Explore the vast range of titles available.

Brain-derived neurotrophic factor (BDNF), or abrineurin, is a member of the neurotrophin family of growth factors that acts on both the central and peripheral nervous systems. BDNF is also well known for its cardinal role in normal neural maturation. It binds to at least two receptors at the cell surface known as tyrosine kinase B (TrkB) and p75NTR. Additional neurotrophins that are anatomically linked with BDNF include neurotrophin-3 (NT-3), neurotrophin-4 (NT-4), and nerve growth factor (NGF). It is evident that BDNF levels in patients with Alzheimer’s disease (AD) are altered. AD is a progressive disorder and a form of dementia, where the mental function of an elderly person is disrupted. It is associated with a progressive decline in cognitive function, which mainly targets the thinking, memory, and behavior of the person. The degeneration of neurons occurs in the cerebral cortex region of brain. The two major sources responsible for neuronal degeneration are protein fragment amyloid-beta (Aβ), which builds up in the spaces between the nerve cells, known as plaques, disrupting the neuron signaling pathway and leading to dementia, and neurofibrillary tangles (NFTs), which are the twisted fibers of proteins that build up inside the cells. AD is highly prevalent, with recent data indicating nearly 5.8 million Americans aged 65 and older with AD in 2020, and with 80% of patients 75 and older. AD is recognized as the sixth leading cause of death in the USA, and its prevalence is predicted to increase exponentially in the coming years. As AD worsens over time, it becomes increasingly important to understand the exact pathophysiology, biomarkers, and treatment. In this article, we focus primarily on the controversial aspect of BDNF in AD, including its influence on various other proteins and enzymes and the current treatments associated with BDNF, along with future perspectives.

Charcot–Marie–Tooth (CMT) neuropathies represent a heterogeneous group of peripheral nerve disorders affecting 1 in 2,500 persons. One variant, CMT1A, is a primary Schwann cell (SC) disorder, and represents the single most common variant. In previous studies, we showed that neurotrophin-3 (NT-3) improved the tremblerJ (TrJ) mouse and also showed efficacy in CMT1A patients. Long-term treatment with NT-3 was not possible related to its short half-life and lack of availability. This led to considerations of NT-3 gene therapy via adenoassociated virus (AAV) delivery to muscle, acting as secretory organ for widespread distribution of this neurotrophic agent. In the TrJ model of demyelinating CMT, rAAV1.NT-3 therapy resulted in measurable NT-3 secretion levels in blood sufficient to provide improvement in motor function, histopathology, and electrophysiology of peripheral nerves. Furthermore, we showed that the compound muscle action potential amplitude can be used as surrogate for functional improvement and established the therapeutic dose and a preferential muscle-specific promoter to achieve sustained NT-3 levels. These studies of intramuscular (i.m.) delivery of rAAV1.NT-3 serve as a template for future CMT1A clinical trials with a potential to extend treatment to other nerve diseases with impaired nerve regeneration.

BackgroundPrevious studies have revealed altered gut microbial topological structures in patients with colorectal neoplasms, suggesting a potential role of topology in tumorigenesis. We aimed to identify neoplasm-promoting/suppressing microbial topology and develop a topology-based score to distinguish colorectal neoplasms.MethodsThis analysis included stool samples of metagenomic sequencing data from 5,540 participants in the Chinese colorectal cancer (CRC) screening multicenter cohort. Species were first screened associated with colorectal neoplasms (OR 1.1) via generalized linear models. Species interactions were identified using Fisher’s exact test with 50 bootstrap iterations. Clustering analysis categorized interactions into neoplasm-promoting (T1) and neoplasm-suppressing (T2) topological clusters. A neoplasm-associated topology score was developed as: (#T1/NT1 − #T2/NT2 + 1)/2, where #T1 and #T2 represent the counts of detected T1 and T2 species in a patient, and NT1 and NT2 denote the total identified T1 and T2 species.ResultsA total of 3,897 participants (757 non-advanced adenomas, 233 advanced adenomas, and 41 CRC) were included in the final analysis. Following a 5:5 split into training and validation sets, we identified 133 species with robust interactions (adjusted p < 0.001), forming T1 cluster comprising 70 species (e.g., Clostridium symbiosum, Alistipes onderdonkii) and T2 cluster comprising 63 species (e.g., Roseburia spp.) (IDDF2025-ABS-0157 figure 1). Intra-cluster interactions were predominantly positive (co-promotion), whereas inter-cluster interactions were primarily negative (co-exclusion). The topology score was significantly higher in adenoma groups compared to healthy controls across both training and validation sets (p < 0.001) and associated with colorectal adenoma risk after adjusting for covariates. External validation confirmed intra-cluster co-promotion and inter-cluster exclusion topology. In 5 of 8 external cohorts, the score was significantly elevated in colorectal neoplasm groups (vs. healthy controls) and effectively differentiated CRC (AUC: 0.69–0.79) (IDDF2025-ABS-0157 figure 2), with an upward trend in the remaining three cohorts.Abstract IDDF2025-ABS-0157 Figure 1Abstract IDDF2025-ABS-0157 Figure 2ConclusionsThis multicenter study identified adenoma-promoting/suppressing topological microbiota. The derived topology score, reflecting individual microbial topology patterns, robustly stratifies colorectal neoplasm risk, offering a novel tool for early screening and mechanistic exploration.

