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The recent Nobel Prizes awarded to Ambros and Ruvkun have refocused attention on microRNAs (miRNAs). The importance of miRNAs for basic science has always been clear, but the application to therapy has lagged behind. This delay has been made even more apparent by the accelerating pace of successful programs using duplex RNAs and antisense oligonucleotides to target mRNA. Why has progress been slow? A clear understanding of how miRNAs function in mammalian cells is obscured by the fact that miRNAs can exert their effects through multiple complex mechanisms. This gap in our knowledge has complicated progress in drug discovery. Better insights into the mechanism of miRNAs, more rigorous definitions of miRNAs, and more powerful tools for establishing the physical contacts necessary for miRNA action are now available. These advances lead to a central question for nucleic acid therapy-can miRNAs be productive targets for drug discovery and development?

Argonaute protein is associated with post-transcriptional control of cytoplasmic gene expression through miRNA-induced silencing complexes (miRISC). Specific cellular and environmental conditions can trigger AGO protein to accumulate in the nucleus. Localization of AGO is central to understanding miRNA action, yet the consequences of AGO being in the nucleus are undefined. We show nuclear enrichment of AGO2 in HCT116 cells grown in two-dimensional culture to high density, HCT116 cells grown in three-dimensional tumor spheroid culture, and human colon tumors. The shift in localization of AGO2 from cytoplasm to nucleus de-represses cytoplasmic AGO2-eCLIP targets that were candidates for canonical regulation by miRISC. Constitutive nuclear localization of AGO2 using an engineered nuclear localization signal increases cell migration. Critical RNAi factors also affect the localization of AGO2. Knocking out an enzyme essential for miRNA biogenesis, DROSHA, depletes mature miRNAs and restricts AGO2 localization to the cytoplasm, while knocking out the miRISC scaffolding protein, TNRC6, results in nuclear localization of AGO2. These data suggest that AGO2 localization and miRNA activity can be regulated depending on environmental conditions, expression of mature miRNAs, and expression of miRISC cofactors. Localization and expression of core miRISC protein machinery should be considered when investigating the roles of miRNAs., (© The Author(s) 2023. Published by Oxford University Press on behalf of Nucleic Acids Research.)

Synthetic antisense oligonucleotides (ASOs) and duplex RNAs (dsRNAs) are an increasingly successful strategy for drug development. After a slow start, the pace of success has accelerated since the approval of Spinraza (nusinersen) in 2016 with several drug approvals. These accomplishments have been achieved even though oligonucleotides are large, negatively charged, and have little resemblance to traditional small-molecule drugs-a remarkable achievement of basic and applied science. The goal of this review is to summarize the foundation underlying recent progress and describe ongoing research programs that may increase the scope and impact of oligonucleotide therapeutics., Competing Interests: Declaration of interests The authors declare no competing interests., (Copyright © 2023 Elsevier Ltd. All rights reserved.)

The Lophophora genus of the Cactaceae family includes Lophophora diffusa and Lophophora williamsii, which has traditionally been used as a natural analgesic; however, its use is now under strict regulation worldwide as it contains mescaline, a unique psychotropic agent. Recently, non-medical and illegal distribution and abuse of L. williamsii have increased worldwide; thus, effective species identification methods are urgently needed. Here, we identified a new variable number tandem repeat (VNTR) marker in the trnL intron region to identify and characterize species in forensic analyses. The VNTR marker has a unique structure of tandem repeats, each with 13 nucleotides; one repeat unit was found in L. williamsii and two in L. diffusa. Phylogenetic and length polymorphism analyses confirmed that this novel VNTR marker could distinguish between Lophophora species. Furthermore, our newly developed TaqMan genotyping assay utilizes two probes; the color and position of dots on the discrimination plot differ according to the tandem repeat count within the VNTR marker. The limits of detection of the assay were 0.000063 ng (LW-VNTR probe-1) and 0.000066 ng (LW-VNTR probe-2), indicating high sensitivity. Moreover, when crime scene samples of 16 presumed L. williamsii species were analyzed, the results coincided with those of gas chromatography-mass spectrometry, confirming the applicability of our marker for Lophophora species identification. Thus, the tandem repeats within the trnL intron region can be exploited as a VNTR marker to identify L. williamsii and L. diffusa. Our dual TaqMan genotyping assay based on a novel marker demonstrates potential for forensic applications., (© 2024. The Author(s), under exclusive licence to Springer-Verlag GmbH Germany, part of Springer Nature.)

Background: Global developmental delay with speech and behavioral abnormalities (OMIM: 619243) is an autosomal dominant disease caused by variants in TNRC6B gene., Method: We reviewed and summarized clinical manifestations and genotypes in patients previously reported with TNRC6B gene variants. We used several prediction tools to predict pathogenicity and performed minigene assays to verify the function of the synonymous variant affecting RNA splicing., Result: The patient presented with convulsive seizures and developmental delay. WES combined with functional studies diagnosed a child with a synonymous variant in TNRC6B gene. Through minigene assay and Sanger sequencing, we demonstrated that c.3141G > A variant induced exon 7 skipping and the synonymous variant was pathogenic., Conclusion: Synonymous variants do not change the amino acids encoded by the codon, so we usually consider synonymous variants to be benign and ignore their pathogenicity. Minigene assay is a valuable tool to identify the effect of variation on RNA splicing and identify synonymous variants' benign or pathogenic. We showed that the synonymous variant was pathogenic by minigene assay. WES combined with minigene assay establishes a robust basis for genetic counseling and diagnosing diseases., (© 2024. The Author(s), under exclusive licence to Springer Nature B.V.)

Diabetes mellitus is associated with a wide range of neuropathies, vasculopathies, and immunopathies, resulting in many complications. More than 30% of diabetic patients risk developing diabetic foot ulcers (DFUs). Non-coding RNAs (ncRNAs), including microRNAs (miRNAs), long non-coding RNAs (lncRNAs), and circular RNAs (circRNAs), play essential roles in various biological functions in the hyperglycaemic environment that determines the development of DFU. Ulceration results in tissue breakdown and skin barrier scavenging, thereby facilitating bacterial infection and biofilm formation. Many bacteria contribute to diabetic foot infection (DFI), including Staphylococcus aureus (S. aureus) et al. A heterogeneous group of "ncRNAs," termed small RNAs (sRNAs), powerfully regulates biofilm formation and DFI healing. Multidisciplinary foot care interventions have been identified for nonhealing ulcers. With an appreciation of the link between disease processes and ncRNAs, a novel therapeutic model of bioactive materials loaded with ncRNAs has been developed to prevent and manage diabetic foot complications., (© 2023 John Wiley & Sons Ltd.)

