Search Results (1,168)

Spinal muscular atrophy (SMA) is a fatal motor neuron disease characterized by five clinical subtypes, each presenting with different rates of disease progression and varying responses to recently approved therapies. The identification of reliable biomarkers is essential for improving diagnosis and prognosis, monitoring disease progression, enabling personalized treatment strategies, and evaluating therapeutic responses. In this review, we conducted a comprehensive literature search using PubMed and Web of Science with the keywords “spinal muscular atrophy”, “biomarker” and advanced technologies such as “single-cell omics”, “nanopore and long-read sequencing” and “epigenetics” to identify and summarize current advances in SMA biomarker discovery and application. We begin with a brief overview of SMA and its current treatment barriers. We then conclude with well-established and emerging molecular and non-molecular biomarkers, followed by a conclusion of emerging technologies in biomarker discovery. In the meantime, we highlight the application of biomarkers in key areas, including early diagnosis and disease stratification, monitoring of disease progression, and prediction of treatment response. Finally, we summarize biomarker-targeted therapies, addressing current challenges in biomarker research, with the goal of improving clinical outcomes for patients with SMA. Full article

Objectives: Insulin plays a crucial role in neuronal survival and oxidative stress modulation, making it a potential therapeutic target. This study investigates the effects of insulin in combination with a mesenchymal cell-derived secretome in patients with degenerative neuroretinal diseases. Methods: Sixty-four patients with severe neuroretinal diseases who had previously undergone the Limoli Retinal Restoration Technique (LRRT) were included in this longitudinal study and divided into groups: group 1 received a single injection of 5 units of insulin lispro into the suprachoroidal space of the worse-seeing eye; group 2 received insulin injection in the better-seeing eye. Retinal function was assessed using microperimetry (MY) before and after treatment (approximately 1 year for eye drops). Group 3 consisted of patients who demonstrated improvement in MY after insulin injection. These patients continued treatment with daily insulin eye drops. Results: In group 1, insulin-treated eyes showed a significant increase in retinal sensitivity from 10.09 dB to 10.75 dB (p = 0.0067), while untreated eyes declined from 12.35 dB to 11.92 dB (p = 0.0448). In group 2, insulin-treated eyes improved from 10.8 dB to 11.63 dB (p = 0.05), whereas untreated eyes exhibited a decline from 8.68 dB to 8.50 dB (p = 0.6771). In group 3, patients using insulin eye drops showed a stabilization or mild increase in retinal sensitivity, from 11.39 dB to 11.73 dB (p = 0.231). Conclusions: The addition of insulin in patients previously treated with the LRRT was associated with improved sensitivity and a stabilizing effect on neuroretinal function. Full article

Quickly and accurately identifying weed areas is of great significance for improving weeding efficiency, reducing pesticide residues, protecting soil ecological environment, and increasing crop yield and quality. Targeting low detection efficiency in complex agricultural environments and inability of multispectral input in weed recognition of minor grain based on unmanned aerial vehicles (UAVs), a semantic segmentation model for buckwheat weeds based on MSU-Net (multispectral U-shaped network) was proposed to explore the influence of different band optimizations on recognition accuracy. Five spectral features—red (R), blue (B), green (G), red edge (REdge), and near-infrared (NIR)—were collected in August when the weeds were more prominent. Based on the U-net image semantic segmentation model, the input module was improved to adaptively adjust the input bands. The neuron death caused by the original ReLU activation function may lead to misidentification, so it was replaced by the Swish function to improve the adaptability to complex inputs. Five single-band multispectral datasets and nine groups of multi-band combined data were, respectively, input into the improved MSU-Net model to verify the performance of our method. Experimental results show that in the single-band recognition results, the B band performs better than other bands, with mean pixel accuracy (mPA), mean intersection over union (mIoU), Dice, and F1 values of 0.75, 0.61, 0.87, and 0.80, respectively. In the multi-band recognition results, the R+G+B+NIR band performs better than other combined bands, with mPA, mIoU, Dice, and F1 values of 0.76, 0.65, 0.85, and 0.78, respectively. Compared with U-Net, DenseASPP, PSPNet, and DeepLabv3, our method achieved a preferable balance between model accuracy and resource consumption. These results indicate that our method can adapt to multispectral input bands and achieve good results in weed segmentation tasks. It can also provide reference for multispectral data analysis and semantic segmentation in the field of minor grain crops. Full article

