Inflammation-induced oxidative stress in macrophages and microglia is associated with excessive production of reactive oxygen species, initiating a damaging cycle of neuroinflammation and cellular injury. These processes are significant contributors to the pathophysiology of autism spectrum disorders, which involve neuronal dysfunction, cell loss, and behavioral impairments. Under conditions of oxidative stress, activated microglia release pro-inflammatory mediators, further intensifying neuronal damage. Bismuth subsalicylate (BSS), a compound with well-documented anti-inflammatory and antioxidant properties, has shown potential in mitigating such neurodegenerative processes. This study aimed to evaluate the effects of BSS in reducing neuroinflammation and oxidative stress in a propionic acid (PPA)-induced autism model, alongside its impact on behavioral outcomes. The study utilized 30 male Wistar albino rats, with PPA administered intraperitoneally at 250 mg/kg/day for 5 days to induce an autism-like phenotype. Rats were divided into three groups: Group 1 (Normal control, n = 10); Group 2 (PPA + saline, PPAS, n = 10); and Group 3 (PPA + BSS, PPAB, n = 10). Treatments were administered for 15 days. Behavioral performance was assessed through three-chamber sociability, open field, and passive avoidance learning tests, followed by biochemical and histological evaluations of brain tissues. Biochemical analysis revealed a significant increase in malondialdehyde, tumor necrosis factor-alpha, and interleukin-17 levels in the PPAS group, indicating heightened oxidative stress and inflammation. Treatment notably reduced these markers, suggesting its efficacy in mitigating oxidative damage and inflammatory responses. Immunohistochemical results demonstrated reduced glial activation and enhanced neuronal preservation in the hippocampal and cerebellar regions of treated rats. Additionally, behavioral impairments in social interaction, exploration, and memory were significantly improved with BSS therapy. These results suggest that BSS may confer neuroprotective effects through attenuation of oxidative stress and neuroinflammation, potentially contributing to improved neuronal function and behavioral performance in a PPA-induced autism model.

Brain-derived neurotrophic factor (BDNF) expression is reduced in the brain of various central nervous system (CNS) disorders, but its relation to peripheral expression remains unclear. This study aimed to determine peripheral BDNF expression affected by BDNF promoter IV defect and enriched environment treatment (EET). Promoter IV defect is associated with CNS disorders and chronic stress, whereas EET increases hippocampal BDNF expression and ameliorates CNS dysfunctions.

Enzyme-linked immunosorbent assay measured BDNF protein levels in eleven regions (hippocampus, frontal cortex, heart, lung, liver, spleen, intestine, kidney, intestine, thymus, muscle, serum) in wild-type and knock-in promoter IV (KIV) mice with or without 3 weeks of EET provided after weaning.

Knock-in promoter IV resulted in BDNF levels significantly decreased in muscle, but significantly increased in intestine, liver, thymus, and serum, which suggests compensatory upregulation of other promoters in those tissues. EET increased BDNF levels in muscle and serum of KIV mice and thymus of wild-type mice, suggesting EET's beneficial effects in muscle motor and adaptive immune regulation. EET increased hippocampal BDNF levels in both genotypes, which significantly negatively correlated with intestine BDNF levels, suggesting its role in the brain-gut axis. EET reduced wild-type heart BDNF levels, possibly through parasympathetic regulation. Significant positive BDNF correlations were observed among serum-muscle, serum-thymus, lung-spleen, and intestine-liver, suggesting inter-organ interaction and regulation of BDNF. Partial Least Squares discriminant analyses (PLS-DA) identified that variations in BDNF levels in intestine, liver, frontal cortex, and serum contribute most to classify promoter IV defect, and those in hippocampus, serum, heart, thymus, and liver contribute most to classify EET effects.

This is the first study to demonstrate how genetic and environmental factors affect BDNF expression in peripheral tissues, highlighting the complex BDNF correlations across organ systems and suggesting usefulness of multivariate BDNF analyses for detecting promoter IV defect and enriched environment effects. Elucidation of BDNF's role and regulatory mechanisms in peripheral organ systems may help better our understanding of its connection to CNS disorders and their treatments.