Long non-coding RNAs (LncRNAs) are crucial regulators of gene expression and cellular processes, with significant implications for cancer research. This review focuses on the role of LncRNA CARMN (Cardiac Arrest and Regulated Myocyte Nuclear Protein) in various cancers. CARMN, originally identified for its function in cardiac tissues, has shown dysregulated expression in several tumor types, including cervical, breast, colorectal, and esophageal cancers. Its altered expression often correlates with tumor progression, metastasis, and patient prognosis, suggesting its potential as both a biomarker and therapeutic target. In cervical cancer, CARMN's role as a tumor suppressor is highlighted by its ability to inhibit cell proliferation, migration, and invasion through interaction with the miR-92a-3p/BTG2 axis and modulation of the Wnt/β-catenin signaling pathway. In breast cancer, CARMN acts as an enhancer RNA, affecting epithelial-mesenchymal transition and metastasis by regulating MMP2 via DHX9. The downregulation of CARMN in triple-negative breast cancer is associated with enhanced sensitivity to chemotherapy. In colorectal cancer, CARMN's expression is regulated by m6A methylation and mutant p53, influencing tumor growth through miR-5683 and FGF2. Lastly, in esophageal cancer, genetic variations in CARMN affect cancer susceptibility, with certain SNPs and haplotypes associated with either increased or decreased risk. Additionally, the relationship between CARMN and immune cell dynamics highlights its potential role in cancer immune surveillance and therapy. Finally, we found that CARMN may regulate immune cell exhaustion in the tumor microenvironment by influencing the recruitment and activation of NK cells and T cells, as well as modulating macrophage polarization. This review emphasizes the diverse roles of CARMN across different cancers and its potential as a diagnostic and therapeutic tool. Future research should address the mechanistic details of CARMN's involvement in cancer, validate its clinical utility, and explore its therapeutic potential in combination with existing treatments. [ABSTRACT FROM AUTHOR]

Lung Cancer (LC) is characterized by chemoresistance, which poses a significant clinical challenge and results in a poor prognosis for patients. Long non-coding RNAs (lncRNAs) have recently gained recognition as crucial mediators of chemoresistance in LC. Through the regulation of key cellular processes, these molecules play important roles in the progression of LC and response to therapy. The mechanisms by which lncRNAs affect chemoresistance include the modulation of gene expression, chromatin structure, microRNA interactions, and signaling pathways. Exosomes have emerged as key mediators of lncRNA-driven chemoresistance, facilitating the transfer of resistance-associated lncRNAs between cancer cells and contributing to tumor development. Consequently, exosomal lncRNAs may serve as biomarkers and therapeutic targets for the treatment of LC. Therapeutic strategies targeting lncRNAs offer novel approaches to circumvent chemoresistance. Different approaches, including RNA interference (RNAi) and antisense oligonucleotides (ASOs), are available to degrade lncRNAs or alter their function. ASO-based therapies are effective at reducing lncRNA expression levels, increasing chemotherapy sensitivity, and improving clinical outcomes. The use of these strategies can facilitate the development of targeted interventions designed to disrupt lncRNA-mediated mechanisms of chemoresistance. An important aspect of this review is the discussion of the complex relationship between lncRNAs and drug resistance in LC, particularly through exosomal pathways, and the development of innovative therapeutic strategies to enhance drug efficacy by targeting lncRNAs. The development of new pathways and interventions for treating LC holds promise in overcoming this resistance. [ABSTRACT FROM AUTHOR]

Dental stem cells, with their exceptional proliferative capacity and multidirectional differentiation potential, hold significant promise for dental and oral tissue regeneration. Epigenetic inheritance, which involves stable and heritable changes in gene expression and function without alterations to the DNA sequence, plays a critical role in numerous biological processes. Environmental factors are particularly influential in epigenetic inheritance, as variations in exposure can lead to changes in epigenetic modifications that subsequently impact gene expression. Epigenetic mechanisms are widely involved in processes such as bone homeostasis, embryogenesis, stem cell fate determination, and disease development. Recently, the epigenetic regulation of dental stem cells has attracted considerable research attention. This paper reviews studies focused on the epigenetic mechanisms governing the multidirectional differentiation of dental stem cells. [ABSTRACT FROM AUTHOR]

Lung cancer represents a significant public health concern worldwide. Lung cancer typically receives a diagnosis at a late stage, leading to a generally unfavourable prognosis. Additionally, traditional treatments frequently fail in cases of metastatic lung cancer. However, targeted therapy has advanced considerably in the management of lung cancer, and overcoming drug resistance has emerged as a significant hurdle in achieving optimal treatment outcomes. As a result, there has been a new trend toward precision therapy for lung cancer based on changes at the molecular and genetic levels. On the other hand, for lung cancer, early diagnosis plays a crucial role in treatment and prognosis. Based on existing knowledge, we strongly believe that it is imperative to promptly identify innovative biomarkers. The emergence of microRNAs (miRNAs) provides new ideas. The expression profiles of miRNAs have been investigated using noninvasive blood samples to explore the regulatory mechanisms played by miRNAs during the progression and targeted therapy resistance of lung cancer. Due to the complexity of miRNA profiles, they may play the role of tumour suppressors or oncogenes. However, specific regulatory mechanisms are still a huge topic to be explored. In this Review, we summarize the latest research that has shed light on the potential regulatory mechanisms of miRNAs in driving lung cancer progression, their value for clinical application as biomarkers and their role in targeted therapy resistance. [ABSTRACT FROM AUTHOR]

AKT, or protein kinase B, is a central node of the PI3K signaling pathway that is pivotal for a range of normal cellular physiologies that also underlie several pathological conditions, including inflammatory and autoimmune diseases, overgrowth syndromes, and neoplastic transformation. These pathologies, notably cancer, arise if either the activity of AKT or its positive or negative upstream or downstream regulators or effectors goes unchecked, superimposed on by its intersection with a slew of other pathways. Targeting the PI3K/AKT pathway is, therefore, a prudent countermeasure. AKT inhibitors have been tested in many clinical trials, primarily in combination with other drugs. While some have recently garnered attention for their favorable profile, concern over resistance and off-target effects have continued to hinder their widespread adoption in the clinic, mandating a discussion on alternative modes of targeting. In this review, we discuss isoform-centric targeting that may be more effective and less toxic than traditional pan-AKT inhibitors and its significance for disease prevention and treatment, including immunotherapy. We also touch on the emerging mutant- or allele-selective covalent allosteric AKT inhibitors (CAAIs), as well as indirect, novel AKT-targeting approaches, and end with a briefing on the ongoing quest for more reliable biomarkers predicting sensitivity and response to AKT inhibitors, and their current state of affairs. [ABSTRACT FROM AUTHOR]

Background: Antisense oligonucleotides (AON) represent a promising treatment for Duchenne muscular dystrophy (DMD) carrying out-of-frame deletions, but also show limitations. In a completed clinical trial golodirsen, approved by FDA to induce skipping of DMD gene exon 53 in eligible patients, we demonstrated increase in DMD expression and protein production, albeit with inter-patient variability. Methods: Here, we investigate further the golodirsen mechanism of action using myotubes derived from MyoD transfected fibroblasts isolated from DMD patients at the baseline of the clinical trial SRP-4053. Results: We confirm golodirsen's selectivity and efficiency in removing only exon 53. For the first time in human cells, we revealed a significant reduction in the so called DMD "transcript imbalance", in golodirsen-treated DMD muscle cultures. The transcript imbalance is a unique DMD phenomenon characterized by non-homogeneous transcript expression along its entire length and responsible for the reduced stability of the transcript. Our in-vivo study also showed that the efficiency of exon skipping did not always correspond to a proportional restoration of the dystrophin protein. Predominant nuclear localization of the DMD transcript, observed in patients and animal models, persists even after exon skipping. Conclusion: All these findings suggest challenges other than AON delivery for high level of protein restoration in DMD, highlighting the importance of investigating the biological mechanisms upstream of protein production to further enhance the efficiency of any AON treatment in this condition. [ABSTRACT FROM AUTHOR]

