Search Results (368)

Congenital hearing loss, frequently resulting from defective hair cells, remains poorly understood due to the incomplete identification of key pathogenic genes. Oncomodulin (OCM) is a kind of calcium-binding protein (CaBP) that regulates diverse cellular processes and is thought to play crucial roles in auditory function. In teleost fish, parvalbumin 8 (pvalb8) and parvalbumin 9 (pvalb9) belong to the oncomodulin lineage and are highly expressed in hair cells. In this study, we first reported the oncomodulin lineage function in fish and identified pvalb8 as an essential regulator of hair cell development. Single-cell RNA sequencing (scRNA-seq) and whole-mount in situ hybridization (WISH) revealed that pvalb8 is highly and specifically expressed in supporting cells and hair cells. Functional loss of pvalb8, achieved via CRISPR/Cas9 knockout or morpholino knockdown, resulted in reduced neuromast size and a significant decrease in neuromast hair cell number, leading to auditory behavioral deficits. In addition, pvalb9 mutants exhibited hair cell defects similar to those observed in pvalb8 mutants, including a significant reduction in hair cell number. Moreover, pvalb8 loss strongly inhibited the proliferation of supporting cells, which likely accounts for the reduced number of differentiated hair cells. The expression levels of Wnt target genes, axin2, ccnd1, and myca, were all significantly reduced in pvalb8 mutants compared to control zebrafish, while activation of the Wnt signaling pathway rescued the hair cell loss observed in pvalb8 mutants, indicating that pvalb8 promotes hair cell development via Wnt-dependent proliferative signaling. These findings highlight pvalb8 as a critical factor in the regulation of auditory hair cell formation and function in zebrafish, offering new insights into the role of oncomodulin lineage in sensory cell development. Full article

Objective: Molecular biology techniques were employed to investigate the effects of thrombospondin-4 (Thbs4) expression in dorsal root ganglion (DRG) on peripheral nerve injury repair and regeneration, as well as to elucidate the underlying molecular mechanisms. Methods: A sciatic nerve transection model in rat was established to analyze Thbs4 expression and localization in DRG tissues after injury. Both siRNA and adeno-associated virus (AAV) were used to knockdown or overexpress Thbs4. The effects of knockdown and overexpression of Thbs4 on axon growth were assessed using immunofluorescence staining. The roles of Thbs4 in peripheral nerve injury repair and regeneration were determined using behavioral assays, electrophysiological recordings, and transmission electron microscopy. Results: Thbs4 was primarily localized in the cell membrane and cytoplasm of DRG neurons but was also found in the intercellular spaces. In vitro experiments demonstrated that Thbs4 overexpression promoted axonal regeneration and reduced neuronal apoptosis. They also showed that Thbs4 overexpression accelerated sciatic nerve regeneration and enhanced the recovery of motor and sensory functions. Conversely, Thbs4 knockdown had the opposite effects. This study also showed that the knockdown or overexpression of Thbs4 significantly altered the expression of NF-κB and ERK signaling pathways, suggesting their involvement in peripheral nerve repair and regeneration. Conclusions: Thbs4 expression in DRG tissues is significantly altered following sciatic nerve injury. The NF-κB and ERK may be involved in regulating the repair and regeneration of the peripheral nerve by Thbs4. Full article

