The function and mechanism of circRNAs in 5-fluorouracil resistance in tumors: Biological mechanisms and future potential.

5-Fluorouracil (5-FU) is a well-known chemotherapy drug extensively used in the treatment of breast cancer. It works by inhibiting cancer cell proliferation and inducing cell death through direct incorporation into DNA and RNA via thymidylate synthase (TS). Circular RNAs (circRNAs), a novel family of endogenous non-coding RNAs (ncRNAs) with limited protein-coding potential, contribute to 5-FU resistance. Their identification and targeting are crucial for enhancing chemosensitivity. CircRNAs can regulate tumor formation and invasion by adhering to microRNAs (miRNAs) and interacting with RNA-binding proteins, regulating transcription and translation. MiRNAs can influence enzymes responsible for 5-FU metabolism in cancer cells, affecting their sensitivity or resistance to the drug. In the context of 5-FU resistance, circRNAs can target miRNAs and regulate biological processes such as cell proliferation, cell death, glucose metabolism, hypoxia, epithelial-to-mesenchymal transition (EMT), and drug efflux. This review focuses on the function of circRNAs in 5-FU resistance, discussing the underlying molecular pathways and biological mechanisms. It also presents recent circRNA/miRNA-targeted cancer therapeutic strategies for future clinical application.

The landscape of circRNAs in gliomas temozolomide resistance: Insights into molecular pathways.

As the deadliest type of primary brain tumor, gliomas represent a significant worldwide health concern. Circular RNA (circRNA), a unique non-coding RNA molecule, seems to be one of the most alluring target molecules involved in the pathophysiology of many kinds of cancers. CircRNAs have been identified as prospective targets and biomarkers for the diagnosis and treatment of numerous disorders, particularly malignancies. Recent research has established a clinical link between temozolomide (TMZ) resistance and certain circRNA dysregulations in glioma tumors. CircRNAs may play a therapeutic role in controlling or overcoming TMZ resistance in gliomas and may provide guidance for a novel kind of individualized glioma therapy. To address the biological characteristics of circRNAs and their potential to induce resistance to TMZ, this review has highlighted and summarized the possible roles that circRNAs may play in molecular pathways of drug resistance, including the Ras/Raf/ERK PI3K/Akt signaling pathway and metabolic processes in gliomas.

Insight into the cardioprotective effects of melatonin: shining a spotlight on intercellular Sirt signaling communication.

Cardiovascular diseases (CVDs) are the leading causes of death and illness worldwide. While there have been advancements in the treatment of CVDs using medication and medical procedures, these conventional methods have limited effectiveness in halting the progression of heart diseases to complete heart failure. However, in recent years, the hormone melatonin has shown promise as a protective agent for the heart. Melatonin, which is secreted by the pineal gland and regulates our sleep-wake cycle, plays a role in various biological processes including oxidative stress, mitochondrial function, and cell death. The Sirtuin (Sirt) family of proteins has gained attention for their involvement in many cellular functions related to heart health. It has been well established that melatonin activates the Sirt signaling pathways, leading to several beneficial effects on the heart. These include preserving mitochondrial function, reducing oxidative stress, decreasing inflammation, preventing cell death, and regulating autophagy in cardiac cells. Therefore, melatonin could play crucial roles in ameliorating various cardiovascular pathologies, such as sepsis, drug toxicity-induced myocardial injury, myocardial ischemia-reperfusion injury, hypertension, heart failure, and diabetic cardiomyopathy. These effects may be partly attributed to the modulation of different Sirt family members by melatonin. This review summarizes the existing body of literature highlighting the cardioprotective effects of melatonin, specifically the ones including modulation of Sirt signaling pathways. Also, we discuss the potential use of melatonin-Sirt interactions as a forthcoming therapeutic target for managing and preventing CVDs.

Mechanistic insights into circRNA-mediated regulation of PI3K signaling pathway in glioma progression.