Sepsis, a severe and life-threatening condition arising from a dysfunctional host response to infection, presents considerable challenges to the health care system and is characterized by high mortality rates and substantial economic costs. Exosomes have garnered attention as potential diagnostic markers because of their capacity to mirror the pathophysiological milieu of sepsis. This discourse reviews the progression of sepsis classification from Sepsis 1.0 to Sepsis 3.0, highlighting the imperative for sensitive and specific biomarkers to facilitate timely diagnosis and optimize patient outcomes. Existing biomarkers, such as procalcitonin (PCT) and C-reactive protein (CRP), exhibit certain limitations, thereby prompting the quest for more dependable diagnostic indicators. Exosomal cargoes, which encompass proteins and miRNAs, present a trove of biomarker candidates, attributable to their stability, pervasive presence, and indicative nature of the disease status. The potential of exosomal biomarkers in the identification of sepsis-induced organ damage, including cardiomyopathy, acute kidney injury, and acute lung injury, is emphasized, as they provide real-time insights into cardiac and renal impairments. Despite promising prospects, hurdles persist in the standardization of exosome extraction and the need for extensive clinical trials to validate their efficacy. The combination of biomarker development and sophisticated exosome detection techniques represents a pioneering strategy in the realm of sepsis diagnosis and management, underscoring the significance of further research and clinical validation. [ABSTRACT FROM AUTHOR]

Tinnitus is a common sensorineural complication that can occur de novo or after cancer treatments involving cisplatin or radiotherapy. Considering the heterogeneous etiology and pathophysiology of tinnitus, the extent to which shared genetic risk factors contribute to de novo tinnitus and cancer treatment-induced tinnitus is not clear. Here we report a GWAS for de novo tinnitus using the UK Biobank cohort with nine loci showing significantly associated variants (p < 5 × 10–8). To our knowledge, significant associations in four of these loci are novel, represented by rs7336872, rs115125870, rs1532898 and rs2537, with UBAC2, NUDT9, TGM4 and MPP2 as their nearest protein coding genes, respectively. Through quantitative comparison of results from GWAS of de novo tinnitus with GWAS of radiation-induced tinnitus, two intronic variants (rs7023227 and rs3780395) from a locus within immunoregulatory gene PD-L1 (CD274) reached the replication threshold using comparison thresholds of 10–5 and 10–4, with no other shared genetic risk factors identified. We did not observe shared genetic risk factors between de novo and cisplatin-induced tinnitus. Our results suggest that genetic risk factors are mainly distinct based on etiology of tinnitus and future efforts to study, prevent or treat tinnitus are expected to benefit from strategies that allow for distinction of cases based on the primary environmental risk factor. [ABSTRACT FROM AUTHOR]

Urologic malignancies, characterized by their high aggressiveness and metastatic potential, pose a significant public health challenge globally. Ferroptosis, a novel mode of cell death, typically arises from intracellular iron ion overload and the accumulation of lipid peroxides. This process has been shown to play a crucial regulatory role in various pathological conditions, particularly in cancer, including urologic cancers. However, the comprehensive regulatory mechanisms underlying ferroptosis remain poorly understood, which somewhat limits its broader application in cancer therapy. Non-coding RNAs (ncRNAs), which encompass microRNAs (miRNAs), long non-coding RNAs (lncRNAs), and circular RNAs (circRNAs), are non-coding transcripts that play pivotal roles in various physiological processes, such as proliferation, differentiation, apoptosis, and cell cycle regulation, by modulating the expression of target genes. The biological functions and potential regulatory mechanisms of ncRNAs in the context of cancer-related ferroptosis have been partially elucidated. Research indicates that ncRNAs can influence the progression of urologic cancers by affecting cell proliferation, migration, and drug resistance through the regulation of ferroptosis. Consequently, this review aims to clarify the functions and mechanisms of the ncRNA-ferroptosis axis in urologic cancers and to evaluate the clinical significance of ferroptosis-related ncRNAs, thereby providing new insights into cancer biology and therapeutic strategies that may ultimately benefit a diverse range of cancer patients. [ABSTRACT FROM AUTHOR]

Metabolism reprogramming (MR) is one of the top ten hallmarks of malignant tumors. The aberrant activation of MR has been recognized as a critical contributory factor to the malignant progression of solid tumors. Moreover, various long non-coding RNAs (lncRNAs) are implicated in the aberrant activation of MR in solid tumor cells. Therefore, in this review, we mainly focus on summarizing the functional relevance and molecular mechanistic underpinnings of lncRNAs in modulating MR of solid tumors by targeting glucose metabolism, lipid metabolism, affecting mitochondrial function, and regulating interactions between tumor and non-tumor cells in tumor microenvironment. Besides, we also underscore the potential for constructing lncRNAs-centered tumor metabolic regulation networks and developing novel anti-tumor strategies by targeting lncRNAs and abnormal MR. Ultimately, this review seeks to offer new targets and avenues for the clinical treatment of solid tumors in the future. [ABSTRACT FROM AUTHOR]

This study aimed to investigate the gratitude experience of young and middle-aged patients with spinal muscular atrophy (SMA) during hospitalisation to provide a theoretical basis for medical professionals to develop gratitude intervention programs. Methods: Patients with SMA who were treated with nusinersen in the Department of Neurology of the First Hospital of Jilin University between April 20 and May 20, 2024 were selected using the purposive sampling method, and semi-structured interviews were conducted. The interview data were analysed using Colaizzi's 7-step analysis method. Results: Four themes were extracted: gratitude stimulated positive emotions; gratitude enhanced life motivation; gratitude reflected the level of social support; and gratitude promoted life restructuring planning. Conclusion: Patients with SMA have gratitude experience and their own perception of life. Strengthened feelings of gratitude could be helpful to the psychological resilience of patients, influence their view of life in a grateful way of thinking and help them actively plan all aspects of their lives, from daily living to social re-integration. [ABSTRACT FROM AUTHOR]

The mammalian target of Rapamycin complex 1 (mTORC1) is a serine/threonine kinase that couples nutrient and growth factor signaling to the cellular control of metabolism and plays a fundamental role in aberrant proliferation in cancer. mTORC1 has previously been considered an "on/off" switch, capable of phosphorylating the entire pool of its substrates when activated. However, recent studies have indicated that mTORC1 may be active toward its canonical substrates, eukaryotic translation initiation factor 4E-binding protein 1 (4EBP1) and S6 kinase (S6K), involved in mRNA translation and protein synthesis, and inactive toward TFEB and TFE3, transcription factors involved in the regulation of lysosome biogenesis, in several pathological contexts. Among these conditions are Birt–Hogg–Dubé syndrome (BHD) and, recently, tuberous sclerosis complex (TSC). Furthermore, increased TFEB and TFE3 nuclear localization in these syndromes, and in translocation renal cell carcinomas (tRCC), drives mTORC1 activity toward the canonical substrates, through the transcriptional activation of the Rag GTPases, thereby positioning TFEB and TFE3 upstream of mTORC1 activity toward 4EBP1 and S6K. The expanding importance of TFEB and TFE3 in the pathogenesis of these renal diseases warrants a novel clinical grouping that we term "TFEopathies." Currently, there are no therapeutic options directly targeting TFEB and TFE3, which represents a challenging and critically required avenue for cancer research. [ABSTRACT FROM AUTHOR]