Introduction: Sepsis-associated encephalopathy (SAE) is an acute brain dysfunction secondary to systemic infection, occurring without direct central nervous system involvement. Despite its clinical relevance, reliable biomarkers for diagnosing SAE and assessing its severity remain limited. This study aimed to evaluate the feasibility of amide proton transfer-weighted (APTw) chemical exchange saturation transfer (CEST) MRI as a non-invasive molecular imaging technique for detecting metabolic alterations related to neuroinflammation in SAE. Using a lipopolysaccharide (LPS)-induced rat model, we focused on hippocampal changes associated with neuronal inflammation. Materials and Methods: Twenty-one Sprague–Dawley rats (8 weeks old, male) were divided into three groups: control (CTRL, n = 7), LPS-induced sepsis at 5 mg/kg (LPS05, n = 7), and 10 mg/kg (LPS10, n = 7). Sepsis was induced via a single intraperitoneal injection of LPS. APTw imaging was performed using a 7 T preclinical MRI system, and signal quantification in the hippocampus was conducted using the magnetization transfer ratio asymmetry analysis. Results and Discussion: APTw imaging at 7 T demonstrated significantly elevated hippocampal APTw signals in SAE model rats (LPS05 and LPS10) compared to the control (CTRL) group: CTRL (−1.940 ± 0.207%) vs. LPS05 (−0.472 ± 0.485%) (p < 0.001) and CTRL vs. LPS10 (−0.491 ± 0.279%) (p < 0.001). However, no statistically significant difference was observed between the LPS05 and LPS10 groups (p = 0.994). These results suggest that APTw imaging can effectively detect neuroinflammation-related metabolic alterations in the hippocampus. Conclusion: Our findings support the feasibility of APTw CEST imaging as a non-invasive molecular MRI technique for SAE, with potential applications in diagnosis, disease monitoring, and therapeutic evaluation. Full article

The lateral hypothalamic area (LHA) serves as a central integrative hub for the regulation of energy homeostasis and motivational behaviors, including feeding and arousal. Recent advances in single-cell transcriptomics have revealed remarkable molecular heterogeneity within the LHA, identifying more than 30 distinct neuronal subtypes, such as GABAergic (LHA^Vgat), glutamatergic (LHA^Vglut2), orexin, melanin-concentrating hormone (MCH), and leptin receptor-expressing (LHA^Lepr) neurons. These neuronal populations sense peripheral metabolic signals—such as leptin, insulin, and glucose—both directly and indirectly, and they coordinate appropriate physiological and behavioral responses through local circuits and reciprocal connections with other hypothalamic nuclei. Furthermore, the LHA interfaces with extrahypothalamic regions, including the ventral tegmental area (VTA), nucleus accumbens (NAc), and lateral habenula (LHb), thereby linking metabolic state to reward processing and behavioral prioritization. In this review, we summarize and integrate recent molecular and functional findings to present a comprehensive view of the LHA as a dynamic, multifunctional center in the central regulation of metabolism. A deeper understanding of these mechanisms may offer new therapeutic avenues for addressing obesity and related metabolic disorders. Full article

Trigeminal neuralgia is a chronic pain disorder due to neuronal damage. The present study was designed to investigate the effect of 7,8-dimethoxy coumarin (DMC) in a rat model of trigeminal neuralgia. The neuropathic pain was induced by the single endoneural injection of tumor necrosis factor-alpha (TNF-α; 0.1 μL: stock 10 pg/mL) in the rat trigeminal nerve. The DMC (100 and 200 mg/kg) and carbamazepine (100 mg/kg) were administered orally for 10 consecutive days from the 5th day of TNF-α injection. The battery of behavioral tests, i.e., acetone drop and Von Frey filament test, was performed to assess the degree of thermal and mechanical allodynia on 0, 1st, 7th, and 14th days. In addition, the biochemical tests, i.e., total protein, thiobarbituric acid reactive substances (TBARS), reduced glutathione (GSH), and TNF-α, were also performed in trigeminal nerve tissue. Furthermore, TNF-α-induced neuronal histopathological changes were also evaluated by the eosin and hematoxylin staining method. The administration of DMC was shown to demonstrate the significant (p < 0.05) reversal of TNF-α-induced percentage reduction of thermal and mechanical sensitivity, along with a rise in TBARS and TNF-α and a decrease in GSH levels. Further, DMC also attenuates the histopathological changes. It may be concluded that DMC may be a potential therapeutic agent for the management of trigeminal neuralgia disorders. Full article

