Brain‑derived neurotrophic factor precursor (proBDNF) plays a critical role in the pathogenesis and progression of various human diseases. Through its interaction with p75NTR and sortilin receptors, proBDNF promotes apoptosis, impairs synaptic plasticity, and contributes to the regulation of immune system function, inflammatory responses and cellular metabolic processes. proBDNF is widely distributed throughout the body, and as such, extensive research has demonstrated that proBDNF is significantly associated with the pathophysiological mechanisms underlying several diseases. In the present review, the mechanisms by which proBDNF contributes to different diseases are summarized to highlight its potential therapeutic and diagnostic implications. Specifically, the role of proBDNF in cognitive disorders, focusing on its effects on synaptic function and neural network dynamics, while analyzing the cascade reactions involving proBDNF and downstream effector molecules in inflammatory diseases, to elucidate its bidirectional regulatory effects in tumor initiation and progression. Furthermore, the function of proBDNF in neurogenesis, the mechanism by which it regulates the memory of fear, and enhances individual behavioral flexibility is discussed. Finally, the potential of proBDNF as a biomarker for disease diagnosis and the therapeutic prospects of targeting it using monoclonal antibodies are highlighted while also proposing future research directions. The present review can serve as a reference for translational medical research on proBDNF and its receptors.

Depression is a potentially life-threatening psychiatric disorder that affects the physical and mental health of millions of individuals worldwide. It can manifest at any stage of life, inducing profound emotional despondency, negative cognitions, and, in severe cases, suicidal ideation, often accompanied by physical symptoms, bringing a significant burden on both families and society. Brain-derived neurotrophic factor (BDNF), a member of the neurotrophic factor family, is widely expressed in the central nervous system (CNS), particularly in regions, such as the hippocampus and cortex. Numerous studies have shown that an imbalance or inadequate conversion of pro-brain-derived neurotrophic factor (proBDNF) into its mature form, mature BDNF (mBDNF), may impair neuronal plasticity, which is crucial to the pathogenesis of depression. This paper provides a comprehensive review of the neurotrophic mechanisms implicated in depression, covering the location, expression, and release of BDNF; the relationship between proBDNF, mBDNF, and depression; and the downstream signaling pathways triggered by BNDF binding to its receptors. This review aims to provide a theoretical foundation for understanding the pathogenesis and clinical treatment of depression.

The nervous and immune systems are two major components that maintain body homeostasis, with their functional roles often overlapping significantly. Both systems are capable of identifying, integrating, and organizing responsive reactions to various external stimuli. The gut, referred to as the "second brain" and the largest immune organ in the body, serves as the most frequent focal site for neuroimmune interactions. Colorectal cancer (CRC), as the predominant solid tumor arising in this neuroimmune-rich microenvironment, remains understudied through the lens of neuroimmune regulatory mechanisms. This review systematically synthesizes current evidence to elucidate the neuroimmune axis in CRC pathogenesis, with particular emphasis on neuroimmune crosstalk-mediated remodeling of tumor immunity. We comprehensively catalog the immunomodulatory effects exerted by principal neuroregulatory mediators, categorized as: (1) neurotransmitters (glutamate, glutamine, γ-aminobutyric acid, epinephrine, norepinephrine, dopamine, serotonin, acetylcholine, and gaseous signaling molecules); (2) neuropeptides (substance P, calcitonin gene-related peptide, vasoactive intestinal peptide); and (3) neurotrophic factors. Furthermore, we critically evaluate the translational prospects and therapeutic challenges of targeting neuroimmune pathways and propose strategic priorities and research focuses for advancing the development of neuroimmune interaction-related therapeutic approaches in CRC.

Physical rehabilitation complements the treatment of Parkinson's disease (PD). The applied physical exercises are effective in PD by promoting activity-dependent neuroplasticity. The main aim of this study was to assess the effect of a 16-week moderate-intensity functional physical rehabilitation program (FPR) on the concentration of mature brain-derived neurotrophic factor (BDNF) and its precursor (proBDNF) in blood serum and the severity of symptoms and quality of life in people with PD. People with PD (Hoehn and Yahr stage 3) were randomly assigned to the experimental (FPR) and control (CG) groups. FPR participated in movement training to improve functional mobility, motor coordination, and balance. Pre- and post-intervention assessments included serum levels of proBDNF, mature BDNF, MDS-UPDRS sub-scales, and the PDQ-39 quality of life measured. In the FPR group, a statistically significant increase in serum proBDNF levels by 39.42% (p = 0.006) was observed, as well as an improvement in motor and non-motor aspects of daily functioning, motor complications, and overall quality of life. No statistically significant changes in BDNF levels were observed. The results indicate that moderately intensive FPR enhances neurotrophic mechanisms, primarily through regulating proBDNF and improving motor functions and quality of life in patients with PD. The results underline the potential of targeted rehabilitation programs to increase neuroplasticity and improve clinical outcomes in PD.

Acute ischemic stroke (AIS) is a focal neurological deficit due to sudden occlusion of cerebral vessels in the brain. AIS-induced neuronal injury and associated excite-toxicity and neurodegeneration affect the synthesis and the release of different neurotrophic factors such as brain-derived neurotropic factor (BDNF) and its precursor proBDNF. Both BDNF and proBDNF act on the specific receptors with different neurological effects. BDNF activates tropomyosin receptor kinase B (TrkB) receptor results in promoting neuronal survival, synaptic plasticity, and neuronal growth. However, the proBDNF activates p75 neurotrophin receptor (p75NTR) and sortilin which attenuates synaptic plasticity and promotes neuronal apoptosis. Dysregulation of central and peripheral expression of proBDNF/BDNF is linked with the severity and clinical outcomes of AIS. Therefore, this review aims to discuss the alterations of proBDNF/BDNF signaling in AIS. Findings from the present review illustrated that proBDNF/p75NTR/sortilin signaling pathway is exaggerated whereas; BDNF-TrkB signaling is reduced in AIS leading to neuronal apoptosis. Therefore, activation of BDNF-TrkB signaling, and inhibition of proBDNF/p75NTR/sortilin signaling pathway could be a promising therapeutic strategy in the management of AIS.

Although human mature brain-derived neurotrophic factor (hmBDNF) offers potential neuronal protection, its clinical translation remains challenging. Messenger RNA (mRNA) technology is promising in selectively upregulating protein cleavage products. This proof-of-concept study aims to evaluate the neuronal protective effects of hmBDNF mRNA in vitro.

We optimized and synthesized hmBDNF mRNA and conducted dose-response and time-response analyses in SH-SY5Y cells. mRNA expression was assessed via qPCR, while protein expression was evaluated through immunostaining and ELISA. Cell survival rate was measured using cell counting kit-8. We examined cell survival rates in both differentiated and non-differentiated SH-SY5Y cells exposed to H2O2 or serum deprivation following hmBDNF mRNA incubation. Additionally, we assessed the expression of synapse-relevant genes (MAP2, synaptophysin) and the mBDNF receptor (TrkB) in both cell types.