Exosomes have grown as promising carriers for noncoding RNAs (ncRNAs) in the treatment of inflammation, particularly in conditions like ischemic stroke and myocardial infarction. These ncRNAs, which include microRNAs (miRNAs) and long noncoding RNAs (lncRNAs), play a crucial role in regulating inflammatory pathways, presenting new therapeutic opportunities. In both ischemic stroke and myocardial infarction, inflammation significantly influences disease progression and severity. Exosomes can deliver ncRNAs directly to specific cells and tissues, providing a targeted approach to modulate gene expression and reduce inflammation. Their biocompatibility and low risk of inducing immune responses make exosomes ideal therapeutic vehicles. Ongoing research is focused on optimizing the loading of ncRNAs into exosomes, ensuring efficient delivery, and understanding the mechanisms by which these ncRNAs mitigate inflammation. In ischemic stroke, exosome-derived ncRNAs originate from various cell types, including neurons, M2 microglia, patient serum, genetically engineered HEK293T cells, and mesenchymal stromal cells. In the case of myocardial infarction, these ncRNAs are sourced from mesenchymal stem cells, endothelial cells, and patient plasma. These exosome-loaded ncRNAs play a significant role in modulating inflammation in both ischemic stroke and myocardial infarction. As this research advances, therapies based on exosomes may completely change how diseases linked to inflammation are treated, offering new avenues for patient care and recovery. This review explores the latest advancements in understanding how exosomes impact specific inflammatory components, with a particular emphasis on the role of ncRNAs contained in exosomes. The review concludes by highlighting the clinical potential of exosome-derived ncRNAs as innovative therapeutic and diagnostic tools. [ABSTRACT FROM AUTHOR]

Chronic wounds with high disability are among the most common and serious complications of diabetes. Angiogenesis dysfunction impair wound healing in patients with diabetes. Compared with traditional therapies that can only provide symptomatic treatment, stem cells—owing to their powerful paracrine properties, can alleviate the pathogenesis of chronic diabetic wounds and even cure them. Exosome-derived microRNAs (miRNAs), important components of stem cell paracrine signaling, have been reported for therapeutic use in various disease models, including diabetic wounds. Exosome-derived miRNAs have been widely reported to be involved in regulating vascular function and have promising applications in the repair and regeneration of skin wounds. Therefore, this article aims to review the current status of the pathophysiology of exosome-derived miRNAs in the diabetes-induced impairment of wound healing, along with current knowledge of the underlying mechanisms, emphasizing the regulatory mechanism of angiogenesis, we hope to document the emerging theoretical basis for improving wound repair by restoring angiogenesis in diabetes. [ABSTRACT FROM AUTHOR]

Background: Spinal cord injury (SCI) often leads to a loss of motor and sensory function. Axon regeneration and outgrowth are key events for functional recovery after spinal cord injury. Endogenous growth of axons is associated with a variety of factors. Inspired by the relationship between developing nerves and blood vessels, we believe spinal cord-derived microvascular endothelial cells (SCMECs) play an important role in axon growth. Results: We found SCMECs could promote axon growth when co-cultured with neurons in direct and indirect co-culture systems via downregulating the miR-323-5p expression of neurons. In rats with spinal cord injury, neuron-targeting nanoparticles were employed to regulate miR-323-5p expression in residual neurons and promote function recovery. Conclusions: Our study suggests that SCMEC can promote axon outgrowth by downregulating miR-323-5p expression within neurons, and miR-323-5p could be selected as a potential target for spinal cord injury repair. [ABSTRACT FROM AUTHOR]

A previous study using Thermostable Group II Intron Reverse Transcriptase sequencing (TGIRT-seq) found human plasma contains short (≤300 nt) structured full-length excised linear intron (FLEXI) RNAs with potential to serve as blood-based biomarkers. Here, TGIRT-seq identified >9,000 different FLEXI RNAs in human cell lines, including relatively abundant FLEXIs with cell-type-specific expression patterns. Analysis of public CLIP-seq datasets identified 126 RNA-binding proteins (RBPs) that have binding sites within the region corresponding to the FLEXI or overlapping FLEXI splice sites in pre-mRNAs, including 53 RBPs with binding sites for ≥30 different FLEXIs. These included splicing factors, transcription factors, a chromatin remodeling protein, cellular growth regulators, and proteins with cytoplasmic functions. Analysis of ENCODE datasets identified subsets of these RBPs whose knockdown impacted FLEXI host gene mRNA levels or proximate alternative splicing, indicating functional interactions. Hierarchical clustering identified six subsets of RBPs whose FLEXI binding sites were co-enriched in six subsets of functionally related host genes: AGO1-4 and DICER, including but not limited to agotrons or mirtron pre-miRNAs; DKC1, NOLC1, SMNDC1, and AATF (Apoptosis Antagonizing Transcription Factor), including but not limited to snoRNA-encoding FLEXIs; two subsets of alternative splicing factors; and two subsets that included RBPs with cytoplasmic functions (e.g., LARP4, PABPC4, METAP2, and ZNF622) together with regulatory proteins. Cell fractionation experiments showed cytoplasmic enrichment of FLEXI RNAs with binding sites for RBPs with cytoplasmic functions. The subsets of host genes encoding FLEXIs with binding sites for different subsets of RBPs were co-enriched with non-FLEXI other short and long introns with binding sites for the same RBPs, suggesting overarching mechanisms for coordinately regulating expression of functionally related genes. Our findings identify FLEXIs as a previously unrecognized large class of cellular RNAs and provide a comprehensive roadmap for further analyzing their biological functions and the relationship of their RBPs to cellular regulatory mechanisms. Author summary: We characterized a previously unrecognized, large class of full-length excised liner intron (FLEXI) RNAs that are ≤300 nucleotides in length and relatively stable in human cells and plasma. These included subsets of FLEXIs with binding sites for different subsets of RNA-binding proteins (RBPs) that have different cellular functions and are co-enriched in subsets of functionally related genes with other short and long introns with binding sites for the same RBPs, potentially enabling coordinate regulation of different gene sets. Many of the proteins that have binding sites in different subsets of FLEXIs were also identified as interacting with each other by STRING protein-network analysis, potentially enabling co-localization of subsets of proteins to different intracellular locations, including the cytoplasm. Our findings provide a comprehensive road map for further analysis of the functions of FLEXIs and their associated RBPs and for the identification of FLEXIs that can serve as biomarkers in human cells and plasma. [ABSTRACT FROM AUTHOR]

