Circular RNAs as Biomarkers and Therapeutic Targets in Diabetic Cardiovascular Complications

Emerging roles of circular RNAs in systemic lupus erythematosus

Circular RNAs (circRNAs) are novel noncoding RNAs with covalently closed-loop structures that can regulate eukaryotic gene expression. Due to their stable structure, circRNAs are widely distributed in the cytoplasm and have important biological functions, including as microRNA sponges, RNA-binding protein conjugates, transcription regulators, and translation templates. Breast cancer is among the most common malignant cancers diagnosed in women worldwide. Despite the development of comprehensive treatments, breast cancer still has high mortality rates. Recent studies have unmasked critical roles for circRNAs in breast cancer as regulators of tumour initiation, progression, and metastasis. Further, research has revealed that some circRNAs have the potential for use as diagnostic and prognostic biomarkers in clinical practice. Herein, we review the biogenesis and biological functions of circRNAs, as well as their roles in different breast cancer subtypes. Moreover, we provide a comprehensive summary of the clinical significance of circRNAs in breast cancer. CircRNAs are believed to be a hot focus in basic and clinical research of breast cancer, and innovative future research directions of circRNAs could be used as biomarkers, therapeutic targets, or novel drugs. Abbreviations: CeRNA: Competitive endogenous RNA; ciRNA: Circular intronic RNA; circRNA: Circular RNA; EIciRNA: Exon-intron circRNA; EMT: Epithelial–mesenchymal transition; IRES: Internal ribosome entry site; lncRNA: Long non-coding RNA; miRNA: MicroRNA; MRE: MiRNA response element; ncRNA: Non-coding RNA; RBP: RNA-binding protein; RNA-seq: RNA sequencing; RT-PCR: Reverse transcription-polymerase chain reaction

Pancreatic cancer (PC), characterized by its insidious onset and extreme malignancy, is one of the most aggressive and lethal malignancies and poses significant challenges in clinical management, with a dismal 5-year survival rate due to late diagnosis and limited treatment options. Although advances have been made in understanding adult pancreatic tumors, pediatric pancreatic tumors (PPTs) remain understudied, with research on their molecular mechanisms and potential biomarkers still in the early stages. Circular RNAs (circRNAs), a newly discovered class of endogenous noncoding RNA molecules, have recently been identified as key regulators in tumorigenesis, progression, and therapeutic response. Unlike linear RNAs, circRNAs possess a unique covalently closed-loop structure, which confers exceptional stability and resistance to degradation. This feature makes them promising candidates as diagnostic biomarkers and therapeutic targets. A growing body of evidence suggests that circRNAs play crucial roles in various cancers, including pancreatic tumors, by modulating gene expression, interacting with microRNAs, and influencing signaling pathways. In PPT, the exploration of circRNAs is still nascent, yet preliminary studies indicate their involvement in tumor development and progression. Some circRNAs have been found to promote cell proliferation, invasion, and metastasis, while others may act as tumor suppressors. Identifying specific circRNA signatures in PPT could enhance early detection, improve prognostic assessment, and uncover novel therapeutic strategies. This review summarizes the current understanding of circRNAs in PPT, highlighting their potential as diagnostic markers and therapeutic targets. Elucidating their molecular mechanisms may inspire innovative approaches in managing this rare but devastating disease. Further investigations are needed to validate the findings gleaned thus far and translate them into clinical practice.

Circular RNAs are a class of noncoding RNAs with covalently linked 5' and 3' ends that arise from backsplicing events. The absence of a 5' cap and a 3' poly(A) tail makes circular RNAs relatively more stable than their linear counterparts. They are evolutionary conserved and tissue-specific, and some show disease-specific expression patterns. Although their biological functions remain largely unknown, circular RNAs have been shown to play regulatory roles by acting as microRNA sponges, regulators of RNA-binding proteins, alternative splicing, and parental gene expression, and they could even encode proteins. Over the past few decades, circular RNAs have attracted wide attention in oncology owing to their implications in various tumors. Many circular RNAs have been characterized as key players in gastrointestinal cancers and influence cancer growth, progression, metastasis, and therapeutic resistance. Accumulating evidence reveals that their unique characteristics, coupled with their critical roles in tumorigenesis, make circular RNAs promising non-invasive clinical biomarkers for gastrointestinal cancers. In the present review, we summarized the biological roles of the emerging circular RNAs and their potential as biomarkers and therapeutic targets, which may help better understand their clinical significance in the management of gastrointestinal cancers.