The optimized hmBDNF mRNA effectively upregulated hmBDNF expression in SH-SY5Y cells with minimal impact on endogenous proBDNF expression. Dose-response and time-response analyses identified the optimal dose and time point for maximum hmBDNF expression. hmBDNF mRNA significantly increased cell survival in differentiated SH-SY5Y cells expressing MAP2, synaptophysin and TrkB after exposure to oxidative stress or serum deprivation. However, hmBDNF mRNA did not enhance cell survival in non-differentiated SH-SY5Y cells.

The optimized hmBDNF mRNA demonstrated a capacity for neuronal protection in vitro. Further in-vivo studies are required to assess its potential for clinical translation.

Brain-derived neurotrophic factor (BDNF) is a neurotrophin that plays a central role in neuronal health. BDNF exists in two primary isoforms, the mature form (mBDNF) and its precursor (proBDNF), with opposing downstream effects on neuronal function. The positive effect of exercise on plasma levels of the BDNF isoforms has been extensively studied in adults. However, equivalent investigations are lacking in children and adolescents. Twenty healthy children (9-12 years old), 19 adolescents (13-17 years old) and 39 adults (23-49 years old) donated venous blood before and after a 45-minute run. Platelet-poor plasma was analysed for pro- and mBDNF using an enzyme-linked immunosorbent assay. Maximal oxygen uptake and anthropometric data were assessed in all participants, while Tanner stage, circulating sex hormones and accelerometry-based activity level were assessed in children and adolescents only. We found that children, adolescents and adults have similar circulating levels of plasma pro- and mBDNF at rest. For children and adolescents, resting levels of mBDNF correlated with average time spent in vigorous activity. In response to the acute endurance exercise intervention, mBDNF increased in all age groups, but the greatest rise in mBDNF was seen in adults. The acute endurance exercise did not affect proBDNF levels. Our results demonstrate that plasma mBDNF levels, but not proBDNF, increase following endurance exercise in all age groups, with a greater effect in adults. We also show that high-intensity physical activity, but not underlying fitness, is contributing to sustained elevated mBDNF levels. KEY POINTS: We show that in children and adolescents, regular vigorous physical activity is key to increased basal levels of plasma mature brain-derived neurotrophic factor (mBDNF), a factor linked to neuroplasticity and brain health. The ability to elevate mBDNF through exercise is present across all age groups, with the greatest increase in adults. The mBDNF response to physical exercise seems to be independent of underlying physical fitness. Our findings suggest that basal plasma mBDNF levels may reflect the cumulative effects of repeated exercise rather than an individual's overall physical fitness.

Brain-derived neurotrophic factor (BDNF) is an important neuromodulator of nervous system functions and plays a key role in neuronal growth and survival, neurotransmission, and synaptic plasticity. The effects of BDNF are mainly mediated by the activation of tropomyosin receptor kinase B (TrkB), expressed in both the peripheral and central nervous system. BDNF has been implicated in several neuropsychiatric conditions such as schizophrenia and anxio-depressive disorders, as well as in pain states. This review summarizes the evidence for a critical role of BDNF throughout the pain system and describes contrasting findings of its pro- and anti-nociceptive effects. Different cellular sources of BDNF, its influence on neuroimmune signaling in pain conditions, and its effects in different cell types and regions are described. These and endogenous BDNF levels, downstream signaling mechanisms, route of administration, and approaches to manipulate BDNF functions could explain the bidirectional effects in pain plasticity and pain modulation. Finally, current knowledge gaps concerning BDNF signaling in pain are discussed, including sex- and pathway-specific differences.

Suicide is a particularly major public health concern among young people as it is the fourth cause of death in youth aged 15-29. Despite various prevention strategies and efforts, the rate of suicide attempts among youth has increased over time and has risen even further since the COVID-19 pandemic.

The aim of this study was to ascertain the prevalence of suicide reattempts within 3months in a cohort of young first-time suicide attempters aged 16 to 25years. Exploratory objectives were to investigate potential risk factors associated with reattempts in this population.

We conducted a prospective, naturalistic, single-center cohort study including 182 patients hospitalized in emergency psychiatry for a first suicide attempt. Data on 31 sociodemographic, clinical and biological factors known to be associated with suicide were collected at baseline.

Out of the 182 patients included, 146 participants remained for the 3-months follow-up analysis (mean age: 19.71±2.5years, 71.9% female). Twenty of them reattempted suicide: yielding a prevalence of 13.7% (14.3% of females and 12.2% of males). Only four clinical and biological factors under study were significantly associated with suicide reattempt.

Our findings underscore the critical need for targeted prevention strategies for adolescents and young adults, as they represent a high-risk group for early suicide reattempts. Further research into the factors associated with recurrent suicide attempts is essential to more accurately characterize the profiles of young individuals who reattempt suicide, thereby informing the development of effective preventive interventions and avoiding negative outcomes.

Brain-derived neurotrophic factor (BDNF) has been proposed to play a role in chronic alcohol consumption. However, studies investigating the association of single nucleotide polymorphisms (SNPs) in the BDNF gene with alcohol use disorder (AUD), including alcohol dependence, have obtained inconsistent results. This meta-analysis aims to examine the role of BDNF SNPs (rs6265, rs16917204, rs7103411, and rs11030104) in the risk of AUD.

A multidatabase search identified 17 articles (20 studies) for inclusion. Pooled odds ratios (ORs) and 95% confidence intervals (CIs) were calculated to estimate associations using standard genetic models (homozygous, recessive, dominant, and codominant). Significant associations were defined as those with a p-value ≤ 0.05 after applying the Bonferroni correction (pBC). Subgroup analysis was conducted based on ethnicity (Caucasian and Asian populations). Sources of heterogeneity were investigated through outlier treatment and meta-regression analysis. Only significant outcomes were further subjected to sensitivity analysis and assessment of publication bias.

This meta-analysis generated four significant pooled ORs, representing the core outcomes, all of which indicated reduced risks. Overall, the results indicated a significant association between the BDNF polymorphism and the risk of AUD in homozygous (OR = 0.72, 95% CIs = 0.60-0.85, pBC = 0.0038) and codominant (OR = 0.84, 95% CIs = 0.78-0.91, pBC = 0.0019) model. In subgroup analysis by ethnicity, homozygous (OR = 0.59, 95% CIs = 0.44-0.78, pBC = 0.0057) and recessive (OR = 0.61, 95% CIs = 0.46-0.81, pBC = 0.0133) models of BDNF polymorphisms were significantly associated with a reduced risk of AUD in Caucasians. However, no significant associations were found in Asians. Meta-regression analysis did not identify any covariates that significantly contributed to the observed heterogeneity. The core significant associations were robust and showed no evidence of publication bias.