Osimertinib, a third-generation inhibitor of epidermal growth factor receptor (EGFR) tyrosine kinase, exhibits remarkable efficacy in prolonging the survival of patients with non-small cell lung cancer (NSCLC) carrying EGFR mutations, surpassing the efficacy of first- and second-generation EGFR tyrosine kinases. Nevertheless, the emergence of osimertinib resistance is inevitable, necessitating an investigation into the underlying mechanisms. Increasing evidence has revealed that non-coding RNAs (ncRNAs), including microRNAs, long ncRNAs, and circular RNAs, play a significant role in the development and progression of lung cancer. These ncRNAs regulate essential signaling pathways, offering a novel avenue for understanding the fundamental mechanisms of osimertinib resistance. Recent studies have reported the significant impact of ncRNAs on osimertinib resistance, achieved through various mechanisms that modulate treatment sensitivity. We provide a concise overview of the functions and underlying mechanisms of extensively researched ncRNAs in the development of osimertinib resistance and emphasize their potential clinical application in EGFR-mutated NSCLC resistant to osimertinib. Finally, we discuss the obstacles that must be addressed to effectively translate ncRNA-based approaches into clinical practice. [ABSTRACT FROM AUTHOR]

Dysregulation of master regulator c-MYC (MYC) plays a central role in hepatocellular carcinoma (HCC) and other cancers but remains an elusive target for therapeutic intervention. MYC expression is epigenetically modulated within naturally occurring DNA loop structures, Insulated Genomic Domains (IGDs). We present a therapeutic approach using an epigenomic controller (EC), a programmable epigenomic mRNA medicine, to precisely modify MYC IGD sub-elements, leading to methylation of MYC regulatory elements and durable downregulation of MYC mRNA transcription. Significant antitumor activity is observed in preclinical models of HCC treated with the MYC-targeted EC, as monotherapy or in combination with tyrosine kinase or immune checkpoint inhibitors. These findings pave the way for clinical development of MYC-targeting epigenomic controllers in HCC patients and provide a framework for programmable epigenomic mRNA therapeutics for cancer and other diseases. Development of targeted MYC inhibitors for cancer therapy remains challenging. Here, the authors design an mRNA medicine which downregulates MYC gene transcription via epigenetic modification of MYC regulatory elements, showing significant antitumor activity in preclinical models of hepatocellular carcinoma. [ABSTRACT FROM AUTHOR]

RNA-binding proteins (RBPs) are a major class of proteins that interact with RNAs to change their fate or function. RBPs and the ribonucleoprotein complexes they constitute are involved in many essential cellular processes. In many cases, the molecular details of RBP:RNA interactions differ between viruses, prokaryotes and eukaryotes, making prokaryotic and viral RBPs good potential drug targets. However, targeting RBPs with small molecules has so far been met with limited success as RNA-binding sites tend to be extended, shallow and dynamic with a mixture of charged, polar and hydrophobic interactions. Here, we show that peptide nucleic acids (PNAs) with nucleic acid-like binding properties and a highly stable peptide-like backbone can be used to target some RBPs. We have designed PNAs to mimic the short RNA stem-loop sequence required for the initiation of prokaryotic signal recognition particle (SRP) assembly, a target for antibiotics development. Using a range of biophysical and biochemical assays, the designed PNAs were demonstrated to fold into a hairpin structure, bind the targeted protein and compete with the native RNA hairpin to inhibit SRP formation. To show the applicability of PNAs against other RBPs, a PNA was also shown to bind Nsp9 from SARS-CoV-2, a protein that exhibits non-sequence-specific RNA binding but preferentially binds hairpin structures. Taken together, our results support that PNAs can be a promising class of compounds for targeting RNA-binding activities in RBPs. [ABSTRACT FROM AUTHOR]

Background: MicroRNA isoforms (isomiRs), tRNA-derived fragments (tRFs), and rRNA-derived fragments (rRFs) represent most of the small non-coding RNAs (sncRNAs) found in cells. Members of these three classes modulate messenger RNA (mRNA) and protein abundance and are dysregulated in diseases. Experimental studies to date have assumed that the subcellular distribution of these molecules is well-understood, independent of cell type, and the same for all isoforms of a sncRNA. Results: We tested these assumptions by investigating the subcellular distribution of isomiRs, tRFs, and rRFs in biological replicates from three cell lines from the same tissue and same-sex donors that model the same cancer subtype. In each cell line, we profiled the isomiRs, tRFs, and rRFs in the nucleus, cytoplasm, whole mitochondrion (MT), mitoplast (MP), and whole cell. Using a rigorous mathematical model we developed, we accounted for cross-fraction contamination and technical errors and adjusted the measured abundances accordingly. Analyses of the adjusted abundances show that isomiRs, tRFs, and rRFs exhibit complex patterns of subcellular distributions. These patterns depend on each sncRNA's exact sequence and the cell type. Even in the same cell line, isoforms of the same sncRNA whose sequences differ by a few nucleotides (nts) can have different subcellular distributions. Conclusions: SncRNAs with similar sequences have different subcellular distributions within and across cell lines, suggesting that each isoform could have a different function. Future computational and experimental studies of isomiRs, tRFs, and rRFs will need to distinguish among each molecule's various isoforms and account for differences in each isoform's subcellular distribution in the cell line at hand. While the findings add to a growing body of evidence that isomiRs, tRFs, rRFs, tRNAs, and rRNAs follow complex intracellular trafficking rules, further investigation is needed to exclude alternative explanations for the observed subcellular distribution of sncRNAs. [ABSTRACT FROM AUTHOR]

Glioma is a primary brain tumor that grows quickly, has an unfavorable prognosis, and can spread intracerebrally. Glioma cells rely on glucose as the major energy source, and glycolysis plays a critical role in tumorigenesis and progression. Substrate utilization shifts throughout glioma progression to facilitate energy generation and biomass accumulation. This metabolic reprogramming promotes glioma cell proliferation and metastasis and ultimately decreases the efficacy of conventional treatments. Non-coding RNAs (ncRNAs) are involved in several glucose metabolism pathways during tumor initiation and progression. These RNAs influence cell viability and glucose metabolism by modulating the expression of key genes of the glycolytic pathway. They can directly or indirectly affect glycolysis in glioma cells by influencing the transcription and post-transcriptional regulation of oncogenes and suppressor genes. In this review, we discussed the role of ncRNAs in the metabolic reprogramming of glioma cells and tumor microenvironments and their abnormal expression in the glucometabolic pathway in glioma. In addition, we consolidated the existing theoretical knowledge to facilitate the use of this emerging class of biomarkers as biological indicators and potential therapeutic targets for glioma. [ABSTRACT FROM AUTHOR]

3′UTR-APAs have been extensively studied, but intronic polyadenylations (IPAs) remain largely unexplored. We characterized the profiles of 22 260 IPAs in 9679 patient samples across 32 cancer types from the Cancer Genome Atlas cohort. By comparing tumor and paired normal tissues, we identified 180 ~ 4645 dysregulated IPAs in 132 ~ 2249 genes in each of 690 patient tumors from 22 cancer types that showed consistent patterns within individual cancer types. We selected 2741 genes that showed consistently patterns across cancer types, including 1834 pan-cancer tumor-enriched and 907 tumor-depleted IPA genes; the former were amply represented in the functional pathways such as deoxyribonucleic acid damage repair. Expression of IPA isoforms was associated with tumor mutation burden and patient characteristics (e.g. sex, race, cancer stages, and subtypes) in cancer-specific and feature-specific manners, and could be a more accurate prognostic marker than gene expression (summary of all isoforms). In summary, our study reveals the roles and the clinical relevance of tumor-associated IPAs. [ABSTRACT FROM AUTHOR]