Repairing the central nervous system (CNS) remains one of the most difficult obstacles to overcome in translational neurosciences. This is due to intrinsic growth inhibitors, extracellular matrix issues, the glial scar–form barrier, chronic neuroinflammation, and epigenetic silencing. The purpose of this review is to bring together findings from recent developments in genome editing and computational approaches, which center around the possible convergence of clustered regularly interspaced short palindromic repeats (CRISPR) platforms and artificial intelligence (AI), towards precision neuroregeneration. We wished to outline possible ways in which CRISPR-based systems, including but not limited to Cas9 and Cas12 nucleases, RNA-targeting Cas13, base and prime editors, and transcriptional regulators such as CRISPRa/i, can be applied to potentially reactivate axon-growth programs, alter inhibitory extracellular signaling, reprogram or lineage transform glia to functional neurons, and block oncogenic pathways in glioblastoma. In addition, we wanted to highlight how AI approaches, such as single-cell multi-omics, radiogenomic prediction, development of digital twins, and design of adaptive clinical trials, will increasingly be positioned to act as system-level architects that allow translation of complex datasets into predictive and actionable therapeutic approaches. We examine convergence consumers in spinal cord injury and adaptive neuro-oncology and discuss expanse consumers in ischemic stroke, Alzheimer’s disease, Parkinson’s disease, and rare neurogenetic syndromes. Finally, we discuss the ethical and regulatory landscape around beyond off-target editing and genomic stability of CRISPR, algorithmic bias, explainability, and equitable access to advanced neurotherapies. Our intent was not to provide a comprehensive inventory of possibilities but rather to provide a conceptual tool where CRISPR acts as a molecular manipulator and AI as a computational integrator, converging to create pathways towards precision neuroregeneration, personalized medicine, and adaptive neurotherapeutics that are ethically sound. Full article

Astrocyte-derived extracellular vesicles (ADEVs) have emerged as promising neuroprotective agents for ischemic stroke. In this study, we evaluated the therapeutic potential of hypoxia-conditioned ADEVs (HxEVs) administered intracerebroventricularly in a rat model of transient middle cerebral artery occlusion (tMCAO). Serial magnetic resonance imaging (MRI) with diffusion tensor imaging (DTI) was performed at 1, 7, 14, and 21 days post-stroke. HxEV treatment produced a significant reduction in infarct volume from day 1, sustained through day 21, and was accompanied by improvements in motor and sensory recovery. DTI analyses showed progressive normalization of fractional anisotropy (FA) and radial diffusivity (RD), particularly in the corpus callosum and striatum, reflecting microstructural repair. In contrast, mean diffusivity (MD) was less sensitive to these treatment effects. Regional differences in therapeutic response were evident, with earlier and more sustained recovery in the corpus callosum than in other brain regions. Histological findings confirmed greater preservation of dendrites and axons in HxEV-treated animals, supporting the role of these vesicles in accelerating post-stroke neurorepair. Together, these results demonstrate that hypoxia-conditioned ADEVs promote both structural and functional recovery after ischemic stroke. They also highlight the value of DTI-derived biomarkers as non-invasive tools to monitor neurorepair. The identification of region-specific therapeutic effects and the validation of reliable imaging markers provide a strong foundation for future research and development. Full article

Traumatic injuries to the brain and spinal cord remain among the most challenging conditions in clinical neuroscience due to the complexity of repair mechanisms and the limited regenerative capacity of neural tissues. Nanotechnology has emerged as a transformative field, offering precise diagnostic tools, targeted therapeutic delivery systems, and advanced scaffolding platforms that are capable of overcoming the biological barriers to regeneration. This review summarizes the recent advances in nanoscale diagnostic markers, functionalized nanoparticles for drug delivery, and nanostructured scaffolds designed to modulate the injured microenvironment and support axonal regrowth and remyelination. Emerging evidence indicates that nanotechnology enables real-time, minimally invasive detection of inflammation, oxidative stress, and cellular damage, while improving therapeutic efficacy and reducing systemic side effects through targeted delivery. Electroconductive scaffolds and hybrid strategies that integrate electrical stimulation, gene therapy, and artificial intelligence further expand opportunities for personalized neuroregeneration. Despite these advances, significant challenges remain, including long-term safety, immune compatibility, the scalability of large-scale production, and translational barriers, such as small sample sizes, heterogeneous preclinical models, and limited follow-up in existing studies. Addressing these issues will be critical to realize the full potential of nanotechnology in traumatic brain and spinal cord injury and to accelerate the transition from promising preclinical findings to effective clinical therapies. Full article