Key Points Neurotrophins bind to several combinations of cell surface receptors to regulate neuronal survival, function and plasticity. The p75 neurotrophin receptor has numerous functions and is not just a 'death' receptor; under some circumstances it may counteract neurodegenerative signalling. Potential factors that limit the application of neurotrophins as neurological therapeutics include their limited stability, poor central nervous system (CNS) bioavailability, binding to multiple (rather than individual) neurotrophin receptors and mechanism-based side effects. Studies using synthetic oligopeptides have demonstrated the feasibility of creating small molecules that can act as ligands for neurotrophin receptors. Small-molecule ligands can be targeted to specific neurotrophin receptors to modulate signalling. Ligands have been developed that mimic, partially mimic or inhibit the actions of neurotrophins and, importantly, achieve effects that are distinct from those of neurotrophins. Small-molecule modulation of neurotrophin receptor signalling can correct or counteract the deleterious intracellular signalling patterns that exist in various neuropathological states. The administration of small-molecule ligands to several in vivo neurological disease models can correct neuropathological and behavioural abnormalities. Small-molecule ligands are in early stages of clinical development. Although neurotrophins could provide benefit in neurological diseases, their therapeutic application is limited by poor pharmacological properties and undesirable pleiotropic actions. Here, Longo and Massa highlight recent progress in the targeting of individual neurotrophin receptors using small-molecule ligands in an effort to overcome these limitations. Neurotrophins and their receptors modulate multiple signalling pathways to regulate neuronal survival and to maintain axonal and dendritic networks and synaptic plasticity. Neurotrophins have potential for the treatment of neurological diseases. However, their therapeutic application has been limited owing to their poor plasma stability, restricted nervous system penetration and, importantly, the pleiotropic actions that derive from their concomitant binding to multiple receptors. One strategy to overcome these limitations is to target individual neurotrophin receptors — such as tropomyosin receptor kinase A (TRKA), TRKB, TRKC, the p75 neurotrophin receptor or sortilin — with small-molecule ligands. Such small molecules might also modulate various aspects of these signalling pathways in ways that are distinct from the programmes triggered by native neurotrophins. By departing from conventional neurotrophin signalling, these ligands might provide novel therapeutic options for a broad range of neurological indications.

•The transition from childhood to adolescence is defined by social development.•Prosocial behavior increases with age, yet empathy peaks in late childhood.•Ventral striatum activity during prosocial behavior shows a peak in late childhood.•dACC, insula and striatum activity dips in late childhood when being socially included.•Changes in VS and mPFC activity co-occur with changes in prosocial behavior. Acting prosocially and feeling socially included are important factors for developing social relations. However, little is known about the development of neural trajectories of prosocial behavior and social inclusion in the transition from middle childhood to early adolescence. In this pre-registered study, we investigated the development of prosocial behavior, social inclusion, and their neural mechanisms in a three-wave longitudinal design (ages 7–13 years; NT1 = 512; NT2 = 456; NT3 = 336). We used the Prosocial Cyberball Game, a ball tossing game in which one player is excluded, to measure prosocial compensating behavior. Prosocial compensating behavior showed a linear developmental increase, similar to parent-reported prosocial behavior, whereas parent-reported empathy showed a quadratic trajectory with highest levels in late childhood. On a neural level we found a peak in ventral striatum activity during prosocial compensating behavior. Neural activity during social inclusion showed quadratic age effects in anterior cingulate cortex, insula, striatum, and precuneus, and a linear increase in temporo-parietal junction. Finally, changes in prosocial compensating behavior were negatively associated with changes in ventral striatum and mPFC activity during social inclusion, indicating an important co-occurrence between development in brain and social behavior. Together these findings shed a light on the mechanisms underlying social development from childhood into adolescence.