The last decade has witnessed major breakthroughs in identifying novel genetic causes of hereditary ataxias, deepening our understanding of disease mechanisms, and developing therapies for these debilitating disorders. This article reviews the currently approved and most promising candidate pharmacotherapies in relation to the known disease mechanisms of the most prevalent autosomal recessive ataxias. Omaveloxolone is an Nrf2 activator that increases antioxidant defense and was recently approved for treatment of Friedreich ataxia. Its therapeutic effect is modest, and further research is needed to find synergistic treatments that would halt or reverse disease progression. Promising approaches include upregulation of frataxin expression by epigenetic mechanisms, direct protein replacement, and gene replacement therapy. For ataxia-telangiectasia, promising approaches include splice-switching antisense oligonucleotides and small molecules targeting oxidative stress, inflammation, and mitochondrial function. Rare recessive ataxias for which disease-modifying therapies exist are also reviewed, emphasizing recently approved therapies. Evidence supporting the use of riluzole and acetyl-leucine in recessive ataxias is discussed. Advances in genetic therapies for other neurogenetic conditions have paved the way to implement feasible approaches with potential dramatic benefits. Particularly, as we develop effective treatments for these conditions, we may need to combine therapies, consider newborn testing for pre-symptomatic treatment, and optimize non-pharmacological approaches. [ABSTRACT FROM AUTHOR]

MicroRNAs (miRNAs) are small non-coding RNAs that regulate gene expression post-transcriptionally. In animals, this regulation is achieved via base-pairing with partially complementary sequences on mainly 3' UTR region of messenger RNAs (mRNAs). Computational approaches that predict miRNA target interactions (MTIs) facilitate the process of narrowing down potential targets for experimental validation. The availability of new datasets of high-throughput, direct MTIs has led to the development of machine learning (ML) based methods for MTI prediction. To train an ML algorithm, it is beneficial to provide entries from all class labels (i.e., positive and negative). Currently, no high-throughput assays exist for capturing negative examples. Therefore, current ML approaches must rely on either artificially generated or inferred negative examples deduced from experimentally identified positive miRNA-target datasets. Moreover, the lack of uniform standards for generating such data leads to biased results and hampers comparisons between studies. In this comprehensive study, we collected methods for generating negative data for animal miRNAs–target interactions and investigated their impact on the classification of true human MTIs. Our study relies on training ML models on a fixed positive dataset in combination with different negative datasets and evaluating their intra- and cross-dataset performance. As a result, we were able to examine each method independently and evaluate ML models' sensitivity to the methodologies utilized in negative data generation. To achieve a deep understanding of the performance results, we analyzed unique features that distinguish between datasets. In addition, we examined whether one-class classification models that utilize solely positive interactions for training are suitable for the task of MTI classification. We demonstrate the importance of negative data in MTI classification, analyze specific methodological characteristics that differentiate negative datasets, and highlight the challenge of ML models generalizing interaction rules from training to testing sets derived from different approaches. This study provides valuable insights into the computational prediction of MTIs that can be further used to establish standards in the field. Author summary: Gene expression regulation is fundamental for all organisms' development, homeostasis, and environmental adaptation. microRNAs (miRNAs) play a central role in post-transcriptional gene regulation by binding to target mRNAs and repressing their translation or mediating their degradation. Technical challenges in experimental miRNA target identification led to growing interest in computational target prediction. While machine learning (ML) models have shown success in this area, they rely heavily on artificially generated negative examples due to limited experimental data. The diversity of methods for generating negative interactions and the lack of a uniform standardized approach introduce bias and hinder the comparison of results across different studies. In this study, we collected methods for generating negative data for animal miRNAs–target interactions and analyzed their impact on classifying true interactions in humans. Using an ML approach, we evaluated miRNA–target prediction performance within and across negative datasets. We also analyzed unique features distinguishing between the negative datasets to understand the performance results better. Our study shows that negative data is essential for accurately classifying miRNA–target interactions and that ML models struggle to apply what they have learned from the training set when faced with new data derived from different approaches. This study particularly appeals to researchers interested in miRNA–target classification. It emphasizes the need for standardized methods to enhance comparability between studies. [ABSTRACT FROM AUTHOR]

The development of drug resistance remains a major challenge in cancer treatment. Ferroptosis, a unique type of regulated cell death, plays a pivotal role in inhibiting tumour growth, presenting new opportunities in treating chemotherapeutic resistance. Accumulating studies indicate that epigenetic modifications by non-coding RNAs (ncRNA) can determine cancer cell vulnerability to ferroptosis. In this review, we first summarize the role of chemotherapeutic resistance in cancer growth/development. Then, we summarize the core molecular mechanisms of ferroptosis, its upstream epigenetic regulation, and its downstream effects on chemotherapeutic resistance. Finally, we review recent advances in understanding how ncRNAs regulate ferroptosis and from such modulate chemotherapeutic resistance. This review aims to enhance general understanding of the ncRNA-mediated epigenetic regulatory mechanisms which modulate ferroptosis, highlighting the ncRNA-ferroptosis axis as a key druggable target in overcoming chemotherapeutic resistance. [ABSTRACT FROM AUTHOR]

R-loops are trimeric nucleic acid structures that form when an RNA molecule hybridizes with its complementary DNA strand, displacing the opposite strand. These structures regulate transcription as well as replication, but aberrant R-loops can form, leading to DNA breaks and genomic instability if unresolved. R-loop levels are elevated in many cancers as well as cells that maintain high-risk human papillomaviruses. We investigated how the distribution as well as function of R-loops changed between normal keratinocytes and HPV positive cells derived from a precancerous lesion of the cervix (CIN I). The levels of R-loops associated with cellular genes were found to be up to 10-fold higher in HPV positive cells than in normal keratinocytes while increases at ALU1 elements increased by up to 500-fold. The presence of enhanced R-loops resulted in altered levels of gene transcription, with equal numbers increased as decreased. While no uniform global effects on transcription due to the enhanced levels of R-loops were detected, genes in several pathways were coordinately increased or decreased in expression only in the HPV positive cells. This included the downregulation of genes in the innate immune pathway, such as DDX58, IL-6, STAT1, IFN-β, and NLRP3. All differentially expressed innate immune genes dependent on R-loops were also associated with H3K36me3 modified histones. Genes that were upregulated by the presence of R-loops in HPV positive cells included those in the DNA damage repair such as ATM, ATRX, and members of the Fanconi Anemia pathway. These genes exhibited a linkage between R-loops and H3K36me3 as well as γH2AX histone marks only in HPV positive cells. These studies identify a potential link in HPV positive cells between DNA damage repair as well as innate immune regulatory pathways with R-loops and γH2AX/H3K36me3 histone marks that may contribute to regulating important functions for HPV pathogenesis. Author summary: R-loops are trimeric RNA: DNA hybrids that regulate transcription but can also lead to DNA breaks. R-loop levels are elevated in many cancers as well in precancerous cells containing high-risk HPVs. How the distribution and function of R-loops changes due to the presence of viral genomes was examined by comparing cells derived from an HPV 31 positive precancer (CIN 612) to normal keratinocytes. Up to 10-fold higher R-loop levels were detected on cellular genes in CIN 612 cells, with over 500-fold increases at ALU elements. Analysis of the changes in R-loop landscape between normal and HPV positive cells identified a functional association between R-loop formation, gene expression, and chromatin states. R-loop formation in HPV postive cells was equally associated with negatively and positively regulated gene expression; however, coordinated expression of genes in specific pathways by R-loops was observed. This included repression of genes in the innate immune surveillance pathway, while those regulating DNA damage repair and metabolism were activated. [ABSTRACT FROM AUTHOR]