Circular RNAs (CircRNAs) are non-coding RNAs (ncRNAs) characterized by a stable circular structure that regulates gene expression at both transcriptional and post-transcriptional levels. They play diverse roles, including protein interactions, DNA methylation modification, protein-coding potential, pseudogene creation, and miRNA sponging, all of which influence various physiological processes. CircRNAs are often highly expressed in brain tissues, and their levels vary with neural development, suggesting their significance in nervous system diseases such as gliomas. Research has shown that circRNA expression related to the PI3K pathway correlates with various clinical features of gliomas. There is an interact between circRNAs and the PI3K pathway to regulate glioma cell processes such as proliferation, differentiation, apoptosis, inflammation, angiogenesis, and treatment resistance. Additionally, PI3K pathway-associated circRNAs hold potential as biomarkers for cancer diagnosis, prognosis, and treatment. In this study, we reviewed the latest advances in the expression and cellular roles of PI3K-mediated circRNAs and their connections to glioma carcinogenesis and progression. We also highlighted the significance of circRNAs as diagnostic and prognostic biomarkers and therapeutic targets in glioma.

The emerging role of circular RNAs in cisplatin resistance in ovarian cancer: From molecular mechanism to future potential.

Ovarian cancer (OC) is the most common cause of death in female cancers. The prognosis of OC is very poor due to delayed diagnosis and identification of most patients in advanced stages, metastasis, recurrence, and resistance to chemotherapy. As chemotherapy with platinum-based drugs such as cisplatin (DDP) is the main treatment in most OC cases, resistance to DDP is an important obstacle to achieving satisfactory therapeutic efficacy. Consequently, knowing the different molecular mechanisms involved in resistance to DDP is necessary to achieve new therapeutic approaches. According to numerous recent studies, non-coding RNAs (ncRNAs) could regulate proliferation, differentiation, apoptosis, and chemoresistance in many cancers, including OC. Most of these ncRNAs are released by tumor cells into human fluid, allowing them to be used as tools for diagnosis. CircRNAs are ncRNA family members that have a role in the initiation, progression, and chemoresistance regulation of various cancers. In the current study, we investigated the roles of several circRNAs and their signaling pathways on OC progression and also on DDP resistance during chemotherapy.

The potential role of circular RNAs -regulated PI3K signaling in non-small cell lung cancer: Molecular insights and clinical perspective.

Non-small cell lung cancer (NSCLC), accounting for more than 80% of all cases, is the predominant form of lung cancer and the leading cause of cancer-related deaths worldwide. Significant progress has been made in diagnostic techniques, surgical interventions, chemotherapy protocols, and targeted therapies at the molecular level, leading to enhanced treatment outcomes in patients with NSCLC. Extensive evidence supports the use of circular RNAs (circRNAs), a specific category of naturally occurring non-coding small RNAs (ncRNAs), for the diagnosis, monitoring of treatment efficacy, and assessment of survival in NSCLC. CircRNAs have been identified to play significant roles in various aspects of cancer formation, either as tumor suppressors or tumor promoters, contributing to cancer development through several signaling pathways, including the phosphoinositide 3-kinases (PI3Ks) pathway. This pathway is well-established because of its regulatory role in essential cellular processes. CircRNAs regulate the PI3K/AKT pathway by targeting diverse cellular elements. This review aims to provide insight into the involvement of several circRNAs linked to the PI3K/AKT pathway in NSCLC.

Role of long noncoding RNAs in pathological cardiac remodeling after myocardial infarction: An emerging insight into molecular mechanisms and therapeutic potential.

Myocardial infarction (MI) is the leading cause of heart failure (HF), accounting for high mortality and morbidity worldwide. As a consequence of ischemia/reperfusion injury during MI, multiple cellular processes such as oxidative stress-induced damage, cardiomyocyte death, and inflammatory responses occur. In the next stage, the proliferation and activation of cardiac fibroblasts results in myocardial fibrosis and HF progression. Therefore, developing a novel therapeutic strategy is urgently warranted to restrict the progression of pathological cardiac remodeling. Recently, targeting long non-coding RNAs (lncRNAs) provided a novel insight into treating several disorders. In this regard, numerous investigations have indicated that several lncRNAs could participate in the pathogenesis of MI-induced cardiac remodeling, suggesting their potential therapeutic applications. In this review, we summarized lncRNAs displayed in the pathophysiology of cardiac remodeling after MI, emphasizing molecular mechanisms. Also, we highlighted the possible translational role of lncRNAs as therapeutic targets for this condition and discussed the potential role of exosomes in delivering the lncRNAs involved in post-MI cardiac remodeling.