The current meta-analysis suggests that the examined BDNF SNPs have a protective effect in the overall analysis (homozygous and codominant) and in the Caucasians subgroup (homozygous and recessive) while the Asians exhibited no effects of BDNF SNPs on AUD. BDNF polymorphisms might serve as a protective factor against the risk of AUD and could be useful markers in the clinical genetics of AUD.

proBDNF and its main proteolytic product BDNF play crucial roles in maturation of neuromuscular junctions during development or reinnervation. We investigated the mechanisms of acute proBDNF effects on synaptic transmission in mouse motor synapses regenerating after nerve crush. The cleavage-resistant proBDNF mimicked the previously shown effect of cleavable proBDNF- GIRK-mediated decrease in the miniature endplate potential (MEPP) frequency accompanied by slight hyperpolarization of postsynaptic membrane. Remarkably, this effect did not utilize canonical proBDNF signaling pathway since inhibition of either p75 receptors with LM11A-31 or sortilin with AF38469 was not able to prevent it. Without sortilin activity, proBDNF downregulated the quantal content of multiquantal endplate potentials (EPP). This non-canonical action of proneurotrophin via TrkB receptors highlights the important role of sortilin as a safeguard preventing the spread of the negative effect of proBDNF on the evoked neurotransmitter release in regenerating motor synapses. In the absence of sortilin activity L-type calcium channels emerged as the key players providing proBDNF-induced decrease of EPP quantal content, while they were not involved in proBDNF-induced decrease of MEPP frequency. Sortilin-independent but TrkB- and GIRK-mediated inhibition of spontaneous release by proBDNF was not associated with the activity of acetylcholine (M2) or purinergic (A1 and P2Y13) metabotropic receptors. We propose that depending on sortilin involvement, proBDNF selectively affects spontaneous or evoked quantal neurotransmitter release via different branches of signaling pathway that ensure the presynaptic activation of GIRK or L-type calcium channels, respectively.

Among neurotrophins, including nerve growth factor (NGF), brain-derived neurotrophic factor (BDNF), neurotrophin-3 (NT-3), and neurotrophin-4 (NT-4/5), BDNF has been extensively studied for its physiological role in cell survival and synaptic regulation in the central nervous system's (CNS's) neurons. BDNF binds to TrkB (a tyrosine kinase) with high affinity, and the resulting downstream intracellular signaling cascades play crucial roles in determining cell fate, including neuronal differentiation and maturation of the CNS neurons. It has been well demonstrated that the downregulation/dysregulation of the BDNF/TrkB system is implicated in the pathogenesis of neurologic and psychiatric disorders, such as Alzheimer's disease (AD) and depression. Interestingly, the effects of BDNF mimetic compounds including flavonoids, small molecules which can activate TrkB-mediated signaling, have been extensively investigated as potential therapeutic strategies for brain diseases, given that p75NTR, a common neurotrophin receptor, also contributes to cell death under a variety of pathological conditions such as neurodegeneration. Since the downregulation of the BDNF/TrkB system is associated with the pathophysiology of neurodegenerative diseases and psychiatric disorders, understanding how alterations in the BDNF/TrkB system contribute to disease progression could provide valuable insight for the prevention of these brain diseases. The present review shows recent advances in the molecular mechanisms underlying the BDNF/TrkB system in neuronal survival and plasticity, providing critical insights into the potential therapeutic impact of BDNF mimetics in the pathophysiology of brain diseases.

The vector of modern obstetrics is aimed at finding ways to predict various placenta-associated complications, including those associated with neuronal dysfunction on in fetal growth restriction (FGR). The technology of fetal neuronal exosome (FNE) isolation from the maternal bloodstream opens up unique opportunities for detecting early signs of fetal brain damage. Using this method, FNEs were isolated from the blood of pregnant women with and without early-onset FGR, and the expression of a number of proteins in their composition was assessed (Western blotting). Significant changes in the level of proteins involved in neurogenesis (pro-BDNF (brain-derived neurotrophic factor), pro-NGF (nerve growth factor), TAG1/Contactin2) and presynaptic transmission (Synapsin 1, Synaptophysin) were revealed. The preliminary data on the expression of FNE proteins that perform post-translational modifications-sumoylation (SUMO 1, UBC9) and neddylation (NEDD8, UBC12)-were obtained. A relationship was established between altered protein expression and neonatal outcomes in newborns with growth restriction. Our study opens up new possibilities for non-invasive prenatal monitoring of fetal neurodevelopment disorders and possibilities of their correction in placenta-associated diseases.

Inflammation plays a key role in the development of neurodegenerative disorders that are currently incurable. Licochalcone A (LCA) has been described as an emerging anti-inflammatory drug with multiple therapeutical properties that could potentially prevent neurodegeneration. However, its neuroprotective mechanism remains unclear. Here, we investigated if LCA prevents cognitive decline induced by Lipopolysaccharide (LPS) and elucidated its potential benefits. For that, 8-week-old C57BL6/J male mice were intraperitonially (i.p.) treated with saline solution or LCA (15 mg/kg/day, 3 times per week) for two weeks. The last day, a single i.p injection of LPS (1 mg/kg) or saline solution was administered 24 h before sacrifice. The results revealed a significant reduction in mRNA expression in genes involved in oxidative stress (Sod1, Cat, Pkm, Pdha1, Ndyfv1, Uqcrb1, Cycs and Cox4i1), metabolism (Slc2a1, Slc2a2, Prkaa1 and Gsk3b) and synapsis (Bdnf, Nrxn3 and Nlgn2) in LPS group compared to saline. These findings were linked to memory impairment and depressive-like behavior observed in this group. Interestingly, LCA protected against LPS alterations through its anti-inflammatory effect, reducing gliosis and regulating M1/M2 markers. Moreover, LCA-treated animals showed a significant improvement of antioxidant mechanisms, such as citrate synthase activity and SOD2. Additionally, LCA demonstrated protection against metabolic disturbances, downregulating GLUT4 and P-AKT, and enhanced the expression of synaptic-related proteins (P-CREB, BDNF, PSD95, DBN1 and NLG3), leading all together to dendritic spine preservation. In conclusion, our results demonstrate that LCA treatment prevents LPS-induced cognitive decline by reducing inflammation, enhancing the antioxidant response, protecting against metabolic disruptions and improving synapsis related mechanisms.

Functional recovery following spinal cord injury will require the regeneration and repair of damaged neuronal pathways. It is well known that the tissue response to injury involves inflammation and the formation of a glial scar at the lesion site, which significantly impairs the capacity for neuronal regeneration and functional recovery. There are initial attempts by both supraspinal and intraspinal neurons to regenerate damaged axons, often influenced by the neighboring tissue pathology. Many experimental therapeutic strategies are targeted to further stimulate the initial axonal regrowth, with little consideration for the diversity of the affected neuronal populations. Notably, recent studies reveal that the neuronal response to injury is variable, based on multiple factors, including the location of the injury with respect to the neuronal cell bodies and the affected neuronal populations. New insights into regenerative mechanisms have shown that neurons are not homogenous but instead exhibit a wide array of diversity in their gene expression, physiology, and intrinsic responses to injury. Understanding this diverse intrinsic response is crucial, as complete functional recovery requires the successful coordinated regeneration and reorganization of various neuron pathways.