Circular RNAs (circRNAs) play vital roles in transcription and translation. Identification of circRNA-RBP (RNA-binding protein) interaction sites has become a fundamental step in molecular and cell biology. Deep learning (DL)-based methods have been proposed to predict circRNA-RBP interaction sites and achieved impressive identification performance. However, those methods cannot effectively capture long-distance dependencies, and cannot effectively utilize the interaction information of multiple features. To overcome those limitations, we propose a DL-based model iCRBP-LKHA using deep hybrid networks for identifying circRNA-RBP interaction sites. iCRBP-LKHA adopts five encoding schemes. Meanwhile, the neural network architecture, which consists of large kernel convolutional neural network (LKCNN), convolutional block attention module with one-dimensional convolution (CBAM-1D) and bidirectional gating recurrent unit (BiGRU), can explore local information, global context information and multiple features interaction information automatically. To verify the effectiveness of iCRBP-LKHA, we compared its performance with shallow learning algorithms on 37 circRNAs datasets and 37 circRNAs stringent datasets. And we compared its performance with state-of-the-art DL-based methods on 37 circRNAs datasets, 37 circRNAs stringent datasets and 31 linear RNAs datasets. The experimental results not only show that iCRBP-LKHA outperforms other competing methods, but also demonstrate the potential of this model in identifying other RNA-RBP interaction sites. Author summary: The interaction between circRNAs and RBPs is one of the main activities of circRNAs. CircRNAs participate in the occurrence and development of diseases by interacting with RBPs. Identifying circRNA-RBP interaction sites have become a fundamental step for exploring the role of circRNA in the occurrence and progression of diseases. Many computational methods have been proposed to predict circRNA-RBP interaction sites. Nevertheless, they still have several limitations. For long nucleotide sequence data of circRNA, traditional CNN or LSTM cannot effectively capture long-distance dependencies (relationships between non-adjacent nucleotides in a circRNA). Furthermore, existing methods fail to effectively utilize the interaction information of multiple features, and insufficient consideration of interaction information leads to biased circRNA-RBP interaction relationships. To overcome these limitations, we propose iCRBP-LKHA, based on a large convolutional kernel and hybrid channel-spatial attention for identifying circRNA-RBP interaction sites. We compared its performance with state-of-the-art DL-based methods on 37 circRNAs datasets, 37 circRNAs stringent datasets and 31 linear RNAs datasets. Experimental results not only show that iCRBP-LKHA outperforms competing methods, but also demonstrate the potential of this model in identifying other RNA-RBP interaction sites. [ABSTRACT FROM AUTHOR]

Gene therapy has made considerable strides in recent years. More than 4000 protein-coding genes have been implicated in more than 6000 genetic diseases; next-generation sequencing has dramatically revolutionized the diagnosis of genetic diseases. Most genetic diseases are considered very rare or ultrarare, defined here as having fewer than 1:100,000 cases, but only one of the 12 approved gene therapies (excluding RNA therapies) targets an ultrarare disease. This article explores three gene supplementation therapy approaches suitable for various rare genetic diseases: lentiviral vector-modified autologous CD34+ hematopoietic stem cell transplantation, systemic delivery of adeno-associated virus (AAV) vectors to the liver, and local AAV delivery to the cerebrospinal fluid and brain. Together with RNA therapies, we propose a potential business model for these gene therapies. [ABSTRACT FROM AUTHOR]

Although immune checkpoint inhibitors (anti-PD-1 antibody, anti-PD-L1 antibody, and anti-CTLA-4 antibody) have displayed considerable success in the treatment of malignant tumors, the therapeutic effect is still unsatisfactory for a portion of patients. Therefore, it is imperative to develop strategies to enhance the effect of these ICIs. Increasing evidence strongly suggests that the key to this issue is to transform the tumor immune microenvironment from a state of no or low immune infiltration to a state of high immune infiltration and enhance the tumor cell-killing effect of T cells. Therefore, some combination strategies have been proposed and this review appraise a summary of 39 strategies aiming at enhancing the effectiveness of ICIs, which comprise combining 10 clinical approaches and 29 foundational research strategies. Moreover, this review improves the comprehensive understanding of combination therapy with ICIs and inspires novel ideas for tumor immunotherapy. [ABSTRACT FROM AUTHOR]

MicroRNAs are emerging as crucial regulators within the complex, dynamic environment of the synapse, and they offer a promising new avenue for the treatment of neurological disease. These small noncoding RNAs modify gene expression in several ways, including posttranscriptional modulation via binding to complementary and semicomplementary sites on target mRNAs. This rapid, finely tuned regulation of gene expression is essential to meet the dynamic demands of the synapse. Here, we provide a detailed review of the multifaceted world of synaptic microRNA regulation. We discuss the many mechanisms by which microRNAs regulate gene expression at the synapse, particularly in the context of neuronal plasticity. We also describe the various factors, such as age, sex, and neurological disease, that can influence microRNA expression and activity in neurons. In summary, microRNAs play a crucial role in the intricate and quickly changing functional requirements of the synapse, and context is essential in the study of microRNAs and their potential therapeutic applications. [ABSTRACT FROM AUTHOR]

Background: Ulcerative colitis (UC) is a common chronic disease associated with inflammation and oxidative stress. This study aimed to construct a long noncoding RNA (lncRNA)-microRNA (miRNA)-messenger RNA (mRNA) network based on bioinformatics analysis and to explore oxidative stress-related genes underlying the pathogenesis of UC. Methods: The GSE75214 , GSE48959 , and GSE114603 datasets were downloaded from the Gene Expression Omnibus database. Following differentially expressed (DE) analysis, the regulatory relationships among these DERNAs were identified through miRDB, miRTarBase, and TargetScan; then, the lncRNA-miRNA-mRNA network was established. The Molecular Signatures Database (MSigDB) was used to search oxidative stress-related genes. Gene Ontology (GO) and Kyoto Encyclopedia of Genes and Genomes (KEGG) analyses were performed for functional annotation and enrichment analyses. Based on the drug gene interaction database DGIdb, drugs that interact with oxidative stress-associated genes were explored. A dextran sulfate sodium (DSS)-induced UC mouse model was used for experimental validation. Results: A total of 30 DE-lncRNAs, 3 DE-miRNAs, and 19 DE-mRNAs were used to construct a lncRNA-miRNA-mRNA network. By comparing these 19 DE-mRNAs with oxidative stress-related genes in MSigDB, three oxidative stress-related genes (CAV1, SLC7A11, and SLC7A5) were found in the 19 DEM sets, which were all negatively associated with miR-194. GO and KEGG analyses showed that CAV1, SLC7A11, and SLC7A5 were associated with immune inflammation and steroid hormone synthesis. In animal experiments, the results showed that dexamethasone, a well-known glucocorticoid drug, could significantly decrease the expression of CAV1, SLC7A11, and SLC7A5 as well as improve UC histology, restore antioxidant activities, inhibit inflammation, and decrease myeloperoxidase activity. Conclusion: SLC7A5 was identified as a representative gene associated with glucocorticoid therapy resistance and thus may be a new therapeutic target for the treatment of UC in the clinic. [ABSTRACT FROM AUTHOR]