Circular RNAs are abundant and conserved endogenous RNAs that are formed by exon skipping or back‑splicing events and occur in all forms of life. They have been proven to exhibit tissue‑ or cell‑type specificity and to be able to regulate cell behavior through multiple pathways. In cancer research, numerous studies have indicated that circular RNAs serve as potential biomarkers and therapeutic targets. Furthermore, differential expression of certain circular RNAs clearly predicts the clinical outcomes of cancer patients. Circular RNAs regulate carcinogenesis and cancer progression by acting as a microRNA sponge, coding for proteins and interacting with proteins. The present review mainly focuses on the recent literature regarding the role of circular RNAs in cancer, which may suggest novel strategies for cancer prognosis, diagnosis and clinical treatment.

Diabetes mellitus is a predominant cause of mortality and morbidity worldwide. One of its serious health problems is cardiovascular complications. Advanced glycation end products (AGEs) are a group of heterogeneous toxic oxidant compounds that are formed after a non-enzymatic reaction between monosaccharides and free amino groups of proteins, compound lipids, and nucleic acids. AGE interacts with various types of cells through a receptor for AGE (RAGE). The interaction between AGE and RAGE is responsible for a cascade of inflammation, oxidative stress, and disruption of calcium homeostasis in cardiac cells of diabetic patients. There is striking evidence that the AGE/RAGE axis with its consequences on inflammation and oxidative stress plays a major role in the development of cardiovascular complications. Therefore, considering AGE as a therapeutic target with foreseeable results would be a wise direction for future research. Interestingly, several studies on nutraceutical, pharmaceutical, and natural products have begun to reveal promising therapeutic results, and this could lead to better health outcomes for many diabetic patients worldwide. This article discusses the current literature addressing the connection between protein glycation and diabetes cardiovascular complications and suggests future avenues of research.

Cardiovascular complications are a common death cause in type 2 diabetes patients, as they are often combined. Plasminogen-activator Inhibitor 1 (PAI-1) participates in the development and progression of cardiovascular complications in diabetes. Insulin resistance increases PAI-1 production, and high PAI-1 levels lead to an environment conducive to thrombosis and earlier and more severe vascular disease. Current evidence also suggests that PAI-1 has a rhythmic profile of circadian fluctuations and acrophase in the morning within a single day, which might explain the high morning incidence of cardiovascular events. Thus, PAI-1 is a possible drug target. Although several PAI-1 inhibitors have been developed, none have yet been allowed for clinical use. Research on rhythm has also led to the concept of “chronotherapy”, a rhythm-based drug regimen expected to improve the treatment of cardiovascular complications in diabetic patients. Herein, we searched several databases and reviewed relevant articles to describe the circadian rhythm characteristics and endogenous molecular mechanisms of PAI-1, its relationship with insulin resistance, the causes of cardiovascular complications caused by PAI-1, and the current development of PAI-1 inhibitors. We also summarized the possibility of using the circadian rhythm of PAI-1 to treat cardiovascular complications in diabetic patients.

With the advent of cancer diagnostics and therapeutics, circular RNAs (circRNAs) are swiftly becoming one of the significant regulators of gene expression and cellular functions. A plethora of multiple molecular mechanisms has been observed to elicit their influence. Circular RNAs (circRNAs) are a distinct category of endogenous noncoding RNAs designed as a result of exon back splicing events in precursor's mRNAs (pre-mRNAs) and are widely distributed in the transcriptome of eukaryotic cells. Although the role of circRNAs is still in its infancy, they serve as microRNA sponges, protein scaffolds, and modulators of transcription and splicing and occasionally as templates for the production of peptides. It is well known that abnormal circRNA expression is prevalent in malignancies and has been linked to a number of pathophysiological aspects of cancer. This extensively anomalous expression assists in cellular proliferation and growth, sustaining cellular invasiveness and bypassing cellular senescence and death, thus advocating their promise to serve as both clinical biomarkers and therapeutic targets. An overview of the recent status of circRNA will aid in the identification of new biomarkers, therapeutic targets, and their prospect in the diagnosis and therapy of disease. In this review article, we discuss the functional mechanisms of circRNAs, their biomarker potential in disease diagnosis and prognosis, therapeutic approaches, and the associated limitations.