Activation of brown fat thermogenesis increases energy expenditure and alleviates obesity. Sympathetic nervous system (SNS) is important in brown/beige adipocyte thermogenesis. Here we discover a fat-derived “adipokine” neurotrophic factor neurotrophin 3 (NT-3) and its receptor Tropomyosin receptor kinase C (TRKC) as key regulators of SNS growth and innervation in adipose tissue. NT-3 is highly expressed in brown/beige adipocytes, and potently stimulates sympathetic neuron neurite growth. NT-3/TRKC regulates a plethora of pathways in neuronal axonal growth and elongation. Adipose tissue sympathetic innervation is significantly increased in mice with adipocyte-specific NT-3 overexpression, but profoundly reduced in mice with TRKC haploinsufficiency (TRKC +/−). Increasing NT-3 via pharmacological or genetic approach promotes beige adipocyte development, enhances cold-induced thermogenesis and protects against diet-induced obesity (DIO); whereas TRKC + /− or SNS TRKC deficient mice are cold intolerant and prone to DIO. Thus, NT-3 is a fat-derived neurotrophic factor that regulates SNS innervation, energy metabolism and obesity. Activation of brown adipose tissue thermogenesis increases energy expenditure and promotes weight loss in mice. Here the authors identify neurotrophic factor neurotrophin 3 (NT-3) as an adipokine that regulates sympathetic nervous system growth and innervation in adipose tissue and increases white adipose beiging.

Loss of synapses between spiral ganglion neurons and inner hair cells (IHC synaptopathy) leads to an auditory neuropathy called hidden hearing loss (HHL) characterized by normal auditory thresholds but reduced amplitude of sound-evoked auditory potentials. It has been proposed that synaptopathy and HHL result in poor performance in challenging hearing tasks despite a normal audiogram. However, this has only been tested in animals after exposure to noise or ototoxic drugs, which can cause deficits beyond synaptopathy. Furthermore, the impact of supernumerary synapses on auditory processing has not been evaluated. Here, we studied mice in which IHC synapse counts were increased or decreased by altering neurotrophin 3 (Ntf3) expression in IHC supporting cells. As we previously showed, postnatal Ntf3 knockdown or overexpression reduces or increases, respectively, IHC synapse density and suprathreshold amplitude of sound-evoked auditory potentials without changing cochlear thresholds. We now show that IHC synapse density does not influence the magnitude of the acoustic startle reflex or its prepulse inhibition. In contrast, gap-prepulse inhibition, a behavioral test for auditory temporal processing, is reduced or enhanced according to Ntf3 expression levels. These results indicate that IHC synaptopathy causes temporal processing deficits predicted in HHL. Furthermore, the improvement in temporal acuity achieved by increasing Ntf3 expression and synapse density suggests a therapeutic strategy for improving hearing in noise for individuals with synaptopathy of various etiologies.

An improved synthesis of vinblastine and vincristine was observed in Catharanthusroseus L. (G). Don by using NaCl as an elicitor. Various in vitro grown embryogenic tissues were cultivated under salinity stress for enhanced synthesis of alkaloids. Different levels of salt [control (0 mM), NT1 (25 mM), NT2 (50 mM), NT3 (75 mM), NT4 (100 mM), and NT5 (125 mM)] were amended in MS and callus biomass growth (fresh- and dry-weight) and biochemical attributes at various embryogenic stages were studied. Maximum callus biomass reduction was observed in 125 mM NaCl amended medium. Antioxidant enzymes i.e. superoxide dismutase (SOD), catalase (CAT), ascorbate peroxidase and glutathione reductase activities were assayed as in vitro grown tissues were elicitated with NaCl, causing cellular stress. The antioxidant enzymes activity increased linearly with increasing NaCl level in medium, 4.97 EU min−1 mg−1 SOD and 3.14 EU min−1 mg−1 CAT, both being maximum in proliferating embryos at NT5. Quantitative estimation and comparative yield of alkaloids were made in response to NaCl stress in different cultivated tissues by using HPTLC method. Vinblastine content was observed to be maximum in regenerated leaves (14.17 mg/g dry wt) on 25 mM NaCl amended medium, followed by in vitro raised shoots. Similarly, better accumulation of vincristine (5.12 mg/g dry wt) was also noted in NaCl amended medium especially at low level (NT1). The data presented indicate that the synthesis of Catharanthus alkaloids was growth specific and was influenced by NaCl levels.