Pediatric high-grade gliomas (pHGGs), particularly diffuse midline gliomas (DMGs), are among the most lethal brain tumors due to poor survival and resistance to therapies. DMGs possess a distinct genetic profile, primarily driven by hallmark mutations such as H3K27M, ACVR1, and PDGFRA mutations/amplifications and TP53 inactivation, all of which contribute to tumor biology and therapeutic resistance. Developing physiologically relevant preclinical models that replicate both tumor biology and the tumor microenvironment (TME) is critical for advancing effective treatments. This review highlights recent progress in in vitro, ex vivo, and in vivo models, including patient-derived brain organoids, genetically engineered mouse models (GEMMs), and region-specific midline organoids incorporating SHH, BMP, and FGF2/8/19 signaling to model pontine gliomas. Key genetic alterations can now be introduced using lipofectamine-mediated transfection, PiggyBac plasmid systems, and CRISPR-Cas9, allowing the precise study of tumor initiation, progression, and therapy resistance. These models enable the investigation of TME interactions, including immune responses, neuronal infiltration, and therapeutic vulnerabilities. Future advancements involve developing immune-competent organoids, integrating vascularized networks, and applying multi-omics platforms like single-cell RNA sequencing and spatial transcriptomics to dissect tumor heterogeneity and lineage-specific vulnerabilities. These innovative approaches aim to enhance drug screening, identify new therapeutic targets, and accelerate personalized treatments for pediatric gliomas. Full article

Objective: Given the side effects and reduced efficacy of conventional local anesthetics in inflammatory conditions, there is a compelling need for complementary alternative medicine (CAM), particularly those based on phytochemicals. While a previous study showed that in vivo local injection of (-)-epigallocatechin-3-gallate (EGCG) into the peripheral receptive field suppresses the excitability of rat trigeminal ganglion (TG) neurons in the absence of inflammation, the acute effects of EGCG in vivo, especially on TG neurons under inflammatory conditions, are still unknown. We aimed to determine if acute local EGCG administration into inflamed tissue effectively attenuates the excitability of nociceptive TG neurons evoked by mechanical stimulation. Methods: The escape reflex threshold was measured to assess hyperalgesia caused by complete Freund’s adjuvant (CFA)-induced inflammation. To assess neuronal activity, extracellular single-unit recordings were performed on TG neurons in anesthetized CFA-inflamed rats in response to orofacial mechanical stimulation. Results: The mechanical escape threshold was significantly lower in CFA-inflamed rats compared to before CFA injection. EGCG (1–10 mM) reversibly and dose-dependently inhibited the mean firing frequency of TG neurons evoked by both non-noxious and noxious mechanical stimuli (p < 0.05). For comparison, 1% lidocaine (37 mM), a local anesthetic, also caused reversible inhibition of the mean firing frequency in inflamed TG neurons responding to mechanical stimuli. Importantly, 10 mM EGCG produced a significantly greater magnitude of inhibition on TG neuronal discharge frequency than 1% lidocaine (noxious, lidocaine vs. EGCG, 19.7 ± 3.3% vs. 42.3 ± 3.4%, p < 0.05). Conclusions: Local injection of EGCG into inflamed tissue effectively suppresses the excitability of nociceptive primary sensory TG neurons, as indicated by these findings. Significantly, locally administered EGCG exerted a more potent local analgesic action compared to conventional voltage-gated sodium channel blockers. This heightened efficacy originates from EGCG’s ability to inhibit both generator potentials and action potentials directly at nociceptive primary nerve terminals. As a result, EGCG stands out as a compelling candidate for novel analgesic development, holding particular relevance for CAM strategies. Full article

Chronic migraine (CM) is a debilitating neurological disorder, yet the glial-specific mechanisms underlying its pathophysiology in the trigeminal nucleus caudalis (TNC)—a critical hub for craniofacial pain processing—remain poorly understood. Here, we employed single-nucleus RNA sequencing (snRNA-seq) to resolve cell-type-specific transcriptional landscapes in a nitroglycerin (NTG)-induced CM rat model, with a particular focus on microglia and astrocytes. We identified 19 transcriptional clusters representing nine major cell types, among which reactive microglia (NTG-Mic) and astrocytes (NTG-Asts) were markedly expanded. The NTG-Mic displayed a glycolysis-dominant, complement-enriched state, whereas the NTG-Asts exhibited concurrent activation of amino acid transport and cytokine signaling pathways. Pseudotime trajectory analysis revealed bifurcated glial activation paths, with NTG driving both cell types toward terminal reactive states. Intercellular communication inference uncovered suppressed homeostatic interactions (e.g., CSF1-CSF1R) alongside enhanced proinflammatory signaling (e.g., FGF1-FGFR2, PTN-SDC4), particularly affecting neuron–glia and glia–glia crosstalk. Together, these findings define a high-resolution atlas of glial reprogramming in CM, implicating state-specific metabolic–immune transitions and dysregulated glial communication as potential targets for therapeutic intervention. Full article