Heparin-based delivery platforms have gained increasing attention in regenerative medicine due to their exceptional affinity for growth factors and versatility in structural and functional design. This review first introduces the molecular biosynthesis and physicochemical diversity of heparin, which underpin its binding selectivity and degradability. It then categorizes the delivery platforms into microspheres, nanofibers, and hydrogels, with detailed discussions on their fabrication techniques, biofunctional integration of heparin, and release kinetics. Special focus is given to stimuli-responsive systems—including pH-, enzyme-, redox-, thermal-, and ultrasound-sensitive designs—which allow spatiotemporal control over growth factor release. The platform applications are organized by tissue types, encompassing soft tissue regeneration, bone and cartilage repair, neuroregeneration, cardiovascular regeneration, wound healing, anti-fibrotic therapies, and cancer microenvironment modulation. Each section provides recent case studies demonstrating how heparin enhances the bioactivity, localization, and therapeutic efficacy of pro-regenerative or anti-pathologic growth factors. Collectively, these insights highlight heparin’s dual role as both a carrier and modulator, positioning it as a pivotal component in next-generation, precision-targeted delivery systems. Full article

Hearing is essential for animal survival and social communication, relying on the function of sensory hair cells. These cells possess organized stereocilia bundles enriched with mechano-electrical transduction (MET) channels that convert mechanical stimuli into electrical signals. Tip links, fine extracellular filaments connecting adjacent stereocilia, play a critical role in transmitting mechanical forces to MET channels. Over the past three decades, technological advances have significantly enhanced our understanding of the molecular and cellular mechanisms underlying auditory transduction. Zebrafish, with its conserved hair cell structure and function similar to mammals, has become a valuable model in auditory research. The aim of this review is to summarize the research progress on the molecular and cellular mechanisms of MET, tip link, and stereocilia complex, with an emphasis on zebrafish studies, providing an important reference for understanding diseases of the human auditory system. Full article

Background: Parkinson’s disease (PD) is a progressive neurodegenerative disorder characterized by the degeneration of dopaminergic neurons in the substantia nigra (SN), leading to motor impairments and numerous non-motor manifestations, including anxiety. Notably, anxiety has been shown to exacerbate disease progression and hinder treatment outcomes in PD. Botulinum neurotoxin (BoNT), recognized for its ability to block excessive release of acetylcholine (ACh), has been shown to provide clinical effectiveness in managing motor symptoms. BoNT appears to enhance neuroregenerative plasticity and mitigate neuroinflammation through mechanisms speculated to extend beyond its classical mode of action. Nevertheless, reports on its potential anxiolytic and neuroprotective effects in PD remain limited. Aim: This study investigated the effect of BoNT on motor and anxiety-like behaviors in a 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP)-induced mouse model of PD. Methods: The experimental animals were assessed for behavioral changes using the open field test (OFT), rotarod, pole test, light-dark box test (LDBT), and elevated plus maze (EPM). Immunohistochemistry was employed to enumerate tyrosine hydroxylase (TH)-positive dopaminergic neurons and ionized calcium-binding adapter molecule (Iba)-1 expressing microglia in SN. Results: BoNT treatment markedly alleviated motor deficits and anxiety. Quantification of TH- and Iba-1-positive cells revealed that BoNT promotes neuroprotection and minimizes microglial burden in the SN of the PD model. Conclusions: The outcome of the study represents the anxiolytic, neuroprotective, and microglial modulatory potentials of BoNT in PD, supporting its therapeutic promise beyond the management of motor symptoms. Given its multifaceted properties, BoNT can be considered a potential therapeutic candidate for PD and other neurological disorders. Full article

It has long been accepted that breathing gases that are physiologically inert include helium (He), neon (Ne), nitrogen (N₂), argon (Ar), krypton (Kr), xenon (Xe), and hydrogen (H₂). The term “inert gas” has been used to describe them due to their unusually high chemical stability. However, as investigations have advanced, many have shown that inert gas can have specific biological impacts when exposed to high pressure or atmospheric pressure. Additionally, different inert gases have different effects on intracellular signal transduction, ion channels, and cell membrane receptors, which are linked to their anesthetic and cell protection effects in normal or pathological processes. Through a selective analysis of the representative literature, this study offers a concise overview of the state of research on the biological impacts of inert gas and their molecular mechanisms. Full article