Pain, a complex and debilitating condition affecting millions globally, is a significant concern, especially in the context of post-operative recovery. This comprehensive review explores the complexity of pain and its global impact, emphasizing the modulation of voltage-gated sodium channels (VGSC or NaV channels) as a promising avenue for pain management with the aim of reducing reliance on opioids. The article delves into the role of specific NaV isoforms, particularly NaV 1.7, NaV 1.8, and NaV 1.9, in pain process and discusses the development of sodium channel blockers to target these isoforms precisely. Traditional local anesthetics and selective NaV isoform inhibitors, despite showing varying efficacy in pain management, face challenges in systemic distribution and potential side effects. The review highlights the potential of nanomedicine in improving the delivery of local anesthetics, toxins and selective NaV isoform inhibitors for a targeted and sustained release at the site of pain. This innovative strategy seeks to improve drug bioavailability, minimize systemic exposure, and optimize therapeutic outcomes, holding significant promise for secure pain management and enhancing the quality of life for individuals recovering from surgical procedures or suffering from chronic pain. [ABSTRACT FROM AUTHOR]

Despite the increasing number of 3D RNA structures in the Protein Data Bank, the majority of experimental RNA structures lack thorough functional annotations. As the significance of the functional roles played by noncoding RNAs becomes increasingly apparent, comprehensive annotation of RNA function is becoming a pressing concern. In response to this need, we have developed FURNA (Functions of RNAs), the first database for experimental RNA structures that aims to provide a comprehensive repository of high-quality functional annotations. These include Gene Ontology terms, Enzyme Commission numbers, ligand-binding sites, RNA families, protein-binding motifs, and cross-references to related databases. FURNA is available at https://seq2fun.dcmb.med.umich.edu/furna/ to enable quick discovery of RNA functions from their structures and sequences. There is an increasing number of experimentally determined 3D RNA structures, but the majority lack functional annotation. To address this gap, this study provides a database of 3D RNA structures with comprehensive, high-quality functional annotations to enable discovery of RNA functions from structural and sequence information [ABSTRACT FROM AUTHOR]

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Diabetic wounds are characterized by incomplete healing and delayed healing, resulting in a considerable global health care burden. Exosomes are lipid bilayer structures secreted by nearly all cells and express characteristic conserved proteins and parent cell-associated proteins. Exosomes harbor a diverse range of biologically active macromolecules and small molecules that can act as messengers between different cells, triggering functional changes in recipient cells and thus endowing the ability to cure various diseases, including diabetic wounds. Exosomes accelerate diabetic wound healing by regulating cellular function, inhibiting oxidative stress damage, suppressing the inflammatory response, promoting vascular regeneration, accelerating epithelial regeneration, facilitating collagen remodeling, and reducing scarring. Exosomes from different tissues or cells potentially possess functions of varying levels and can promote wound healing. For example, mesenchymal stem cell-derived exosomes (MSC-exos) have favorable potential in the field of healing due to their superior stability, permeability, biocompatibility, and immunomodulatory properties. Exosomes, which are derived from skin cellular components, can modulate inflammation and promote the regeneration of key skin cells, which in turn promotes skin healing. Therefore, this review mainly emphasizes the roles and mechanisms of exosomes from different sources, represented by MSCs and skin sources, in improving diabetic wound healing. A deeper understanding of therapeutic exosomes will yield promising candidates and perspectives for diabetic wound healing management. [ABSTRACT FROM AUTHOR]

Pancreatic cancer, predominantly pancreatic ductal adenocarcinoma (PDAC), remains a highly lethal malignancy with limited therapeutic options and a dismal prognosis. By targeting the underlying molecular abnormalities responsible for PDAC development and progression, gene therapy offers a promising strategy to overcome the challenges posed by conventional radiotherapy and chemotherapy. This study sought to explore the therapeutic potential of small activating RNAs (saRNAs) specifically targeting the CCAAT/enhancer-binding protein alpha (CEBPA) gene in PDAC. To overcome the challenges associated with saRNA delivery, tetrahedral framework nucleic acids (tFNAs) were rationally engineered as nanocarriers. These tFNAs were further functionalized with a truncated transferrin receptor aptamer (tTR14) to enhance targeting specificity for PDAC cells. The constructed tFNA-based saRNA formulation demonstrated exceptional stability, efficient saRNA release ability, substantial cellular uptake, biocompatibility, and nontoxicity. In vitro experiments revealed successful intracellular delivery of CEBPA-saRNA utilizing tTR14-decorated tFNA nanocarriers, resulting in significant activation of tumor suppressor genes, namely, CEBPA and its downstream effector P21, leading to notable inhibition of PDAC cell proliferation. Moreover, in a mouse model of PDAC, the tTR14-decorated tFNA-mediated delivery of CEBPA-saRNA effectively upregulated the expression of the CEBPA and P21 genes, consequently suppressing tumor growth. These compelling findings highlight the potential utility of saRNA delivered via a designed tFNA nanocarrier to induce the activation of tumor suppressor genes as an innovative therapeutic approach for PDAC. [ABSTRACT FROM AUTHOR]

Recent breakthroughs in discovering novel immune signaling pathways have revolutionized different disease treatments. SERPINB9 (Sb9), also known as Proteinase Inhibitor 9 (PI-9), is a well-known endogenous inhibitor of Granzyme B (GzmB). GzmB is a potent cytotoxic molecule secreted by cytotoxic T lymphocytes and natural killer cells, which plays a crucial role in inducing apoptosis in target cells during immune responses. Sb9 acts as a protective mechanism against the potentially harmful effects of GzmB within the cells of the immune system itself. On the other hand, overexpression of Sb9 is an important mechanism of immune evasion in diseases like cancers and viral infections. The intricate functions of Sb9 in different cell types represent a finetuned regulatory mechanism for preventing immunopathology, protection against autoimmune diseases, and the regulation of cell death, all of which are essential for maintaining health and responding effectively to disease challenges. Dysregulation of the Sb9 will disrupt human normal physiological condition, potentially leading to a range of diseases, including cancers, inflammatory conditions, viral infections or other pathological disorders. Deepening our understanding of the role of Sb9 will aid in the discovery of innovative and effective treatments for various medical conditions. Therefore, the objective of this review is to consolidate current knowledge regarding the biological role of Sb9. It aims to offer insights into its discovery, structure, functions, distribution, its association with various diseases, and the potential of nanoparticle-based therapies targeting Sb9. [ABSTRACT FROM AUTHOR]