Intense noise poses a threat to spiral ganglion neurons (SGNs) in the inner ear, often resulting in limited axonal regeneration during noise injury and leading to noise-induced hearing loss (NIHL). Here, we propose an ultrasound-triggered nitric oxide (NO) release to enhance the sprouting and regeneration of injured axons in SGNs. We developed hollow silicon nanoparticles to load nitrosylated N-acetylcysteine, producing HMSN-SNO, which effectively protects NO from external interferences. Utilizing low-intensity ultrasound stimulation with bone penetration, we achieve the controlled release of NO from HMSN-SNO within the cochlea. In mice with NIHL, a rapid and extensive loss of synaptic connections between hair cells and SGNs is observed within 24 h after exposure to excessive noise. However, this loss could be reversed with the combined treatment, resulting in a hearing functional recovery from 83.57 to 65.00 dB SPL. This positive outcome is attributed to the multifunctional effects of HMSN-SNO, wherein they scavenge reactive oxygen species (ROS) to reverse the pathological microenvironment and simultaneously upregulate the CREB/BDNF/EGR1 signaling pathway, thereby enhancing neuroplasticity and promoting the regeneration of neuronal axons. These findings underscore the potential of nanomedicine for neuroplasticity modulation, which holds promise for advancing both basic research and the further treatment of neurological diseases.

Glaucoma is a group of optic neuropathies characterised by progressive retinal ganglion cell (RGC) degeneration and is the leading cause of irreversible blindness worldwide. Current treatments for glaucoma focus on reducing intraocular pressure (IOP) with topical medications. However, many patients do not achieve sufficient IOP reductions with such treatments. Patient compliance to dosing schedules also poses a significant challenge, further limiting their effectiveness. While surgical options exist for resistant cases, these are invasive and carry risks of complications. Thus, there is a critical need for better strategies to prevent irreversible vision loss in glaucoma. Gene therapy holds significant promise in this regard, offering potential long-term solutions by targeting the disease's underlying causes at a molecular level. Gene therapy strategies for glaucoma primarily target the two key hallmarks of the disease: elevated IOP and RGC death. This review explores key mechanisms underlying these hallmarks and discusses the current state of gene therapies targeting them. In terms of IOP reduction, this review covers strategies aimed at enhancing extracellular matrix turnover in the conventional outflow pathway, targeting fibrosis, regulating aqueous humor production, and targeting myocilin for gene-specific therapy. Neuroprotective strategies explored include targeting neurotrophic factors and their receptors, reducing oxidative stress and mitochondrial dysfunction, and preventing Wallerian degeneration. This review also briefly highlights key research priorities for advancing gene therapies for glaucoma through the clinical pipeline, such as refining delivery vectors and improving transgene regulation. Addressing these priorities will be essential for translating advancements from preclinical models into effective clinical therapies for glaucoma.

Major depressive disorder (MDD) is an enduring and severe mood disorder. Previous studies have indicated that p75NTR is involved in neuronal survival and death. However, the specific mechanism of p75NTR in depression remains unknown. The present study aimed to explore the role and mechanism of p75NTR in depression, and try to provide a new target for the treatment of MDD.

The p75NTR knockout and overexpression mice were used to establish a mouse model of depression induced by chronic restraint stress (CRS), and the behavioral effects and potential mechanisms associated with p75NTR knockout/overexpression on CRS-induced depressive mice were investigated by animal behavior, histopathology, immunofluorescence and western blot, respectively.

The results demonstrate that p75NTR knockout/overexpression can ameliorate the depressive-like behaviors observed in CRS-induced depressive mice. Furthermore, p75NTR knockout/overexpression safeguards the tissue morphology of the hippocampus, inhibits the mTOR signaling pathway to restore autophagy, and modulates apoptosis-related proteins (Bcl-2 and Bax) to reestablish normal levels of autophagy and apoptosis in hippocampal neurons of depressed mice. Importantly, p75NTR knockout/overexpression can improve synaptic plasticity through protecting the dendritic structure and dendritic spines of hippocampal neurons, and upregulating the expression of hippocampal synaptic-related proteins (PSD95 and SYN1).

These findings suggest that p75NTR knockout/overexpression can alleviate CRS-induced depression-like behaviors by reinstating autophagy and suppressing apoptosis in hippocampal neurons, and enhancing hippocampal synaptic plasticity via mTOR pathway. These insights may provide potential targets for clinical treatment of depression.

Brain-derived neurotrophic factor (BDNF), which is primarily expressed in the brain and nervous tissues, is the most abundant neurotrophic factor in the adult brain. BDNF serves not only as a major neurotrophic signaling agent in the human body but also as a crucial neuromodulator. Widely distributed throughout the central nervous system (CNS), both BDNF and its receptors play a significant role in promoting neuronal survival and growth, thereby exerting neuroprotective effects. It is further considered as a guiding medium for the functionality and structural plasticity of the CNS. Increasingly, research has indicated the critical importance of BDNF in understanding human diseases. Activation of intracellular signaling pathways such as the mitogen-activated protein kinase pathway, phosphatidylinositol 3-kinase/protein kinase B/mammalian target of rapamycin pathway, and phospholipase C γ pathway by BDNF can all potentially enhance the growth, survival, proliferation, and migration of cancer cells, influencing cancer development. The loss of BDNF and its receptor, tropomyosin receptor kinase B, in signaling pathways is also associated with increased susceptibility to brain and heart diseases. Additionally, reduced BDNF levels in both the central and peripheral systems have been closely linked to various neurogenic diseases, including neuropathic pain and psychiatric disorders. As such, this review summarizes and analyzes the impact of BDNF on neurogenic diseases, cancer, and cardiovascular diseases. This study thereby aimed to elucidate its effects on these diseases to provide new insights and approaches for their treatment.

Increasing evidence demonstrates that brain-derived neurotrophic factor (BDNF) can be regarded as a biomarker for major depression. Our previous work found that the ratio of mature BDNF (mBDNF) to precursor-BDNF (proBDNF) was a pivotal factor in the pathogenesis of major depressive disorder (MDD). But the mechanism behind the ratio is still obscure. Tissue plasminogen activator (tPA) and plasminogen activator inhibitor-1 (PAI-1) both play essential roles in depression by regulating the ratio of BDNF/proBDNF. In present study, we analyzed BDNF, proBDNF, tPA and PAI-1 in the peripheral blood in 57 MDD patients pre- and post-treatment and in 57 healthy controls. We verified that BDNF and tPA levels were significantly decreased, whereas proBDNF and PAI-1 levels elevated obviously in MDD group pre-treatment. And after 4 weeks SSRIs treatment, the BDNF and tPA levels increased while the proBDNF and PAI-1 levels reduced. The MDD pre-treatment group had the lowest ratio of BDNF to proBDNF compared to MDD post-treatment group and control group. Though the ratio of tPA/PAI-1 in MDD pre-treatment had not reached the significance, it was still the lowest one among the three groups. The combination of tPA + PAI + BDNF showed the best diagnostic value for MDD. In summary, our data suggested that the interaction between tPA and PAI-1 implicated to the MDD and the antidepressant treatment which might through regulating the BDNF/proBDNF ratio. The combination of tPA, PAI-1 and BDNF might offer a helpful way for MDD diagnosis.