Circular RNAs and cervical cancer: friends or foes? A landscape on circRNA-mediated regulation of key signaling pathways involved in the onset and progression of HPV-related cervical neoplasms.

Cervical cancer (CC) is a common gynecologic malignancy, accounting for a significant proportion of women death worldwide. Human papillomavirus (HPV) infection is one of the major etiological causes leading to CC onset; however, genetic, and epigenetic factors are also responsible for disease expansion. Circular RNAs (circRNAs), which are known as a particular subset of non-coding RNA (ncRNA) superfamily, with covalently closed loop structures, have been reported to be involved in the progression of diverse diseases, especially neoplasms. In this framework, abnormally expressed circRNAs are in strong correlation with CC pathogenesis through regulating substantial signaling pathways. Also, these RNA molecules can be considered as promising biomarkers and therapeutic targets for CC diagnosis/prognosis and treatment, respectively. Herein, we first review key molecular mechanisms, including Wnt/ß-catenin, MAPK, and PI3K/Akt/mTOR signaling pathways, as well as angiogenesis and metastasis, by which circRNAs interfere with CC development. Then, diagnostic, prognostic, and therapeutic potentials of these ncRNA molecules will be highlighted in depth.

Recent Insights into the Angioregulatory Role of Long Non-coding RNAs and Circular RNAs in Gliomas: From Signaling Pathways to Clinical Aspects.

The most prevalent and severe malignancy of the central nervous system within the brain is glioma. Glioma is a vascularized cancer, and angiogenesis is necessary for glioma growth, invasion, and recurrence. It is also believed that this factor is this factor to be accountable for therapy resistance in many cancers, including glioma. The process of angiogenesis, which plays a crucial role in both health and disease situations such as cancer, involves the creation of new blood vessels from pre-existing ones. Non-coding RNAs (ncRNAs) are unique molecules that have been found to possess a wide range of abilities to modify the expression of various genes. They carry out their gene-modulating roles at a variety of distinct levels, including post-transcriptional and post-translational levels. Long ncRNAs (lncRNAs) and circular RNAs (circRNAs) are a group of ncRNA that have attracted particular attention and are involved in the angiogenesis mechanism in cancer. Understanding the regulatory mechanisms of these RNAs in the angiogenesis process in gliomas provides unique fundamental information about the process of tumor-associated neovascularization. On the other hand, due to developments in the characterisation of lncRNAs and circRNAs, these novel structures may potentially be used in clinics as possible biomarkers for treatment strategies that target tumor angiogenesis. Throughout the review, new knowledge and views about the angioregulatory function of circRNAs and lncRNAs in gliomas have been presented. Additionally, we talk about the novel idea of ncRNA-based therapeutics for gliomas in the future.

Circular RNAs: Emerging Modulators in the Pathophysiology of Polycystic Ovary Syndrome and their Clinical Implications.

Polycystic ovary syndrome (PCOS) is a prevalent endocrine/metabolic disorder in women of reproductive age. PCOS is characterized by hyperandrogenism, polycystic ovary morphology, and ovulatory dysfunction/anovulation. It involves multiple effects in patients, including granulosa/theca cell hyperplasia, menstrual disturbances, infertility, acne, obesity, insulin resistance, and cardiovascular disorders. Biochemical analyses and the results of RNA sequencing studies in recent years have shown a type of non-coding RNAs as a splicing product known as circular RNAs (circRNAs). Several biological functions have been identified in relation to circRNAs, including a role in miRNA sponge, protein sequestration, increased parental gene expression, and translation leading to polypeptides. These circular molecules are more plentiful and specialized than other types of RNAs. For this reason, they are referred to as potential biomarkers in different diseases. Evidence suggests that circRNAs may have regulatory potentials through different signaling pathways, such as the miRNA network. Probably most experts in the field of obstetricians are not aware of circRNAs as a useful biomarker. Therefore, this review focused on the researches that have been done on the involvement of circRNAs in PCOS and summarized recent supportive evidence, and evaluated the circRNA association and mechanisms involved in PCOS.