Frailty is a common medical syndrome which largely increases the risk of disability, depression, falls, hospitalization and mortality. An increasing number of research suggests that frailty is reversible by medical interventions at its early stage. Therefore, efficient detection is utterly important for frail population. Since numerous biological processes have been indicated in frail population, the critical regulators in these biological processes could provide biomarkers for early detection or treatment for frailty. The brain-derived neurotrophic factor (BDNF) has been associated with several biological process ranging from cognitive function to inflammation, therefore it could be an important regulator for frailty. In this review, we would discuss the mechanism association between different indicators of frailty and BDNF. Furthermore, we summarize the approaches to interfere with BDNF in healthy and pathologic condition, which could lead to identification of potential interventional strategies for frailty.

Following stroke, B cells enter brain regions outside of the ischemic injury to mediate functional recovery. Although B cells produce neurotrophins that support remote plasticity, including brain-derived neurotrophic factor (BDNF), it remains unclear which signal(s) activate B cells in the absence of infarct-localized pro-inflammatory cues. Activation of N-methyl-d-aspartate (NMDA)-type receptor (NMDAR) subunits on neurons can upregulate mature BDNF (mBDNF) production from a pro-BDNF precursor, but whether this occurs in B cells is unknown. We identified GluN2A and GluN2B NMDAR subunits on B cells that respond to glutamate and mediate nearly half of the glutamate-induced Ca2+ responses in activated B cell subsets. Ischemic stroke recruits GluN2A+ B cells into the ipsilesional hemisphere and both stroke and neurophysiologic levels of glutamate regulate gene and surface expression. Regardless of injury, pro-BDNF+ B cells localize to spleen/circulation whereas mBDNF+ B cells localize to the brain, including in aged male and female mice. We confirmed B cell-derived BDNF was required for in vitro and in vivo B cell-mediated neuroprotection. Lastly, GluN2A, GluN2B, glutamate-induced Ca2+ responses, and BDNF expression were all clinically confirmed in B cells from healthy donors, with BDNF+ B cells present in post-stroke human parenchyma. These data suggest that B cells express functional NMDARs that respond to glutamate, enhance NMDAR signaling with activation, and upregulate mature BDNF expression within the brain. This study identifies potential glutamate-induced neurotrophic roles for B cells in the brain; an immune response to neurotransmitters unique from established pro-inflammatory stimuli and relevant to any CNS-localized injury or disease.

The gut microbiota and the immune system are closely connected, influencing early-life brain development. Brain-derived neurotrophic factor (BDNF), crucial for neuronal development, has been demonstrated to be produced by certain immune cells. However, the modulation of BDNF during bacterial antigen and metabolite challenge remains elusive. We investigate the effects of bacterial-derived antigens and metabolites on BDNF secretion in human PBMCs. Although BDNF levels were altered during stimulation, a specific cellular origin of BDNF within PBMCs was indeterminate. Positive magnetic separation of monocytes eliminated both the stimulant-induced BDNF secretion and reduced monocyte-platelet aggregates. Conversely, elevated platelet counts significantly increased BDNF levels, indicating that platelets, when interacting with monocytes and exposed to bacterial antigens, are likely the dominant source of BDNF in PBMC cultures. As previously described, platelets are a crucial source of circulating peripheral blood BDNF. Our findings emphasize the importance of the interplay between immune-blood cell complexes during microbial stimulation in regulating BDNF levels. This highlights the necessity of investigating such interactions to better understand the early-life gut-brain axis.