Autism Spectrum Disorders (ASD) comprise a range of early age-onset neurodevelopment disorders with genetic heterogeneity. Most ASD related genes are involved in synaptic function, which is regulated by mature brain-derived neurotrophic factor (mBDNF) and its precursor proBDNF in a diametrically opposite manner: proBDNF inhibits while mBDNF potentiates synapses. Here we generated a knock-in mouse line (BDNFmet/leu) in which the conversion of proBDNF to mBDNF is attenuated. Biochemical experiments revealed residual mBDNF but excessive proBDNF in the brain. Similar to other ASD mouse models, the BDNFmet/leu mice showed reduced dendritic arborization, altered spines, and impaired synaptic transmission and plasticity in the hippocampus. They also exhibited ASD-like phenotypes, including stereotypical behaviors and deficits in social interaction. Moreover, the plasma proBDNF/mBDNF ratio was significantly increased in ASD patients compared to normal children in a case-control study. Thus, deficits in proBDNF to mBDNF conversion in the brain may contribute to ASD-like behaviors, and plasma proBDNF/mBDNF ratio may be a potential biomarker for ASD.

Changes in memory performance are one of the main symptoms of normal aging. The storage of similar experiences as different memories (ie. behavioral pattern separation), becomes less efficient as aging progresses. Studies have focused on hippocampus dependent spatial memories and their role in the aging related deficits in behavioral pattern separation (BPS) by targeting high similarity interference conditions. However, parahippocampal cortices such as the perirhinal cortex are also particularly vulnerable to aging. Middle age is thought to be the stage where mild mnemonic deficits begin to emerge. Therefore, a better understanding of the timing of the spatial and object domain memory impairment could shed light over how plasticity changes in the parahipocampal-hippocampal system affects mnemonic function in early aging. In the present work, we compared the performance of young and middle-aged rats in both spatial (spontaneous location recognition) and non-spatial (spontaneous object recognition) behavioral pattern separation tasks to understand the comparative progression of these deficits from early stages of aging. Moreover, we explored the impact of environmental enrichment (EE) as an intervention with important translational value. Although a bulk of studies have examined the contribution of EE for preventing age related memory decline in diverse cognitive domains, there is limited knowledge of how this intervention could specifically impact on BPS function in middle-aged animals. Here we evaluate the effects of EE as modulator of BPS, and its ability to revert the deficits caused by normal aging at early stages. We reveal a domain-dependent impairment in behavioral pattern separation in middle-aged rats, with spatial memories affected independently of the similarity of the experiences and object memories only affected when the stimuli are similar, an effect that could be linked to the higher interference seen in this group. Moreover, we found that EE significantly enhanced behavioral performance in middle-aged rats in the spatial and object domain, and this improvement is specific of the high similarity load condition. In conclusion, these results suggest that memory is differentially affected by aging in the object and spatial domains, but that BPS function is responsive to an EE intervention in a multidomain manner.

Alcohol use disorders (AUDs) are complex pathologies with a myriad of molecular actors involved in both disease progression and remission. Brain-derived neurotrophic factor (BDNF) is suspected to be one such actor due to its neurotrophic effects. The BDNF precursor, pro-BDNF, has different effects, as it mainly promotes neuronal apoptosis. Both forms also play a role in depression and depressive episodes (DE). The aim of this exploratory study was to compare serum BDNF and pro-BDNF levels in patients with AUDs after withdrawal and according to DE status with those of controls without AUDs or DE.

Ninety-nine AUD patients and 40 controls were included. Questionnaires were used to assess both alcohol and psychiatric domains: the severity of hazardous alcohol consumption was assessed using Alcohol Use Disorders Identification Test (AUDIT), craving was assessed using Obsessive and Compulsive Drinking Scale (OCDS), anxiety was assessed with Hamilton Anxiety Rating Scale (HAM-A) and depression with Montgomery-Åsberg Depression Rating Scale (MADRS). Blood samples were collected during two visits: at the time of alcohol withdrawal (M0) and two months later (M2). ELISAs to measure serum BDNF and pro-BDNF levels were performed. AUD patients were categorized according to depression status at M2. Forty-five patients remained abstinent whereas 54 relapsed. BDNF serum levels rose after alcohol withdrawal, but pro-BDNF levels did not vary between M0 and M2.

AUD subjects without DE at M2 had higher BDNF levels at both M0 and M2 than AUD subjects with DE at M2. AUD subjects showed lower MADRS and OCD scores at M2 than at M0. AUD subjects without DE had lower BDNF levels at M0 than controls but not at M2, regardless of abstinence maintenance.

BDNF serum levels were reduced in AUD patients compared to controls and were further reduced in patients with both AUDs and DE. Alcohol withdrawal treatment was sufficient to induce an increase in serum BDNF levels after 2 months, regardless of whether abstinence was maintained during this time period.

Horticulture in controlled environments has been increasingly used to tackle limitations on crop production. As a crucial environmental factor, light regulate plant growth and metabolism. In the present study, basil plants were subjected to different light durations and intensities considering constant daily light integral (DLI). The lighting environment included 200, 300, and 400 µmol m- 2 s- 1 intensities for 18, 12, and 9 h, respectively. DLI amounted to 12.96 mol m- 2 d- 1 among all light treatments (LI200 for 18 h, LI300 for 12 h, and LI400 for 9 h). Half of the plants under each light treatment were exposed to 30 µmol m- 2 s- 1 of far-red light. The results indicated the general negative impact of LI400/9 on the growth of basils. Exposure to far-red light hurt the growth of the shoot, while it enhanced stem and petiole elongation. This effect was due to higher gibberellin accumulation, which resulted in shade avoidance responses. Exposure to far-red light also reduced anthocyanin and flavonoid contents, as two important nutritional components. Soluble carbohydrates increased, while storage carbohydrates decreased by increasing lighting duration/decreasing light intensity or by far-red light inclusion. The lowest antioxidant activity was detected in LI400/9. In the LI200/18, the highest level of auxin and the lowest level of cytokinin were detected, while the LI300/12 exhibited the highest level of gibberellin hormone. Low light intensity and long photoperiod enhanced plant biomass and phytochemical production and are recommended for basil production in controlled environments.

Force sensing is a fundamental ability that allows cells and organisms to interact with their physical environment. The eye is constantly subjected to mechanical forces such as blinking and eye movements. Furthermore, elevated intraocular pressure (IOP) can cause mechanical strain at the optic nerve head, resulting in retinal ganglion cell death (RGC) in glaucoma. How mechanical stimuli are sensed and affect cellular physiology in the eye is unclear. Recent studies have shown that mechanosensitive ion channels are expressed in many ocular tissues relevant to glaucoma and may influence IOP regulation and RGC survival. Furthermore, variants in mechanosensitive ion channel genes may be associated with risk for primary open angle glaucoma. These findings suggest that mechanosensitive channels may be important mechanosensors mediating cellular responses to pressure signals in the eye. In this review, we focus on mechanosensitive ion channels from three major channel families-PIEZO, two-pore potassium and transient receptor potential channels. We review the key properties of these channels, their effects on cell function and physiology, and discuss their possible roles in glaucoma pathophysiology.