The use of Botulinum Neurotoxin A (BoNT/A) to treat peripheral neuropathic pain from nerve injury has garnered interest for its long-lasting effects and safety. This study examined the effects of IncobotulinumtoxinA (Inco/A), a BoNT/A variant without accessory proteins, on nerve regeneration in rats using the chronic constriction injury (CCI) model. Inco/A was administered perineurally at two time points: on days 0 and 21 post CCI. Functional and histological assessments were conducted to evaluate the effect of Inco/A on nerve regeneration. Sciatic Functional Index (SFI) measurements and Compound Muscle Action Potential (CMAP) recordings were conducted at different time points following CCI. Inco/A-treated animals exhibited a 65% improved SFI and 22% reduction in CMAP onset latencies compared to the vehicle-treated group, suggesting accelerated functional nerve recovery. Tissue analysis revealed enhanced remyelination in Inco/A-treated animals and 60% reduction in CGRP and double S100β signal expression compared to controls. Strikingly, 30% reduced immune cell influx into the injury site was observed following Inco/A treatment, suggesting that its anti-inflammatory effect contributes to nerve regeneration. These findings show that two injections of Inco/A promote functional recovery by enhancing neuroregeneration and modulating inflammatory processes, supporting the hypothesis that Inco/A has a neuroprotective and restorative role in nerve injury conditions. Full article

Spinal cord injury (SCI) is a debilitating condition that results from a culmination of acute and chronic damage to neural tissue, specifically the myelin sheath, thus impacting neurons’ abilities to synergistically perform their physiological roles. This review explores the molecular underpinnings of myelination, demyelination, and remyelination, emphasizing the role of oligodendrocyte progenitor cells (OPCs), astrocytes, and microglia in physiological, and pathophysiological, healing. Furthermore, we link these processes with emerging therapeutic strategies currently under investigation in animal and human models, underscoring areas of translational medicine that remain underutilized. The goal of this review is to provide a framework for developing more advanced interventions to restore function and improve outcomes for individuals with SCI. Full article

High-altitude cognitive impairment (HACI) results from acute or chronic exposure to hypoxic conditions. Brain lipid homeostasis is crucial for cognitive function, and lipid droplet (LD) accumulation in glia cells is linked to cognitive decline in aging and stroke. However, whether high-altitude exposure affects brain lipid homeostasis is unclear. Microglia, key regulators of brain homeostasis and inflammation, play a significant role in pathological cognitive impairment and are implicated in LD formation. This study investigates whether lipid dysregulation contributes to HACI and explores microglia-driven mechanisms and potential interventions. Mice were exposed to a simulated 7000 m altitude for 48 h, followed by a week of recovery. Cognitive function and LD accumulation in brain cells were assessed. Microglia were depleted using PLX5622, and mice were exposed to hypoxia or lipopolysaccharide (LPS) to validate microglia’s role in driving astrocytic LD accumulation and cognitive decline. Minocycline was used to inhibit inflammation. In vitro, co-culture systems of microglia and astrocytes were employed to confirm microglia-derived pro-inflammatory factors’ role in astrocytic LD accumulation. Hypobaric hypoxia exposure induced persistent cognitive impairment and LD accumulation in hippocampal astrocytes and microglia. Microglia depletion alleviated cognitive deficits and reduced astrocytic LD accumulation. Hypoxia or LPS did not directly cause LD accumulation in astrocytes but activated microglia to release IL-1β, inducing astrocytic LD accumulation. Microglia depletion also mitigated LPS-induced cognitive impairment and astrocytic LD accumulation. Minocycline reduced hypoxia-induced LD accumulation in co-cultured astrocytes and improved cognitive function. Hypoxia triggers pro-inflammatory microglial activation, leading to LD accumulation and the release of IL-1β, which drives astrocytic LD accumulation and neuroinflammation, exacerbating HACI. Minocycline effectively restores brain lipid homeostasis and mitigates cognitive impairment. This study provides novel insights into HACI mechanisms and suggests potential therapeutic strategies. Full article