Benzo[a]pyrene (B[a]P) is a carcinogenic contaminant widely present in the environment. Recently, increasing studies have paid attention to the developmental neurotoxicity of B[a]P in offspring in their early life stages; however, the underlying molecular mechanisms have not been clearly elucidated. In this study, we aimed to evaluate the effects of prenatal B[a]P exposure on neurobehavior of pups during their brain growth spurt (BGS) period and also explore the potential underlying mechanisms. Pregnant Sprague-Dawley (SD) rats were intraperitoneally exposed to 0, 10, 20, or 40 mg/kg-bw B[a]P for three consecutive days during embryonic days 17-19. The physiological development index of pups was observed, and a series of neurobehavioral tests assessing sensory and motor maturation were performed. The complexity of dendritic branches and the basal dendritic spine density of CA1 pyramidal neurons were examined using Golgi-Cox staining during PND 1-14. In addition, the mRNA and protein expression levels of hippocampal BDNF, SYP, Arc, PSD-95, DNMT1, and DNMT3a, and the level of 5-mC were detected using RT-qPCR, Western blotting, or immunohistochemical staining, respectively. We noted that prenatal B[a]P exposure induced body weight loss and neurobehavioral impairments in the early life stages. Furthermore, this study firstly revealed that maternal exposure to B[a]P impaired the dendritic arborization and complexity of pyramidal neurons in the hippocampus CA1 subfield in offspring during the early postnatal period, and the damage of B[a]P to basal dendritic spine density was also observed in a dose-dependent manner. Correspondingly, maternal exposure to B[a]P markedly reduced BDNF, Arc, SYP, and PSD-95 mRNA and protein levels in the offspring hippocampus. Meanwhile, the levels of hippocampal DNMT1, DNMT3a, and 5-mC significantly increased in the offspring prenatally exposed to B[a]P. In summary, this study firstly demonstrated that maternal B[a]P exposure induced neurobehavioral deficits by destroying the hippocampal synaptic ultrastructure, which was possibly associated with the downregulation of BDNF, Arc, SYP, and PSD95 in the hippocampus through increased DNMTs-mediated DNA methylation in offspring during the BGS period.

Experiences of complex trauma and adversity, especially for children, are ongoing global crises necessitating adaptation. Bioadaptability to adversity and its health consequences emphasizes the dynamism of adaptation to trauma and the potential for research to inform intervention strategies. Epigenetic variability, particularly DNA methylation, associates with chronic adversity while allowing for resilience and adaptability. Epigenetics, including age- and site-specific changes in DNA methylation, gene-environment interactions, pharmacological responses, and biomarker characterization and evaluation, may aid in understanding trauma responses and promoting well-being by facilitating psychological and biological adaptation. Understanding these molecular processes provides a foundation for a biologically adaptive framework to shift public health strategies from restorative to long-term adaptation and resilience. Psychological, cultural, and biological trauma must be addressed in innovative interventions for vulnerable populations, particularly children and adolescents. Understanding molecular changes may provide a biopsychosocial perspective for culturally sensitive, evidence-based interventions that promote resilience and thriving in new settings.

The immune system plays a major part in neurodegenerative diseases. In some, such as multiple sclerosis, it is the primary driver of the disease. In others, such as Alzheimer disease, amyotrophic lateral sclerosis and Parkinson disease, it has an amplifying role. Immunotherapeutic approaches that target the adaptive and innate immune systems are being explored for the treatment of almost all neurological diseases, and the targets and approaches are often common across diseases. Microglia are the primary immune cells in the brain that contribute to disease pathogenesis, and are consequently a common immune target for therapy. Other therapeutic approaches target components of the peripheral immune system, such as regulatory T cells and monocytes, which in turn act within the CNS. This Review considers in detail how microglia, monocytes and T cells contribute to the pathogenesis of multiple sclerosis, Alzheimer disease, amyotrophic lateral sclerosis and Parkinson disease, and their potential as shared therapeutic targets across these diseases. The microbiome is also highlighted as an emerging therapeutic target that indirectly modulates the immune system. Therapeutic approaches being developed to target immune function in neurodegenerative diseases are discussed, highlighting how immune-based approaches developed to treat one disease could be applicable to multiple other neurological diseases.