This study explores the influence of miR-21 and its interaction with the target gene Neurotrophin-3 (NTF3) in cervical cancer (CC). We employed bioinformatics tools, including DIANA, Targetscan, miRDB, and miRDIP, to predict the target genes of miR-21. Immunohistochemistry, RT-qPCR, and Western blotting were performed to quantify the expression levels of miR-21-5p and NTF3 in cervical cancer cells. Additionally, a dual luciferase reporter assay was conducted to examine the specific relationship between miR-21-5P and NTF3. We assessed cell behavior through various tests, including cell viability, scratch wound assays, colony formation, cell invasion experiments, and flow cytometry assays. The dual luciferase reporter assay confirmed that NTF3 is a direct target of miR-21. Overexpression of NTF3 inhibited cell proliferation and migration, while promoting apoptosis, as demonstrated by flow cytometry. Transcriptome sequencing and enrichment analyses (KEGG and GO) revealed NTF3’s involvement in key oncogenic pathways, including PI3K-AKT, MAPK, and calcium signaling. This study underscores the critical role of miR-21 in regulating the proliferation, migration, and apoptosis of cervical cancer cells by targeting NTF3.

Neurotrophin-3 (Ntf3) and brain derived neurotrophic factor (Bdnf) are critical for sensory neuron survival and establishment of neuronal projections to sensory epithelia in the embryonic inner ear, but their postnatal functions remain poorly understood. Using cell-specific inducible gene recombination in mice we found that, in the postnatal inner ear, Bbnf and Ntf3 are required for the formation and maintenance of hair cell ribbon synapses in the vestibular and cochlear epithelia, respectively. We also show that supporting cells in these epithelia are the key endogenous source of the neurotrophins. Using a new hair cell CreERT line with mosaic expression, we also found that Ntf3's effect on cochlear synaptogenesis is highly localized. Moreover, supporting cell-derived Ntf3, but not Bbnf, promoted recovery of cochlear function and ribbon synapse regeneration after acoustic trauma. These results indicate that glial-derived neurotrophins play critical roles in inner ear synapse density and synaptic regeneration after injury. Noise-induced hearing loss is common, and can result from prolonged exposure to moderate levels of noise that are not perceived as painful or even unpleasant. Some hearing loss can be attributed to the death of hair cells in a part of the inner ear called the cochlea. When sound waves hit the cochlea, they cause the fluid inside it to vibrate: the hair cells detect these vibrations and convert them into electrical signals that are sent along neurons to the brain. However, vibrations that are too strong can destroy hair cells. Increasing evidence suggests that hearing loss also results from damage to the synapses that connect the hair cells and the neurons in the cochlea. During development of the inner ear, molecules called growth factors are needed to ensure the survival of these neurons. Wan et al. predicted that these growth factors might also have a role in adult animals, and that producing more of them might help to safeguard hearing from the damaging effects of noise. Consistent with this, mice that were genetically modified to lack a growth factor called neurotrophin-3 had cochleae that did not work properly and had fewer synapses between hair cells and neurons compared to control mice. Conversely, mice that produced too much neurotrophin-3 had more synapses than controls and also recovered more quickly from the effects of 2 hr exposure to 100 dB noise (roughly the volume of a pneumatic drill). Studies of the cochlea revealed that the extra neurotrophin-3 had boosted the regeneration of synapses damaged by the noise. The beneficial effects of neurotrophin-3 were still seen when overproduction was started shortly after noise exposure, suggesting that it could have therapeutic potential. This is particularly significant in the light of recent evidence that the loss of synapses often comes before the death of hair cells in both age-related hearing loss and noise-induced hearing loss.