New Insights into the Long Non-coding RNAs Dependent Modulation of Heart Failure and Cardiac Hypertrophy: From Molecular Function to Diagnosis and Treatment.

Heart failure (HF) is a public health issue that imposes high costs on healthcare systems. Despite the significant advances in therapies and prevention of HF, it remains a leading cause of morbidity and mortality worldwide. The current clinical diagnostic or prognostic biomarkers, as well as therapeutic strategies, have some limitations. Genetic and epigenetic factors have been identified to be central to the pathogenesis of HF. Therefore, they might provide promising novel diagnostic and therapeutic approaches for HF. Long non-coding RNAs (lncRNAs) belong to a group of RNAs that are produced by RNA polymerase II. These molecules play an important role in the functioning of different cell biological processes, such as transcription and regulation of gene expression. LncRNAs can affect different signaling pathways by targeting biological molecules or a variety of different cellular mechanisms. The alteration in their expression has been reported in different types of cardiovascular diseases, including HF, supporting the theory that they are important in the development and progression of heart diseases. Therefore, these molecules can be introduced as diagnostic, prognostic, and therapeutic biomarkers in HF. In this review, we summarize different lncRNAs as diagnostic, prognostic, and therapeutic biomarkers in HF. Moreover, we highlight various molecular mechanisms dysregulated by different lncRNAs in HF.

Unfolded Protein Response Signaling in Hepatic Stem Cell Activation in Liver Fibrosis.

Frequent exposure to various external and internal adverse forces (stresses) disrupts cell protein homeostasis through endoplasmic reticulum (ER) capacity saturation. This process leads to the unfolded protein response (UPR), which aims to re-establish/maintain optimal cellular equilibrium. This complex mechanism is involved in the pathogenesis of various disorders, such as metabolic syndrome, fibrotic diseases, neurodegeneration, and cancer, by altering cellular metabolic changes integral to activating the hepatic stellate cells (HSCs). The development of hepatic fibrosis is one of the consequences of UPR activation. Therefore, novel therapies that target the UPR pathway effectively and specifically are being studied. This article covers the involvement of the UPR signaling pathway in cellular damage in liver fibrosis. Investigating the pathogenic pathways related to the ER/UPR stress axis that contribute to liver fibrosis can help to guide future drug therapy approaches.

Liver Disorders Caused by Inborn Errors of Metabolism.

Inborn errors of metabolism (IEMs) are a vast array of inherited/congenital disorders, affecting a wide variety of metabolic pathways and/or biochemical processes inside the cells. Although IEMs are usually rare, they can be represented as serious health problems. During the neonatal period, these inherited defects can give rise to almost all key signs of liver malfunction, including jaundice, coagulopathy, hepato- and splenomegaly, ascites, etc. Since the liver is a vital organ with multiple synthetic, metabolic, and excretory functions, IEM-related hepatic dysfunction could seriously be considered life-threatening. In this context, the identification of those hepatic manifestations and their associated characteristics may promote the differential diagnosis of IEMs immediately after birth, making therapeutic strategies more successful in preventing the occurrence of subsequent events. Among all possible liver defects caused by IEMs, cholestatic jaundice, hepatosplenomegaly, and liver failure have been shown to be manifested more frequently. Therefore, the current study aims to review substantial IEMs that mostly result in the aforementioned hepatic disorders, relying on clinical principles, especially through the first years of life. In this article, a group of uncommon hepatic manifestations linked to IEMs is also discussed in brief.

Non-coding RNAs in leukemia drug resistance: new perspectives on molecular mechanisms and signaling pathways.

Like almost all cancer types, timely diagnosis is needed for leukemias to be effectively cured. Drug efflux, attenuated drug uptake, altered drug metabolism, and epigenetic alterations are just several of the key mechanisms by which drug resistance develops. All of these mechanisms are orchestrated by up- and downregulators, in which non-coding RNAs (ncRNAs) do not encode specific proteins in most cases; albeit, some of them have been found to exhibit the potential for protein-coding. Notwithstanding, ncRNAs are chiefly known for their contribution to the regulation of physiological processes, as well as the pathological ones, such as cell proliferation, apoptosis, and immune responses. Specifically, in the case of leukemia chemo-resistance, ncRNAs have been recognized to be responsible for modulating the initiation and progression of drug resistance. Herein, we comprehensively reviewed the role of ncRNAs, specifically its effect on molecular mechanisms and signaling pathways, in the development of leukemia drug resistance.

