporter assay. NLRP3 inflammasome was activated with nigericin sodium salt. After CPR treatment, HDAC6 was highly expressed, while miR-138-5p was downregulated. HDAC6 downregulation improved neurofunction and reduced pyroptosis. HDAC6 enrichment on the miR-138-5p promoter deacetylated H3K9ac, inhibiting miR-138-5p, and promoting NLRP3-mediated pyroptosis. Downregulating miR-138-5p partially reversed the protective effect of HDAC6 inhibition after CPR. In Conclusion, HDAC6 enrichment on miR-138-5p promoter deacetylated H3K9ac, inhibiting miR-138-5p expression and promoting NLRP3-mediated pyroptosis, worsening neurological dysfunction in rats after CPR.

Neuroinflammation plays a crucial role in the repair of spinal cord injury (SCI), with microglia, pivotal in neuroinflammation, driving either degeneration or recovery in this pathological process. Recently, plasma-derived exosomes (denoted Exos) have presented a high capacity for promoting functional recovery of SCI through the anti-inflammatory effects, and pretreated exosomes are associated with better outcomes. Thus, we aimed to explore whether melatonin-pretreated plasma-derived exosomes (denoted MExo) could exert superior effects on SCI, and attempted to elucidate the potential mechanisms.

Electron microscopy, nanoparticle tracking analysis, and western blot were applied to delineate the distinctions between Exos and MExos. To assess their therapeutic potentials, we established a contusion SCI rat model, complemented by a battery of in vitro experiments comparing both groups. Subsequently, a miRNA microarray analysis was conducted, followed by a series of rescue experiments to elucidate the specific role of miRNAs in MExos. To further delve into the molecular mechanisms involved, we employed western blot analysis and the luciferase reporter gene assay.

Melatonin promoted the release of exosome from plasma, concurrently amplifying their anti-inflammatory properties. Furthermore, it was discerned that MExos facilitated a transition in microglia polarization from M1 to M2 phenotype, a phenomenon more pronounced than that observed with Exos. In an endeavor to elucidate this variance, we scrutinized miRNAs exhibiting elevated expression levels in MExos, pinpointing miR-138-5p as a pivotal element in this dynamic. Following this, an in-depth investigation into the role of miR-138-5p was undertaken, which uncovered its efficacy in driving phenotypic alterations within microglia. The analysis of downstream genes targeted by miR-138-5p revealed that it exerted a negative regulatory influence on SOX4, which was found to obstruct the generation of M2-type microglia and the secretion of anti-inflammatory cytokines, thereby partially elucidating the mechanism behind miR-138-5p's regulation of microglia polarization.

We innovatively observed that melatonin enhanced the anti-inflammatory function of Exos, which further decreased the expression of SOX4 by delivering miR-138-5p. This inhibition promoted the conversion of M1 microglia to M2 microglia, thus offering a viable option for the treatment of SCI.

This study highlights that melatonin enhances the anti-inflammatory function of Exos through delivery of miR-138-5p. Activation of miR-138-5p/SOX4 axis by engineered melatonin-pretreated plasma exosomes may be a potential target for SCI treatment.

Myocardial infarction (MI) remains a leading cause of mortality worldwide. Despite patients with MI benefit from timely reperfusion therapies, the rates of mortality and morbidity remain substantial, suggesting an enduring need for the development of new approaches. Molecular mechanisms underlying myocardial ischemic injury are associated with both cardiomyocytes and non-cardiomyocytes. Exosomes are nano-sized extracellular vesicles released by almost all eukaryotic cells. They facilitate the communication between various cells by transferring information via their cargo and altering different biological activities in recipient cells. Studies have created great prospects for therapeutic applications of exosomes in MI, as demonstrated through their beneficial effect on heart function and reducing ventricular remodeling in association with fibrosis, angiogenesis, apoptosis, and inflammation. Of note, myocardial ischemic injury is primarily due to restricted blood flow, reducing oxygen availability, and causing inefficient utilization of energy substrates. However, the impact of exosomes on cardiac energy metabolism has not been adequately investigated. Although exosomes have been engineered for targeted delivery to enhance clinical efficacy, challenges must be overcome to utilize them reliably in the clinic. In this review, we summarize the research progress of exosomes for MI with a focus on the known and unknown regarding the role of exosomes in energy metabolism in cardiomyocytes and non-cardiomyocytes; as well as potential research avenues of exosome-mitochondrial energy regulation as well as therapeutic challenges. We aim to help identify more efficient molecular targets that may promote the clinical application of exosomes.