Humans mostly perceive tactile sensations in daily life as a combination of warmth, vibration, and pressure. To understand the complex tactile perception and cognitive processes, in this study, we aimed to develop a multimodal stimulator and investigate changes in neuronal activity. An actuator that can display warmth (W), vibration (V), and pressure (P) on the distal region of the index finger has been developed. Preliminary experiments were conducted with nine subjects. Electroencephalograms were measured for six tactile stimuli—three single stimuli (W, V, and P) and three combination stimuli (W + V, V + P, and W + V + P)—and event-related desynchronization/synchronization (ERD/S) analysis were performed. The actuator can present all kinds of stimuli in the same location and control stimulation parameters quantitatively. For all experiments, there was an ERD in the α and β bands about 0.5 s after stimulation followed by ERS was observed in the C3 area. The change in the peak-to-peak value was the largest for warmth and the smallest for pressure. In contrast, in the duration of the ERD, W was the shortest and P was the longest. As stimulus presented simultaneously, the ERD became longer in both the alpha and beta bands. In the beta band, the peak of ERD became larger. The developed system was confirmed to be capable of providing valid tactile stimulation, inducing appropriate neuronal activation, and enabling multimodal tactile research. Full article

Background: The development of cerebral organoids created from human pluripotent stem cells in 3D culture may greatly improve the discovery of neuropsychiatric medicines. Methods: In the current study we differentiated neural organoids from a human pluripotent stem cell line in vitro, recorded the development of neurophysiological activity using multielectrode arrays (MEAs) and characterized the neuropharmacology of synaptic signaling over 8 months in vitro. In addition, we investigated the ability of these organoids to display epileptiform activity in response to a convulsant agent and the effects of antiseizure medicines to inhibit this abnormal activity. Results: Single and bursts of action potentials from individual neurons and network bursts were recorded on the MEA plates and significantly increased and became more complex from week 7 to week 30, consistent with neural network formation. Neural spiking was reduced by the Na channel blocker tetrodotoxin but increased by the inhibitor of K_V7 potassium channels XE991, confirming the involvement of voltage-gated sodium and potassium channels in action potential activity. The GABA antagonists bicuculline and picrotoxin each increased the spike rate, consistent with inhibitory synaptic signaling. In contrast, the glutamate receptor antagonist kynurenic acid inhibited the spike rate, consistent with excitatory synaptic transmission in the organoids. The convulsant 4-aminopyridine increased spiking, bursts and synchronized firing, consistent with epileptiform activity in vitro. The anticonvulsants carbamazepine, ethosuximide and diazepam each inhibited this epileptiform neural activity. Conclusions: Together, our data demonstrate that neural organoids form inhibitory and excitatory synaptic circuits, generate epileptiform activity in response to a convulsant agent and detect the antiseizure properties of diverse antiepileptic drugs, supporting their value in drug discovery. Full article

TRPA1 (Transient Receptor Potential Ankyrin 1), a cation channel predominantly expressed in sensory neurons, plays a critical role in detecting noxious stimuli and mediating pain signal transmission. As a key player in nociceptive signaling pathways, TRPA1 has emerged as a promising therapeutic target for the development of novel analgesics. Crotalphine (CRP), a 14-amino acid peptide, has been demonstrated to specifically activate TRPA1 and elicit potent analgesic effects. Previous cryo-EM (cryo-electron microscopy) studies have elucidated the structural mechanisms of TRPA1 activation by small-molecule agonists, such as iodoacetamide (IA), through covalent modification of N-terminal cysteine residues. However, the molecular interactions between TRPA1 and peptide ligands, including crotalphine, remain unclear. Here, we present the cryo-EM structure of ligand-free human TRPA1 consistent with the literature, as well as TRPA1 complexed with crotalphine, with resolutions of 3.1 Å and 3.8 Å, respectively. Through a combination of single-particle cryo-EM studies, patch-clamp electrophysiology, and microscale thermophoresis (MST), we have identified the cysteine residue at position 621 (Cys621) within the TRPA1 ion channel as the primary binding site for crotalphine. Upon binding to the reactive pocket containing C621, crotalphine induces rotational and translational movements of the transmembrane domain. This allosteric modulation coordinately dilates both the upper and lower gates, facilitating ion permeation. Full article

