Cancer is a fatal human disease. Early diagnosis of cancer is the most effective method to prevent cancer development and to achieve higher survival rates for patients. Many traditional diagnostic methods for cancer are still not sufficient for early, more convenient and accurate, and noninvasive diagnosis. Recently, the use of microRNAs (miRNAs), such as exosomal microRNA-21(miR-21), as potential biomarkers was widely reported. This initial systematic review analyzes the potential role of exosomal miR-21 as a general biomarker for cancers. A total of 10 studies involving 318 patients and 215 healthy controls have covered 10 types of cancers. The sensitivity and specificity of pooled studies were 75% (0.70–0.80) and 85% (0.81–0.91), with their 95% confidence intervals (CIs), while the area under the summary receiver operating characteristic curve (AUC) was 0.93. Additionally, we examined and evaluated almost all other issues about biomarkers, including cutoff points, internal controls and detection methods, from the literature. This initial meta-analysis indicates that exosomal miR-21 has a strong potential to be used as a universal biomarker to identify cancers, although as a general biomarker the case number for each cancer type is small. Based on the literature, a combination of miRNA panels and other cancer antigens, as well as a selection of appropriate internal controls, has the potential to serve as a more sensitive and accurate cancer diagnosis tool. Additional information on miR-21 would further support its use as a biomarker in cancer.

The p75 neurotrophin receptor (p75^NTR) influences the proliferation, survival, and differentiation of neuronal precursors and its expression is induced in injured brain, where it regulates cell survival. Here, we test the hypotheses that pharmacologic modulation of p75^NTR signaling will promote neural progenitor survival and proliferation, and improve outcomes of traumatic brain injury (TBI). LM11A-31, an orally available, blood-brain barrier-permeant small-molecule p75^NTR signaling modulator, significantly increased proliferation and survival, and decreased JNK phosphorylation, in hippocampal neural stem/progenitor cells in culture expressing wild-type p75^NTR, but had no effect on cells expressing a mutant neurotrophin-unresponsive form of the receptor. The compound also enhanced the production of mature neurons from adult hippocampal neural progenitors in vitro. In vivo, intranasal administration of LM11A-31 decreased postinjury hippocampal and cortical neuronal death, neural progenitor cell death, gliogenesis, and microglial activation, and enhanced long-term hippocampal neurogenesis and reversed spatial memory impairments. LM11A-31 diminished the postinjury increase of SOX2-expressing early progenitor cells, but protected and increased the proliferation of endogenous polysialylated-neural cell adhesion molecule positive intermediate progenitors, and restored the long-term production of mature granule neurons. These findings suggest that modulation of p75^NTR actions using small molecules such as LM11A-31 may constitute a potent therapeutic strategy for TBI. Stem Cells 2013;31:2561–2574

Glioblastoma multiforme (GBM) is the most common malignant glioma. Despite innovative research efforts in tumor therapy, the outcome for most diagnosed patients remains poor; therefore, early diagnosis of GBM is the most effective method for achieving better patient outcomes. In recent years, combined research efforts including cellular, molecular, genetic, and bioinformatics methods have been used to investigate GBM, and the results show that variations in miRNA expression occur in GBM tissues and biological fluids. Some highly stable miRNAs circulate in the blood and cerebrospinal fluid (CSF) of both healthy individuals and diagnosed patients, thus raising the possibility that miRNAs may serve as novel diagnostic markers. In addition, increased understanding of the miRNA and mRNA interactions involved in GBM progression may lead to discovering predictive biomarkers, some of which are clinically relevant for targeted therapy and predicting prognosis. However, as this field is relatively new, some studies have yielded conflicting results. To progress in the field, different advanced techniques must be combined, including bioinformatics methods and molecular and cellular techniques. In addition, we must overcome the various challenges in non-invasive GBM biomarker detection. Here, we discuss the progress and potential of miRNAs as biomarkers for GBM and related signaling pathways. Studying the clinical relevance and applicability of these biomarkers may alter GBM patient diagnosis and treatment.