Acrylamide (ACR) can have adverse environmental effects because of its multiple applications. Relevant scientific literatures of the existence of ACR residues in foods following processing steps have raised concern in the biochemistry, chemistry and safety of this vinyl substance. The interest has focused on the hepatotoxicity of ACR in animals and humans and on the ACR content mitigation and its detoxification. Borax (BX), as a naturally occurring antioxidant featured boron compound, was selected in this investigation to assess its possible neuro-protective potential against ACR-induced neurotoxicity. Nrf2 axis signaling pathways and detoxification response to oxidative stress after exposure to ACR in brains of rainbow trout, and the effect of BX application on reducing ACR-induced neurotoxicity were investigated. Rainbow trout were acutely exposed to ACR (12.5 mg/L) alone or simultaneously treated with BX (0.75 mg/L) during 96h. The exposed fish were sampled at 48th and 96th and oxidative stress response endpoints, 8-OHdG, Nrf2, TNF-α, caspase-3, in addition to IL-6 activities and the levels of AChE and BDNF in brain tissues of rainbow trout (Oncorhynchus mykiss) were evaluated. Samples showed decreases in the levels of ACR-mediated biomarkers used to assess neural toxicity (SOD, CAT, GPx, AChE, BDNF, GSH), increased levels of MDA, MPO, DNA damage and apoptosis. ACR disrupted the Nrf2 pathway, and induced neurotoxicity. Inhibited activities' expressions under simultaneous administration experiments, revealed the protective effects of BX against ACR-induced toxicity damage. The obtained data allow the outline of early multi-parameter signaling pathways in rainbow trout.

Animal and human studies have shown that exposure to hypoxia can increase brain-derived neurotrophic factor (BDNF) protein transcription and reduce systematic inflammatory cytokine response. Therefore, the aim of this study was to investigate the acute and chronic effects of intermittent hypoxic-hyperoxic exposure (IHHE) prior to aerobic exercise on BDNF, interleukin-6 (IL-6), and C-reactive protein (CRP) blood levels in geriatric patients.

Twenty-five geriatric patients (83.1 ± 5.0 yrs, 71.1 ± 10.0 kg, 1.8 ± 0.9 m) participated in a placebo-controlled, single-blinded trial and were randomly assigned to either an intervention (IG) or control group (CG) performing an aerobic cycling training (17 sessions, 20 min·session-1, 3 sessions·week-1). Prior to aerobic cycling exercise, the IG was additionally exposed to IHHE for 30 min, whereas the CG received continuous normoxic air. Blood samples were taken immediately before (pre-exercise) and 10 min (post-exercise) after the first session as well as 48 h (post-training) after the last session to determine serum (BDNFS) and plasma BDNF (BDNFP), IL-6, and CRP levels. Intervention effects were analyzed using a 2 x 2 analysis of covariance with repeated measures. Results were interpreted based on effect sizes with a medium effect considered as meaningful (ηp2 ≥ 0.06, d ≥ 0.5).

CRP was moderately higher (d = 0.51) in the CG compared to the IG at baseline. IHHE had no acute effect on BDNFS (ηp2 = 0.01), BDNFP (ηp2 < 0.01), BDNF serum/plasma-ratio (ηp2 < 0.01), IL-6 (ηp2 < 0.01), or CRP (ηp2 = 0.04). After the 6-week intervention, an interaction was found for BDNF serum/plasma-ratio (ηp2 = 0.06) but not for BDNFS (ηp2 = 0.04), BDNFP (ηp2 < 0.01), IL-6 (ηp2 < 0.01), or CRP (ηp2 < 0.01). BDNF serum/plasma-ratio increased from pre-exercise to post-training (d = 0.67) in the CG compared to the IG (d = 0.51). A main effect of time was found for BDNFP (ηp2 = 0.09) but not for BDNFS (ηp2 = 0.02). Within-group post-hoc analyses revealed a training-related reduction in BDNFP in the IG and CG by 46.1% (d = 0.73) and 24.7% (d = 0.57), respectively.

The addition of 30 min IHHE prior to 20 min aerobic cycling seems not to be effective to increase BDNFS and BDNFP or to reduce IL-6 and CRP levels in geriatric patients after a 6-week intervention.The study was retrospectively registered at drks.de (DRKS-ID: DRKS00025130).