Myocardial infarction (MI) remains a significant global health concern, characterized by cardiomyocyte apoptosis and adverse ventricular remodeling. Nevertheless, the interplay between exosomal miR-21-5p and Yes-associated protein 1 (YAP1) in the context of MI remains unexplored.

Rat mesenchymal stem cells (MSCs) and H9c2 cardiomyocytes were cultured, characterized, and instrumental in our experiments. Exosomes were meticulously isolated, and their identity confirmed. The internalization of these exosomes by H9c2 cells was assessed, while RNA and protein expression were quantified using Quantitative Real-Time PCR and Western blot, respectively. MTT assay was implemented for cell viability, and apoptosis was evaluated via flow cytometric analysis. To elucidate gene interactions, we conducted microarray profiling of miRNA expression, dual luciferase reporter assays, and RNA Immunoprecipitation.

MSC-derived exosomes exhibited a remarkable capacity to attenuate hypoxia-induced inflammation and apoptosis in H9c2 cells. Notably, these exosomes significantly upregulated miR-21-5p levels within H9c2 cells, and the abrogation of miR-21-5p function abated their protective effects. Through computational analysis, we unveiled a miR-21-5p binding site in the 3'UTR of YAP1, which directly inhibited YAP1 expression. Importantly, the inhibition of YAP1 effectively reinstated the protective effects of exosomes in cells with impaired exosomal miR-21-5p.

This study underscores the pivotal role played by MSC-derived exosomes in safeguarding against MI, primarily by mediating the transfer of miR-21-5p, which targets YAP1 signaling pathways.

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Many strategies for regenerating the damaged tissues or degenerating cells are employed in regenerative medicine. Stem cell technology is a modern strategy of the recent approaches, particularly the use of mesenchymal stem cells (MCSs). The ability of MSCs to differentiate as well as their characteristic behaviour as paracrine effector has established them as key elements in tissue repair. Recently, extracellular vesicles (EVs) shed by MSCs have emerged as a promising cell free therapy. This comprehensive review encompasses MSCs-derived exosomes and their therapeutic potential as nanotherapeutics. We also discuss their potency as drug delivery nano-carriers in comparison with liposomes. A better knowledge of EVs behaviour in vivo and of their mechanism of action are key to determine parameters of an optimal formulation in pilot studies and to establish industrial processes.

Cell death constitutes a critical component of the pathophysiology of cardiovascular diseases. A growing array of non-apoptotic forms of regulated cell death (RCD)-such as necroptosis, ferroptosis, pyroptosis, and cuproptosis-has been identified and is intimately linked to various cardiovascular conditions. These forms of RCD are governed by genetically programmed mechanisms within the cell, with epigenetic modifications being a common and crucial regulatory method. Such modifications include DNA methylation, RNA methylation, histone methylation, histone acetylation, and non-coding RNAs. This review recaps the roles of DNA methylation, RNA methylation, histone modifications, and non-coding RNAs in cardiovascular diseases, as well as the mechanisms by which epigenetic modifications regulate key proteins involved in cell death. Furthermore, we systematically catalog the existing epigenetic pharmacological agents targeting novel forms of RCD and their mechanisms of action in cardiovascular diseases. This article aims to underscore the pivotal role of epigenetic modifications in precisely regulating specific pathways of novel RCD in cardiovascular diseases, thus offering potential new therapeutic avenues that may prove more effective and safer than traditional treatments.