Neurotrophins are involved in many physiological and pathological processes in the nervous system. They regulate and modify signal transduction, transcription and translation in neurons. It is recently demonstrated that the neurotrophin expression is regulated by microRNAs (miRNAs), changing our views on neurotrophins and miRNAs. Generally, miRNAs regulate neurotrophins and their receptors in at least two ways: (1) miRNAs bind directly to the 3′ untranslated region (UTR) of isoform-specific mRNAs and post-transcriptionally regulate their expression; (2) miRNAs bind to the 3′ UTR of the regulatory factors of neurotrophins and regulate their expression. On the other hand, neurotrophins can regulate miRNAs. The results of BNDF research show that neurotrophins regulate miRNAs in at least three ways: (1) ERK stimulation enhances the activation of TRBP (HIV-1 TAR RNA-binding protein) and Dicer, leading to the upregulation of miRNA biogenesis; (2) ERK-dependent upregulation of Lin28a (RNA-binding proteins) blocks select miRNA biogenesis; (3) transcriptional regulation of miRNA expression through activation of transcription factors, including CREB and NF-κB. These regulatory processes integrate positive and negative regulatory loops in neurotrophin and miRNA signaling pathways, and also expand the function of neurotrophins and miRNAs. In this review, we summarize the current knowledge of the regulatory networks between neurotrophins and miRNAs in brain diseases and cancers, for which novel cutting edge therapeutic, delivery and diagnostic approaches are emerging.

Microglia and macrophages are pivotal to the brain’s innate immune response and have garnered considerable attention in the context of glioblastoma (GBM) and Alzheimer’s disease (AD) research. This review delineates the complex roles of these cells within the neuropathological landscape, focusing on a range of signaling pathways—namely, NF-κB, microRNAs (miRNAs), and TREM2—that regulate the behavior of tumor-associated macrophages (TAMs) in GBM and disease-associated microglia (DAMs) in AD. These pathways are critical to the processes of neuroinflammation, angiogenesis, and apoptosis, which are hallmarks of GBM and AD. We concentrate on the multifaceted regulation of TAMs by NF-κB signaling in GBM, the influence of TREM2 on DAMs’ responses to amyloid-beta deposition, and the modulation of both TAMs and DAMs by GBM- and AD-related miRNAs. Incorporating recent advancements in molecular biology, immunology, and AI techniques, through a detailed exploration of these molecular mechanisms, we aim to shed light on their distinct and overlapping regulatory functions in GBM and AD. The review culminates with a discussion on how insights into NF-κB, miRNAs, and TREM2 signaling may inform novel therapeutic approaches targeting microglia and macrophages in these neurodegenerative and neoplastic conditions. This comparative analysis underscores the potential for new, targeted treatments, offering a roadmap for future research aimed at mitigating the progression of these complex diseases.

Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) persists throughout the world with over 65 million registered cases of survivors with post-COVID-19 sequelae, also known as LongCOVID-19 (LongC). LongC survivors exhibit various symptoms that span multiple organ systems, including the nervous system. To search for neurological markers of LongC, we investigated the soluble biomolecules present in the plasma and the proteins associated with plasma neuronal-enriched extracellular vesicles (nEVs) in 33 LongC patients with neurological impairment (nLongC), 12 COVID-19 survivors without any LongC symptoms (Cov), and 28 pre-COVID-19 healthy controls (HC). COVID-19 positive participants were infected between 2020 and 2022, not hospitalized, and were vaccinated or unvaccinated before infection. IL-1β was significantly increased in both nLongC and Cov and IL-8 was elevated in only nLongC. Both brain-derived neurotrophic factor and cortisol were significantly elevated in nLongC and Cov compared to HC. nEVs from people with nLongC had significantly elevated protein markers of neuronal dysfunction, including amyloid beta 42, pTau181 and TDP-43. This study shows chronic peripheral inflammation with increased stress after COVID-19 infection. Additionally, differentially expressed nEV neurodegenerative proteins were identified in people recovering from COVID-19 regardless of persistent symptoms.