Parkinson disease represents a significant and growing burden on global healthcare systems, necessitating a deeper understanding of their underlying molecular mechanisms for the development of effective treatments. The AKT and ERK pathways play crucial roles in the disease, influencing multiple cellular pathways that support neuronal survival. Researchers have made notable progress in uncovering how these pathways are controlled by upstream kinases and how their downstream effects contribute to cell signalling. However, as we delve deeper into their intricacies, we encounter increasing complexity, compounded by the convergence of multiple signalling pathways. Many of their targets overlap with those of other kinases, and they not only affect specific substrates but also influence entire signalling networks. This review explores the intricate interplay of the AKT/ERK pathways with several other signalling cascades, including oxidative stress, endoplasmic reticulum stress, calcium homeostasis, inflammation, and autophagy, in the context of Parkinson disease. We discuss how dysregulation of these pathways contributes to disease progression and neuronal dysfunction, highlighting potential therapeutic targets for intervention. By elucidating the complex network of interactions between the AKT/ERK pathways and other signalling cascades, this review aims to provide insights into the pathogenesis of Parkinson disease and describe the development of novel therapeutic strategies.

Brain recovery mechanisms after injuries like aneurysmal subarachnoid hemorrhage (aSAH), ischemic stroke (IS), and traumatic brain injury (TBI) involve brain plasticity, synaptic regeneration, and neuroinflammation. We hypothesized that serum levels of the p75 neurotrophic receptor (p75NTR) and associated signaling proteins, as well as differentially expressed (DE) microRNAs, could predict recovery outcomes irrespective of injury type.

A prospective patient cohort with ischemic stroke (IS, n = 30), aneurysmal subarachnoid hemorrhage (aSAH, n = 31), and traumatic brain injury (TBI, n = 13) were evaluated (total n = 74). Serum samples were collected at two post-injury intervals (early: 1-3 days, late: 4-8 days), and outcomes were assessed after three months using the modified Rankin Scale (mRS), categorizing outcomes as favorable (mRS 0-3) or unfavorable (mRS 4-6). Six proteins were measured using ELISAs: p75NTR, NGF, sortilin, IL1β, TNFα, and cyclophilin. DE microRNAs were identified using DESeq2, and their target genes were predicted. Serum molecules between patients with differing outcomes were compared using a Kolmogorov-Smirnov test, 2-tailed t-test and multivariate linear discriminant analysis (LDA).

Favorable (n = 46) and unfavorable (n = 28) outcome cohorts were balanced with age and sex (p = 0.25 and 0.63). None of the studied proteins correlated with age. Combinatory LDA of the six protein biomarkers indicated strong prognostic value for favorable outcomes (OR 2.09; AUC = 70.3%, p = 0.0058). MicroRNA expression changes over time were identified in the aSAH, TBI, and IS groups (p < 0.05, FDR corrected). Twenty-three microRNAs were commonly DE across all brain injury groups when comparing favorable and unfavorable outcomes (p < 0.05). LDA of four microRNAs targeting the studied proteins showed high prognostic accuracy (OR 11.7; AUC = 94.1%, p = 0.016).

The combined prognostic microRNA and protein biomarker models demonstrated accurate outcome prognostication across diverse injury types, implying the presence of a common recovery mechanism. DE microRNAs were found to target the studied molecules, suggesting a potential mechanistic role in recovery. Further investigation is warranted to study these molecules in prognostication, as well as therapeutic targets for enhancing recovery.

Traumatic brain injury (TBI) is characterized by complex secondary injury processes involving the p75 neurotrophin receptor (p75NTR), which has been proposed as a possible therapeutic target. However, the pathogenic role of the p75NTR co-receptor sortilin in TBI has not been investigated. In this study, we examined whether sortilin contributes to acute and early processes of secondary injury using a murine controlled cortical impact (CCI) model of TBI. Initial expression analysis showed a down-regulation of sortilin mRNA levels 1 and 5 day post injury (dpi) and a reduced expression of sortilin protein 1 dpi. Next, a total of 40 SortilinΔExon14 loss-of-function mouse mutants (Sort1-/-) and wild-type (Sort1+/+) littermate mice were subjected to CCI and examined at 1 and 5 dpi. Neither sensorimotor deficits or brain lesion size nor CCI-induced cell death or calcium-dependent excitotoxicity as evaluated by TUNEL staining or Western blot analysis of alpha II spectrin breakdown products were different between Sort1-/- and Sort1+/+ mice. In addition, CCI induced the up-regulation of pro-inflammatory marker mRNA expression (Il6, Tnfa, Aif1, and Gfap) irrespectively of the genotype. Similarly, the mRNA expressions of neurotrophins (Bdnf, Ngf, Nt3), VPS10P domain receptors others than sortilin (Ngfr, Sorl1, Sorcs2), and the sortilin interactor progranulin were not affected by genotype. Our results suggest that sortilin is a modulatory rather than a critical factor in the acute and early brain tissue response after TBI.

Neurotrophic factors play pivotal roles in shaping brain development and function, with brain-derived neurotrophic factor (BDNF) emerging as a key regulator in various physiological processes. This review explores the intricate relationship between BDNF and anorexia nervosa (AN), a complex psychiatric disorder characterized by disordered eating behaviors and severe medical consequences. Beginning with an overview of BDNF's fundamental functions in neurodevelopment and synaptic plasticity, the review delves into recent clinical and preclinical evidence implicating BDNF in the pathophysiology of AN. Specifically, it examines the impact of BDNF polymorphisms, such as the Val66Met variant, on AN susceptibility, prognosis, and treatment response. Furthermore, the review discusses the interplay between BDNF and stress-related mood disorders, shedding light on the mechanisms underlying AN vulnerability to stress events. Additionally, it explores the involvement of BDNF in metabolic regulation, highlighting its potential implications for understanding the metabolic disturbances observed in AN. Through a comprehensive analysis of clinical data and animal studies, the review elucidates the nuanced role of BDNF in AN etiology and prognosis, emphasizing its potential as a diagnostic and prognostic biomarker. Finally, the review discusses limitations and future directions in BDNF research, underscoring the need for further investigations to elucidate the complex interplay between BDNF signaling and AN pathology.

Regulated cell death is a genetically determined form of programmed cell death that commonly occurs during the development of living organisms. This process plays a crucial role in modulating homeostasis and is evolutionarily conserved across a diverse range of living organisms. Ferroptosis is a classic regulatory mode of cell death. Extensive studies of regulatory cell death in Alzheimer's disease have yielded increasing evidence that ferroptosis is closely related to the occurrence, development, and prognosis of Alzheimer's disease. This review summarizes the molecular mechanisms of ferroptosis and recent research advances in the role of ferroptosis in Alzheimer's disease. Our findings are expected to serve as a theoretical and experimental foundation for clinical research and targeted therapy for Alzheimer's disease.