Efficacy and Safety of Atezolizumab Monotherapy or Combined Therapy with Chemotherapy in Patients with Metastatic Triple-negative Breast Cancer: A Systematic Review and Meta-analysis of Randomized Controlled Trials.

INTRODUCTION: Several successful attempts have been recorded with PD-L1 blockade via atezolizumab monotherapy or combination therapy with chemotherapy in patients with metastatic triple-negative breast cancer (mTNBC). Due to the lack of a large-scale study, we present a meta-analysis aimed at evaluating the safety and efficacy of this promising strategy in patients with mTNBC. METHODS: A comprehensive literature search was conducted using electronic databases to identify eligible RCTs. Twelve studies, including 2479 mTBNC patients treated with atezolizumab monotherapy or in combination with chemotherapy, were included up to January 2022. The PRISMA checklist protocol and the I2 statistic were applied for quality assessment and heterogeneity tests of the selected trials, respectively. Fixed and random-effects models were estimated based on the heterogeneity tests, and statistical analysis was performed using CMA. RESULTS: Our pooled findings demonstrated that the median overall survival (OS) and progression-free survival (PFS) were 16.526 and 5.814 months in mTNBC patients, respectively. Furthermore, when comparing efficacy indicators between PD-L1-positive and PD-L1-negative groups, mTNBC patients with PD-L1 had better OS, PFS, and ORR than PD-L1-negative patients. Also, the immune-related adverse event incident for alopecia was higher (51.9%) than other complications across atezolizumab therapy. CONCLUSION: Moreover, the pooled analysis indicated that the overall rate of lung metastasis following atezolizumab therapy was 42.8%, which was higher than the rates of metastasis in bone (26.9%), brain (5.4%), and lymph node (6.5%). Atezolizumab showed a manageable safety profile and had promising and durable anti-tumor efficacy in TMBC patients. Higher PD-L1 expression may be closely correlated with better clinical efficacy.

Regulating miRNAs Expression by Resveratrol: Novel Insights based on Molecular Mechanism and Strategies for Cancer Therapy.

Resveratrol, a polyphenolic phytoalexin found in a wide range of plants, including grapes, berries, and peanuts, is an extensively researched phytochemical with unique pharmacological capabilities and amazing potential to affect many targets in various cancers. Resveratrol's anti-cancer activities are due to its targeting of a variety of cellular and molecular mechanisms and crucial processes involved in cancer pathogenesis, such as the promotion of growth arrest, stimulation of apoptosis, suppression of cell proliferation, induction of autophagy, regulating oxidative stress and inflammation, and improving the influence of some of the other chemotherapeutic agents. MicroRNAs (miRNAs) are non-coding RNAs that modulate gene expression by degrading mRNA or inhibiting translation. MiRNAs serve critical roles in a wide range of biological activities, and disruption of miRNA expression is strongly linked to cancer progression. Recent research has shown that resveratrol has anti-proliferative and/or pro-apoptotic properties via modulating the miRNA network, which leads to the inhibition of tumor cell proliferation, the activation of apoptosis, or the increase of traditional cancer therapy effectiveness. As a result, employing resveratrol to target miRNAs will be a unique and potential anticancer approach. Here, we discuss the main advances in the modulation of miRNA expression by resveratrol, as well as the several miRNAs that may be influenced by resveratrol in different types of cancer and the significance of this natural drug as a promising strategy in cancer treatment.

Circular RNAs: novel actors of Wnt signaling pathway in lung cancer progression.