Spinal cord injury (SCI) remains one of the toughest obstacles in neuroscience and regenerative medicine due to both severe functional loss and limited healing ability. This article aims to provide a key integrative, mechanism-focused review of the molecular landscape of SCI and the new disruptive therapy technologies that are now evolving in the SCI arena. Our goal is to unify a fundamental pathophysiology of neuroinflammation, ferroptosis, glial scarring, and oxidative stress with the translation of precision treatment approaches driven by artificial intelligence (AI), CRISPR-mediated gene editing, and regenerative bioengineering. Drawing upon advances in single-cell omics, systems biology, and smart biomaterials, we will discuss the potential for reprogramming the spinal cord at multiple levels, from transcriptional programming to biomechanical scaffolds, to change the course from an irreversible degeneration toward a directed regenerative pathway. We will place special emphasis on using AI to improve diagnostic/prognostic and inferred responses, gene and cell therapies enabled by genomic editing, and bioelectronics capable of rehabilitating functional connectivity. Although many of the technologies described below are still in development, they are becoming increasingly disruptive capabilities of what it may mean to recover from an SCI. Instead of prescribing a particular therapeutic fix, we provide a future-looking synthesis of interrelated biological, computational, and bioengineering approaches that conjointly chart a course toward adaptive, personalized neuroregeneration. Our intent is to inspire a paradigm shift to resolve paralysis through precision recovery and to be grounded in a spirit of humility, rigor, and an interdisciplinary approach. Full article

Neural stem cells have shown great potential in the therapy of neurodegenerative diseases such as Parkinson’s disease (PD), because of their ability to differentiate into various types of neural cells and substitute for damaged neurons. Their clinical application is, however, impeded by limitations such as low survival rates following transplantation, low efficiency of differentiation, the potential for tumorigenesis, and the risk of immune rejection by the host. Adipose-derived stem cells (ADSCs) have become increasingly popular as an alternative tool in regenerative medicine due to their accessibility, multipotency, and low immunogenicity. The recent advance in inducing ADSCs into neural stem cell-like cells (iNSCs) opens up a new avenue for the treatment of PD by restoring dopaminergic neuron populations. Here, the biological characteristics, induction protocols, molecular mechanisms, and prospective applications of ADSCs in neural repair are summarized systematically. We also covered current technical challenges, such as differentiation protocol optimization and functional integration, and future perspectives, including biomaterial and gene editing applications to enhance ADSC-based therapies. With these challenges met, ADSCs hold excellent potential for advancing personalized and combination therapies for neurodegenerative diseases. Full article

Astrocytes, which proliferate after brain injury, represent a promising target for cellular reprogramming due to their abundance and ability to support brain repair. In this study, we investigated the in vitro reprogramming of primary cortical astrocytes from neonatal rats into neuronal precursor cells (NPCs) using the transcription factors Oct4, Sox2, and Klf4 (OSK), delivered via lentiviral vectors. We designed a reporter system to trace the conversion of astrocytes to NPCs and neurons by using GFAP-driven iCre and Nestin- or Synapsin1-driven fluorescent reporters. After transduction, we observed morphological changes and the expression of neuronal markers in some cells, while many cells remained in a transitional state, expressing both astrocytic and neuronal features. Importantly, the study was not designed to quantify reprogramming efficiency or demonstrate full astrocyte-to-neuron conversion but rather to establish and evaluate a traceable reporter system. Our data suggest that OSK-mediated reprogramming in this in vitro model can initiate conversion of astrocytes to neuronal precursor-like cells, although the process is complex and incomplete within the one-week timeframe. We also highlight limitations in co-transduction efficiency and potential silencing of the reporter system during reprogramming. These findings provide an initial technical platform to explore astrocyte reprogramming in vitro and inform future studies aiming to refine these methods and apply them in vivo. Full article