Metabolic syndromes (e.g., obesity) are characterized by insulin resistance, chronic inflammation, impaired glucose metabolism, and dyslipidemia. Recently, patients with metabolic syndromes have experienced not only metabolic problems but also neuropathological issues, including cognitive impairment. Several studies have reported blood-brain barrier (BBB) disruption and insulin resistance in the brain of patients with obesity and diabetes. Adenosine, a purine nucleoside, is known to regulate various cellular responses (e.g., the neuroinflammatory response) by binding with adenosine receptors in the central nervous system (CNS). Adenosine has four known receptors: A1R, A2AR, A2BR, and A3R. These receptors play distinct roles in various physiological and pathological processes in the brain, including endothelial cell homeostasis, insulin sensitivity, microglial activation, lipid metabolism, immune cell infiltration, and synaptic plasticity. Here, we review the recent findings on the role of adenosine receptor-mediated signaling in neuropathological issues related to metabolic imbalance. We highlight the importance of adenosine signaling in the development of therapeutic solutions for neuropathological issues in patients with metabolic syndromes.

Age-related cognitive and affective disorders pose significant public health challenges. Notably, emotional and cognitive symptoms co-occur across multiple age-associated conditions like normal aging, Alzheimer's disease (AD), and mood disorders such as depression and anxiety. While the intricate interplay underlying this relationship remains poorly understood, this article highlights the possibility that an imbalance between full-length (TrkB.FL) and truncated (TrkB.T1) isoforms of tyrosine kinase receptor TrkB in the neurotrophic system may significantly affect age-associated emotional and cognitive functions, by altering brain-derived neurotrophic factor (BDNF) signaling, integral to neuronal health, cognitive functions and mood regulation. While the contribution of this imbalance to pathogenesis awaits full elucidation, this review evaluates its potential mediating role, linking emotional and cognitive decline across age-related disorders The interplay between TrkB.T1 and TrkB.FL isoforms may be considered as a pivotal shared regulator underlying this complex relationship. The current review aims to synthesize current knowledge on TrkB isoform imbalance, specifically its contribution to age-related cognitive decline and mood disorders. By examining shared pathogenic pathways between aging, cognitive decline, and mood disorders through the lens of TrkB signaling, this review uncovers potential therapeutic targets not previously considered, offering a fresh perspective on combating age-related mental health issues as well as cognitive deficits.

This study aimed to compare the effects of High-Intensity Interval Training (HIIT) performed in a single session(1xHIIT) versus three daily sessions (3xHIIT) on fitness level and behavior of aged rats. Eighteen-month-old Wistar rats were assigned to Untrained (UN), 1xHIIT, or 3xHIIT (n = 12/group). Both groups, 1xHIIT and 3xHIIT, performed 15 min of a treadmill running HIIT protocol during 8 weeks. 1xHIIT protocol consisted of a single daily session of 15 min, while the 3xHIIT performed three daily sessions of 5 min with a 4 h interval between the sessions. Morris Water Maze (MWM) task was used to evaluate spatial learning and memory. Splash test, Forced Swim test, and Elevated Plus Maze task (EPM) were used to evaluate anhedonic, depressive-like, and anxious behaviors, respectively. Rats were euthanized, and the hippocampus was harvested for western blot analyses (CaMKII and BDNF). Both HIIT protocols improved VO2max and spatial memory. Notably, only the 3xHIIT protocol attenuated anxious and depressive-like behaviors. Western blot analyses of the hippocampus revealed that both HIIT protocols increased BDNF levels. BDNF levels were higher in the 3xHIIT when compared with 1xHIIT group, and we observed increasement of the CamKII levels just in the 3x HIIT group. Therefore, this study provides evidence indicating that accumulated HIIT sessions is more effective than traditional daily HIIT sessions in improving fitness level, cognitive function, memory, inhibiting the development of mood disorders, and enhancing BDNF and CaMKII levels in the hippocampus of aged rats.

Rare study of the non-coding and regulatory regions of the genome limits our ability to decode the mechanisms of fatty liver hemorrhage syndrome (FLHS) in chickens.

Herein, we constructed the high-fat diet-induced FLHS chicken model to investigate the genome-wide active enhancers and transcriptome by H3K27ac target chromatin immunoprecipitation sequencing (ChIP-seq) and RNA sequencing (RNA-Seq) profiles of normal and FLHS liver tissues. Concurrently, an integrative analysis combining ChIP-seq with RNA-Seq and a comparative analysis with chicken FLHS, rat non-alcoholic fatty liver disease (NAFLD) and human NAFLD at the transcriptome level revealed the enhancer and super enhancer target genes and conservative genes involved in metabolic processes.

In total, 56 and 199 peak-genes were identified in upregulated peak-genes positively regulated by H3K27ac (Cor (peak-gene correlation) ≥0.5 and log2(FoldChange) ≥1) (PP) and downregulated peak-genes positively regulated by H3K27ac (Cor (peak-gene correlation) ≥0.5 and log2(FoldChange)≤-1) (PN), respectively; then we screened key regulatory targets mainly distributing in lipid metabolism (PCK1, APOA4, APOA1, INHBE) and apoptosis (KIT, NTRK2) together with MAPK and PPAR signaling pathway in FLHS. Intriguingly, PCK1 was also significantly covered in up-regulated super-enhancers (SEs), which further implied the vital role of PCK1 during the development of FLHS.

Together, our studies have identified potential therapeutic biomarkers of PCK1 and elucidated novel insights into the pathogenesis of FLHS, especially for the epigenetic perspective.

Background and Objectives: One of the members of the neurotrophin (NT) family is the brain-derived neurotrophic factor (BDNF). In addition to its role in the nerve system, it has been found to play a role in lung health and diseases. Materials and Methods: The serum concentrations of BDNF were assessed in 57 patients with COPD and in 19 control individuals and the possible associations of BDNF with the spirometric indexes and disease stages were explored. Results: We did not find a significant difference between the serum concentrations of BDNF of patients and controls (p = 0.521). A significant negative correlation of the serum BDNF levels with the age of the patients (Rho = -0.279, p = 0.036) was observed. In addition, a borderline negative correlation with the age of disease onset (Rho= -0.244, p = 0.063) was also found. When analyzing these correlations in different genders, we found stronger statistical significance in male patients (Rho = -0.398, p = 0.009; and Rho = -0.419, p = 0.006), while no such significance was found in females (p = 0.574 and p = 0.342). The analyses of the possible relations of serum BDNF concentration with the spirometric parameters in the whole group of patients did not reveal any significance (p = 0.231 for FEV1%pr. and p = 0.271 for FEV1/FVC%). However, when the patients were dichotomized on the basis of smoking habits, we obtained a strong positive correlation between BDNF and FEV1%pr. (Rho = 0.501, p = 0.048) in non-smokers, but strong negative correlations with FEV1%pr. (Rho = -0.468, p = 0.003) and with FEV1/FVC% (Rho = -0.331, p = 0.040) in ex/current smokers. Non-smokers with moderate disease (GOLD II) had higher BDNF serum concentrations than patients with GOLD stage III/IV (p = 0.031). In ex/current smokers, there was an opposite association (p = 0.045). Conclusions: The results of our study suggest that the expression and secretion of BDNF are changed in COPD, but its effects and functions may differ according to the smoking history of the patients.