Modulating inflammation is critical to enhance nerve regeneration after injury. However, clinically applicable regenerative therapies that modulate inflammation have not yet been established. Here, we demonstrate synergistic effects of the combination of an HMG-CoA reductase inhibitor, statin/fluvastatin and critical components of the extracellular matrix, Matrix-Bound Nanovesicles (MBV) to enhance axon regeneration and neuroprotection after mouse optic nerve injury. Mechanistically, co-intravitreal injections of fluvastatin and MBV robustly promote infiltration of monocytes and neutrophils, which lead to RGC protection and axon regeneration. Furthermore, monocyte infiltration is triggered by elevated expression of CCL2, a chemokine, in the superficial layer of the retina after treatment with a combination of fluvastatin and MBV or IL-33, a cytokine contained within MBV. Finally, this therapy can be further combined with AAV-based gene therapy blocking anti-regenerative pathways in RGCs to extend regenerated axons. These data highlight novel molecular insights into the development of immunomodulatory regenerative therapy.

FGF, VEGFR-2 and CSF1R signalling pathways play a key role in the pathogenesis of multiple sclerosis (MS). Selective inhibition of FGFR by infigratinib in MOG35-55-induced experimental autoimmune encephalomyelitis (EAE) prevented severe first clinical episodes by 40%; inflammation and neurodegeneration were reduced, and remyelination was enhanced. Multi-kinase inhibition of FGFR1-3, CSFR and VEGFR-2 by fexagratinib (formerly known as AZD4547) may be more efficient in reducing inflammation, neurodegeneration and regeneration in the disease model.

Female C57BL/6J mice were treated with fexagratinib (6.25 or 12.5 mg·kg-1) orally or placebo over 10 days either from time of EAE induction (prevention experiment) or onset of symptoms (suppression experiment). Effects on inflammation, neurodegeneration and remyelination were assessed at the peak of the disease (Day 18/20 post immunization) and the chronic phase of EAE (Day 41/42).

In the prevention experiment, treatment with 6.25 or 12.5 mg·kg-1 fexagratinib prevented severe first clinical episodes by 66.7% or 84.6% respectively. Mice treated with 12.5 mg·kg-1 fexagratinib hardly showed any symptoms in the chronic phase of EAE. In the suppression experiment, fexagratinib resulted in a long-lasting reduction of severe symptoms by 91 or 100%. Inflammation and demyelination were reduced, and axonal density, numbers of oligodendrocytes and their precursor cells, and remyelinated axons were increased by both experimental approaches.

Multi-kinase inhibition by fexagratinib in a well-tolerated dose of 1 mg·kg-1 in humans may be a promising approach to reduce inflammation and neurodegeneration, to slow down disease progression and support remyelination in patients.

The neurotrophic growth factor brain-derived neurotrophic factor (BDNF) plays a crucial role in various neurodegenerative and psychiatric diseases, such as Alzheimer's disease, schizophrenia and depression. BDNF has been proposed as a potential biomarker for diagnosis, prognosis and monitoring therapy. Understanding the factors influencing BDNF levels and whether they follow a circadian rhythm is essential for interpreting fluctuations in BDNF measurements. We aimed to investigate the circadian rhythm of BDNF by collecting multiple peripheral venous blood samples from young, healthy male participants at 12 different time points over 24 h. In addition, vital parameters, cortisol and insulin like growth factor 1 (IGF1) were measured to explore potential regulatory mechanisms, interfering variables and their correlations with BDNF concentration. The findings revealed that plasma BDNF did not exhibit any significant fluctuations over 24 h, suggesting the absence of a circadian rhythm. However, serum BDNF levels decreased during sleep. Furthermore, serum BDNF showed a positive correlation with heart rate but a negative correlation with IGF1. No significant correlation was observed between cortisol and BDNF or IGF1. Although plasma BDNF suggests steady-state conditions, the decline of serum BDNF during the nocturnal period could be attributed to physical inactivity and associated with reduced haemodynamic blood flow (heart rate reduction during sleep). The type of sample collection (peripheral venous cannula vs. blood sampling using a butterfly system) does not significantly affect the measured BDNF levels. The sample collection during the day did not significantly affect BDNF analysis, emphasizing the importance of considering activity levels rather than timing when designing standardized protocols for BDNF assessments.