Background:Osteosarcoma is the most common primary malignant bone tumor, mainly affecting children, young adults, and the elderly. It is an aggressive cancer with a poor prognosis, exhibiting low survival rates even with standard treatment. Recently, circular RNA molecules capable of influencing gene expression through various functions, with their main role being acting as microRNA sponges and reducing their intracellular expression, have been identified. Recent studies have linked circular RNAs to osteosarcoma development and progression. Therefore, the present study aimed to investigate the alteration in circular RNA expression during osteosarcoma development and progression. Methods:An integrative literature review was conducted from September 10th to November 12th, 2021, using the following databases: PubMed/MEDLINE, SCOPUS, Web of Science, OVID, and EMBASE. 129 full articles were included in the review. The obtained data were organized using a standardized data collection instrument, which included the following information: altered expression profile of circular RNAs, associated cancer hallmarks, clinical-pathological relationships of circular RNAs, and perspectives on the studied circular RNAs. Results:A total of 94 distinct circular RNAs were identified, predominantly showing an increased expression pattern. Approximately 91% of the studies that aimed to identify the mechanisms of action of circular RNAs highlighted the function of circular RNAs as microRNA sponges. The most associated cancer hallmarks with the identified circular RNAs were proliferative signaling induction, invasion and metastasis, and resistance to cell death. The altered expression of these circular RNAs generally correlated with a worse prognosis for patients, as evidenced by clinical features such as shorter survival, advanced Enneking and/or TNM stage, higher incidence of metastasis, larger tumor size, and increased chemoresistance. Conslusion:These findings indicate the significance of circular RNA molecules in osteosarcoma carcinogenesis, suggesting their potential as new prognostic and/or diagnostic biomarkers, as well as alternative therapeutic targets in the fight against osteosarcoma.

Pharmacological mechanisms of Taohe Chengqi decoction in diabetic cardiovascular complications: A systematic review, network pharmacology and molecular docking

Cardiovascular disease, the major cause of mortality and morbidity in modern societies, is set to overtake infectious diseases in the developing world as the most common cause of death. The increasing prevalence of major and emerging cardiovascular risk factors accounts for the growing burden of cardiovascular disease in the world. Diabetes in all its forms is one of the main cardiovascular risk factors. Two of 3 diabetic patients will die as a result of cardiovascular complications, and approximately 30% of patients treated in cardiovascular intensive care units have diabetes. This review on the cardiovascular complications of diabetes in sub-Saharan Africa is a bibliographical MEDLINE search of published data over the past 2 decades. Diabetes-related cardiovascular disease complications are considered to be rare in Africa but are on the rise and are regularly associated with classic cardiovascular risk factors. Coronary heart disease may affect 5% to 8% of type 2 diabetic patients and cardiomyopathy, up to 50% of all patients. Close to 15% of patients with stroke have diabetes, and up to 5% of diabetic patients present with cerebrovascular accidents at diagnosis. Peripheral vascular disease prevalence varies across sites from 4% to 28%. It is obvious that diabetes mellitus and related cardiovascular complications are gaining more importance in sub-Saharan Africa. The relative contribution of putative risk factors is not well defined, and further research is therefore needed.