Analysis of the mechanisms underlying autism spectrum disorder (ASD) is an urgent task due to the ever-increasing prevalence of this condition. The study of critical periods of neuroontogenesis is of interest, since the manifestation of ASD is often associated with prenatal disorders of the brain development. One of the currently promising hypotheses postulates a connection between the pathogenesis of ASD and the dysfunction of neurotransmitters and neurotrophins. In this study, we investigated the expression of key dopamine receptors (Drd1, Drd2), brain-derived neurotrophic factor (Bdnf), its receptors (Ntrkb2, Ngfr) and the transcription factor Creb1 that mediates BDNF action, as well as cerebral dopamine neurotrophic factor (Cdnf) during the critical periods of embryogenesis (e14 and e18) and postnatal development (p14, p28, p60) in the hippocampus and frontal cortex of BTBR mice with autism-like behavior compared to the neurotypical C57BL/6 J strain. In BTBR embryos, on the 14th day of prenatal development, an increase in the expression of the Ngfr gene encoding the p75NTR receptor, which may lead to the activation of apoptosis, was found in the hippocampus and frontal cortex. A decrease in the expression of Cdnf, Bdnf and its receptor Ntrkb2, as well as dopamine receptors (Drd1, Drd2) was detected in BTBR mice in the postnatal period of ontogenesis mainly in the frontal cortex, while in the hippocampus of mature mice (p60), only a decrease in the Drd2 mRNA level was revealed. The obtained results suggest that the decrease in the expression levels of CDNF, BDNF-TrkB and dopamine receptors in the frontal cortex in the postnatal period can lead to significant changes in both the morphology of neurons and dopamine neurotransmission in cortical brain structures. At the same time, the increase in p75NTR receptor gene expression observed on the 14th day of embryogenesis, crucial for hippocampus and frontal cortex development, may have direct relevance to the manifestation of early autism.

Depression poses a significant threat to global physical and mental health, impacting around 3.8% of the population with a rising incidence. Current treatment options primarily involve medication and psychological support, yet their effectiveness remains limited, contributing to high relapse rates. There is an urgent need for innovative and more efficacious treatment modalities. Stem cell therapy, a promising avenue in regenerative medicine for a spectrum of neurodegenerative conditions, has recently garnered attention for its potential application in depression. While much of this work remains preclinical, it has demonstrated considerable promise. Identified mechanisms underlying the antidepressant effects of stem cell therapy encompass the stimulation of neurotrophic factors, immune function modulation, and augmented monoamine levels. Nonetheless, these pathways and other undiscovered mechanisms necessitate further investigation. Depression fundamentally manifests as a neurodegenerative disorder. Given stem cell therapy's success in addressing a range of neurodegenerative pathologies, it opens the door to explore its application in depression treatment. This exploration may include repairing damaged nerves directly or indirectly and inhibiting neurotoxicity. Nevertheless, significant challenges must be overcome before stem cell therapies can be applied clinically. Successful resolution of these issues will ultimately determine the feasibility of incorporating stem cell therapies into the clinical landscape. This narrative review provides insights into the progress of research, potential avenues for exploration, and the prevailing challenges in the implementation of stem cell therapy for treatment of depression.

Fructose consumption has increased over the years, especially in adolescents living in urban areas. Growing evidence indicates that daily fructose consumption leads to some pathological conditions, including memory impairment. This review summarizes relevant data describing cognitive deficits after fructose intake and analyzes the underlying neurobiological mechanisms. Preclinical experiments show sex-related deficits in spatial memory; that is, while males exhibit significant imbalances in spatial processing, females seem unaffected by dietary supplementation with fructose. Recognition memory has also been evaluated; however, only female rodents show a significant decline in the novel object recognition test performance. According to mechanistic evidence, fructose intake induces neuroinflammation, mitochondrial dysfunction, and oxidative stress in the short term. Subsequently, these mechanisms can trigger other long-term effects, such as inhibition of neurogenesis, downregulation of trophic factors and receptors, weakening of synaptic plasticity, and long-term potentiation decay. Integrating all these neurobiological mechanisms will help us understand the cellular and molecular processes that trigger the memory impairment induced by fructose.

Neuroinflammation is widely acknowledged as a characteristic feature of almost all neurological disorders and specifically in depression- and anxiety-like disorders. In recent years, there has been significant attention on natural compounds with potent anti-inflammatory effects due to their potential in mitigating neuroinflammation and neuroplasticity.

In the present study, we aimed to evaluate the neuroprotective effects of oleacein (OC), a rare secoiridoid derivative found in extra virgin olive oil. Our goal was to explore the BDNF/TrkB neurotrophic activity of OC and subsequently assess its potential for modulating neuroinflammatory response using human neuroblastoma cells (SH-SY5Y cells) and an in vivo model of depression induced by lipopolysaccharide (LPS)-mediated inflammation.

In SH-SY5Y cells, OC exhibited a significant dose-dependent increase in BDNF expression. This enhancement was absent when cells were co-treated with inhibitors of BDNF's receptor TrkB, as well as downstream molecules PI3K and MEK. Whole-transcriptomics analysis revealed that OC upregulated cell cycle-related genes under normal conditions, while downregulating inflammation-associated genes in LPS-induced conditions. Furthermore, surface plasmon resonance (SPR) assays demonstrated that OC exhibited a stronger and more stable binding affinity to TrkB compared to the positive control, 7,8-dihydroxyflavone. Importantly, bioluminescence imaging revealed that a single oral dose of OC significantly increased BDNF expression in the brains of Bdnf-IRES-AkaLuc mice. Furthermore, oral administration of OC at a dosage of 10 mg/kg body weight for 10 days significantly reduced immobility time in the tail suspension test compared to the LPS-treated group. RT-qPCR analysis revealed that OC significantly decreased the expression of pro-inflammatory cytokines Tnfα, Il6, and Il1β, while simultaneously enhancing Bdnf expression, as well as both pro and mature BDNF protein levels in mice hippocampus. These changes were comparable to those induced by the positive control antidepressant drug fluoxetine. Additionally, microarray analysis of mouse brains confirmed that OC could counteract LPS-induced inflammatory biological events.

Altogether, our study represents the first report on the potential antineuroinflammatory and antidepressant properties of OC via modulation of BDNF/TrkB neurotrophic activity. This finding underscores the potential of OC as a natural therapeutic agent for depression- and anxiety-related disorders.