Circular RNAs (CircRNAs) are a class of regulatory RNA transcripts, which are ubiquitously expressed in eukaryotes. CircRNA dysregulation has been shown to disrupt the interaction of the Wnt/ß-catenin pathway, which regulates several biological processes involved in tumorigenesis, thereby contributing to the development and progression of cancer. Interactions of tumor-derived circRNAs with the Wnt/ß-catenin signaling pathway provide both clinical diagnostic biomarkers and promising therapeutic targets. In this review, we outlined current evidence on the roles of circRNAs associated with the Wnt/ß-catenin pathway in regulating lung cancer formation and development. We believe that our findings will assist in the advancement or establishment of circRNA-based lung cancer therapeutic approaches.

Melatonin as a regulator of apoptosis in leukaemia: molecular mechanism and therapeutic perspectives.

Leukaemia is a dangerous malignancy that causes thousands of deaths every year throughout the world. The rate of morbidity and mortality is significant despite many advancements in therapy strategies for affected individuals. Most antitumour medications used now in clinical oncology use apoptotic signalling pathways to induce cancer cell death. Accumulated data have shown a direct correlation between inducing apoptosis in cancer cells with higher tumour regression and survival. Until now, the efficacy of melatonin as a powerful antitumour agent has been firmly established. A change in melatonin concentrations has been reported in multiple tumours such as endometrial, hematopoietic, and breast cancers. Findings show that melatonin's anticancer properties, such as its prooxidation function and ability to promote apoptosis, indicate the possibility of utilizing this natural substance as a promising agent in innovative cancer therapy approaches. Melatonin stimulates cell apoptosis via the regulation of many apoptosis facilitators, including mitochondria, cytochrome c, Bcl-2, production of reactive oxygen species, and apoptosis receptors. This paper aimed to further assess the anticancer effects of melatonin through the apoptotic pathway, considering the role that cellular apoptosis plays in the pathogenesis of cancer. The effect of melatonin may mean that it is appropriate for use as an adjuvant, along with other therapeutic approaches such as radiotherapy and chemotherapy.

A spotlight on the interplay between Wnt/ß-catenin signaling and circular RNAs in hepatocellular carcinoma progression.

Hepatocellular carcinoma (HCC) is one of the deadliest cancers due to multifocal development and distant metastasis resulting from late diagnosis. Consequently, new approaches to HCC diagnosis and treatment are required to reduce mortality rates. A large body of evidence suggests that non-coding RNAs (ncRNAs) are important in cancer initiation and progression. Cancer cells release many of these ncRNAs into the blood or urine, enabling their use as a diagnostic tool. Circular RNAs (CircRNAs) are as a members of the ncRNAs that regulate cancer cell expansion, migration, metastasis, and chemoresistance through different mechanisms such as the Wnt/ß-catenin Signaling pathway. The Wnt/ß-catenin pathway plays prominent roles in several biological processes including organogenesis, stem cell regeneration, and cell survival. Aberrant signaling of both pathways mentioned above could affect the progression and metastasis of many cancers, including HCC. Based on several studies investigated in the current review, circRNAs have an effect on HCC formation and progression by sponging miRNAs and RNA-binding proteins (RBPs) and regulating the Wnt/ß-catenin signaling pathway. Therefore, circRNAs/miRNAs or RBPs/Wnt/ß-catenin signaling pathway could be considered promising prognostic and therapeutic targets in HCC.

The Significant Role of microRNAs in Gliomas Angiogenesis: A Particular Focus on Molecular Mechanisms and Opportunities for Clinical Application.

MicroRNAs (miRNAs) are non-coding RNAs with only 20-22 nucleic acids that inhibit gene transcription and translation by binding to mRNA. MiRNAs have a diverse set of target genes and can alter most physiological processes, including cell cycle checkpoints, cell survival, and cell death mechanisms, affecting the growth, development, and invasion of various cancers, including gliomas. So optimum management of miRNA expression is essential for preserving a normal biological environment. Due to their small size, stability, and capability of specifically targeting oncogenes, miRNAs have emerged as a promising marker and new biopharmaceutical targeted therapy for glioma patients. This review focuses on the most common miRNAs associated with gliomagenesis and development by controlling glioma-determining markers such as angiogenesis. We also summarized the recent research about miRNA effects on signaling pathways, their mechanistic role and cellular targets in the development of gliomas angiogenesis. Strategies for miRNA-based therapeutic targets, as well as limitations in clinical applications, are also discussed.