Effects of glucagon-like peptide-1 (GLP-1) receptor agonist on cardiovascular complications of diabetes mellitus (DM) were investigated. In total, 132 DM patients treated in Tengzhou Central People's Hospital from April 2013 to September 2016 were included. Of these, 71 cases treated with basic drugs plus GLP-1 were the research group, and 61 cases treated with glipizide controlled release tablets the control group. The improvement of clinical efficacy of patients in the two groups after treatment was observed. The concentrations of FPG, HbAlc, TC, LDL-C, and HDL-C in serum of patients in the two groups before and after treatment were compared, and the incidence rate of cardiovascular disease complications of diabetes was recorded. Expression of FPG, HbAlc, TC, LDL-C, and HDL-C of patients in the two groups were further detected. ROC curve was drawn to analyze its predictive value. In terms of markedly effective treatment rate and overall effective rate, the research group was significantly better than the control group (P<0.05). After treatment, the concentrations of FPG, HbAlc, TC, LDL-C, and HDL-C in serum of patients in the research group were significantly lower than those in the control group (P<0.05). The incidence rate of cardiovascular diseases and residual vascular risks in the research group were significantly higher than those in the control group (P<0.05). After treatment, the AUC of FPG, HbAlc, TC, LDL-C, and HDL-C in serum for predicting cardiovascular complications in DM patients were, respectively, 0.742, 0.780, 0.737, 0.726, and 0.721. In conclusion, GLP-1 receptor agonist can improve the clinical efficacy of patients. Through ROC curve, FPG, HbAlc, TC, LDL-C and HDL-C can be used as predictors of cardiovascular complications in DM patients, which has high clinical value.

The occurrence and development of cardiovascular complications are predominantly responsible for the increased morbidity and mortality observed in patients with diabetes. Oxidative stress under hyperglycemia is currently considered the initial link to diabetic cardiovascular complications and a key node for the prevention and treatment of diabetes-related fatal cardiovascular events. Numerous studies have indicated that the common upstream pathway in the context of oxidative stress in the cardiovascular system under diabetic conditions is the interaction of advanced glycation end products (AGEs) with their receptors (RAGEs). Therefore, a further understanding of the relationship between oxidative stress and AGEs is of great significance for the prevention and treatment of cardiovascular complications in patients with diabetes. In this review, we will briefly summarize the recent research advances in diabetes with an emphasis on oxidative stress and its association with AGEs in diabetic cardiovascular complications.

Circular RNAs, which are a novel subclass of noncoding RNAs, are reported to be involved in various biological processes. Aberrant expression of circular RNAs may promote cancer progression. The function of circular GOLPH3 RNA (circGOLPH3) in oral squamous cell carcinoma (OSCC) is unclear. In this study, the circGOLPH3 levels in OSCC cell lines were determined using quantitative real-time polymerase chain reaction (qRT-PCR). Gain-of-function and loss-of-function experiments were performed to evaluate the roles of circGOLPH3 in OSCC. Cell counting kit 8, migration, and invasion assays were performed to determine the functions of circGOLPH3. The mechanism of circGOLPH3 in OSCC was investigated using qRT-PCR, western blotting, luciferase activity, and RNA pull-down analyses. Furthermore, the function of circGOLPH3 in vivo was evaluated. circGOLPH3 derived from GOLPH3 was mainly localized to the cytoplasm and exhibited high stability. The expression of circGOLPH3 was upregulated in OSCC cells. circGOLPH3 promoted the growth of OSCC in vitro and in vivo. Additionally, circGOLPH3 upregulated OSCC cell migration and invasion. Mechanistically, circGOLPH3 functioned as a microRNA sponge and downregulated miR-1299 expression. miR-1299 downregulated the expression of LIF by targeting its 3’-untranslated region. Inhibition of the circGOLPH3/miR-1299/LIF axis suppressed the growth, migration, and invasion of OSCC cells. These findings indicate that the circGOLPH3/miR-1299/LIF axis promotes OSCC cell growth, migration, and invasion and that this axis is a potential therapeutic target for OSCC.

Circular RNA (circRNA) is a new type of non-coding RNA. It is mainly composed of exons, and prevalent and stable presence among living organisms. Research has revealed that circRNA has many functions such as microRNA (miRNA) sponges, and regulation of alternative splicing and gene expression. Recent evidence suggests that circRNA plays an important role in many diseases. This review summarizes our current understanding of theclassifications, characteristics, functions, and the relationships of circRNA with diseases, in order to aid diagnosis, treatment, and prevention of clinical related diseases. Key words: Circular RNA; Non-coding RNA; MicroRNA sponges