Autism spectrum disorder (ASD) is a neurodevelopmental impairment that occurs due to mutations related to the formation of the nervous system, combined with the impact of various epigenetic and environmental factors. This necessitates the identification of the genetic variations involved in ASD pathogenesis. We performed whole exome sequencing (WES) in a cohort of 22 Bulgarian male and female individuals showing ASD features alongside segregation analyses of their families. A targeted panel of genes was chosen and analyzed for each case, based on a detailed examination of clinical data. Gene analyses revealed that specific variants concern key neurobiological processes involving neuronal architecture, development, and function. These variants occur in a number of genes, including SHANK3, DLG3, NALCN, and PACS2 which are critical for synaptic signaling imbalance, CEP120 and BBS5 for ciliopathies, SPTAN1 for spectrins structure, SPATA5, TRAK1, and VPS13B for neuronal organelles trafficking and integrity, TAF6, SMARCB1, DDX3X, MECP2, and SETD1A for gene expression, CDK13 for cell cycle control, ALDH5A1, DPYD, FH, and PDHX for mitochondrial function, and PQBP1, HUWE1, and WDR45 for neuron homeostasis. Novel single nucleotide variants in the SPATA5, CEP120, BBS5, SETD1A, TRAK1, VPS13B, and DDX3X genes have been identified and proposed for use in ASD diagnostics. Our data contribute to a better understanding of the complex neurobiological features of autism and are applicable in the diagnosis and development of personalized therapeutic approaches. Full article

Tau pathology is one of the main pathological features of Alzheimer’s disease (AD). Intracellular Tau may be released to the extracellular space upon neuron degeneration, where it has the potential to be toxic to other neurons. The propagation of Tau pathology, mediated by extracellular Tau aggregates, may underlie the pathogenesis of AD. Antibody therapies targeting Tau proteins are, therefore, considered highly promising. In this study, the cytotoxicity of extracellular Tau aggregates on SH-SY5Y cells was examined. The effect of extracellular Tau aggregates on intracellular Tau aggregation was also studied using a FRET-based assay. The extracellular Tau aggregates were found to cause intracellular Tau aggregation after entering the cells; meanwhile, ROS (reactive oxygen species) induced by Tau aggregates facilitated this process. A single-chain variable fragment antibody (scFv T1) inhibits Tau aggregation both extracellularly and intracellularly. ScFv T1 also inhibited the accumulation of ROS and alleviated the inflammation and apoptosis induced by Tau aggregates. These findings could provide experimental support for the study of neurotoxicity and related mechanisms of extracellular Tau aggregates, in addition to providing insights into the development of novel therapeutic agents to treat AD. Full article

Background: The blood–brain barrier (BBB) plays a critical role in protecting the central nervous system (CNS) but also limits drug delivery. Insufficient knowledge of how the CNS promotes the onset and maintenance of peripheral neuropathic pain limits therapeutic methods for the treatment of persistent neuropathic pain. Thus, this study aimed to evaluate the ability of a novel combination of Palmitoylethanolamide (PEA) and Equisetum arvense L. (Equisetum A.L.) to cross the BBB and modulate nociceptive pathways. Methods: Using a humanised in vitro BBB tri-culture model, the permeability, cytotoxicity, and integrity of the barrier were assessed after exposure to two different PEA forms, PEA ultramicronized (PEA-um) and PEA80mesh, Equisetum A.L., and a combination of the last two samples. The samples exhibited no cytotoxicity, maintained tight junction integrity, and efficiently crossed the blood–brain barrier (BBB), with the combination displaying the highest permeability. The eluate from the BBB model was then used to stimulate the co-culture of CCF-STTG1 astrocytes and SH-SY5Y neurons pre-treated with H₂O₂ 200 µM. Results: Treatment with the combination significantly increased cell viability (1.8-fold, p < 0.05), reduced oxidative stress (2.5-fold, p < 0.05), and decreased pro-inflammatory cytokines (TNFα, IL-1β) compared to single agents. Mechanistic analysis revealed modulation of key targets involved in pain pathways, including decreased FAAH and NAAA activity, increased levels of endocannabinoids (AEA and 2-AG), upregulation of CB2 receptor expression, enhanced PPARα activity, and reduced phosphorylation of PKA and TRPV1. Conclusions: These findings suggest that the combination of PEA and Equisetum A.L. effectively crosses the BBB and exerts combined anti-inflammatory and analgesic effects at the CNS level, suggesting a possible role in modulating neuroinflammatory and nociception responses. Full article