Neutrophils from skull bone marrow (Nskull) are activated under some brain stresses, but their effects on traumatic brain injury (TBI) are lacking. Here, we find Nskull infiltrates brain tissue quickly and persistently after TBI, which is distinguished by highly and specifically expressed osteocalcin (OCN) from blood-derived neutrophils (Nblood). Reprogramming of glucose metabolism by reducing glycolysis-related enzyme glyceraldehyde 3-phosphate dehydrogenase expression is involved in the antiapoptotic and proliferative abilities of OCN-expressing Nskull. The transcription factor Fos-like 1 governs the specific gene profile of Nskull including C-C motif chemokine receptor-like 2 (CCRL2), arginase 1 (Arg1), and brain-derived neurotrophic factor (BDNF) in addition to OCN. Selective knockout of CCRL2 in Nskull demonstrates that CCRL2 mediates its recruitment, whereas high Arg1 expression is consistent with its immunosuppressive effects on Nblood, and the secretion of BDNF facilitating dendritic growth contributes to its neuroprotection. Thus, our findings provide insight into the roles of Nskull in TBI.

So far, only a small number of medications are effective in progressive multiple sclerosis (MS). The sphingosine-1-phosphate-receptor (S1PR)-1,5 modulator siponimod, licensed for progressive MS, is acting both on peripheral immune cells and in the central nervous system (CNS). So far it remains elusive, whether those effects are related to the neurotrophin brain derived neurotrophic factor (BDNF). We hypothesized that BDNF in immune cells might be a prerequisite to reduce disease activity in experimental autoimmune encephalomyelitis (EAE) and prevent neurotoxicity. MOG35-55 immunized wild type (WT) and BDNF knock-out (BDNFko) mice were treated with siponimod or vehicle and scored daily in a blinded manner. Immune cell phenotyping was performed via flow cytometry. Immune cell infiltration and demyelination of spinal cord were assessed using immunohistochemistry. In vitro, effects on neurotoxicity and mRNA regulation were investigated using dorsal root ganglion cells incubated with EAE splenocyte supernatant. Siponimod led to a dose-dependent reduction of EAE scores in chronic WT EAE. Using a suboptimal dosage of 0.45 µg/day, siponimod reduced clinical signs of EAE independent of BDNF-expression in immune cells in accordance with reduced infiltration and demyelination. Th and Tc cells in secondary lymphoid organs were dose-dependently reduced, paralleled with an increase of regulatory T cells. In vitro, neuronal viability trended towards a deterioration after incubation with EAE supernatant; siponimod showed a slight rescue effect following treatment of WT splenocytes. Neuronal gene expression for CCL2 and CX3CL1 was elevated after incubation with EAE supernatant, which was reversed after siponimod treatment for WT, but not for BNDFko. Apoptosis markers and alternative death pathways were not affected. Siponimod exerts both anti-inflammatory and neuroprotective effects, partially related to BDNF-expression. This might in part explain effectiveness during progression in MS and could be a target for therapy.

The purpose of this study is to investigate regenerative process by immunohistochemical analysis and evaluate periodontal tissue regeneration following a topical application of BDNF to inflamed 3-wall intra-bony defects.

Brain-derived neurotrophic factor (BDNF) plays a role in the survival and differentiation of central and peripheral neurons. BDNF can regulate the functions of non-neural cells, osteoblasts, periodontal ligament cells, endothelial cells, as well as neural cells. Our previous study showed that a topical application of BDNF enhances periodontal tissue regeneration in experimental periodontal defects of dog and that BDNF stimulates the expression of bone (cementum)-related proteins and proliferation of human periodontal ligament cells.

Six weeks after extraction of mandibular first and third premolars, 3-wall intra-bony defects were created in mandibular second and fourth premolars of beagle dogs. Impression material was placed in all of the artificial defects to induce inflammation. Two weeks after the first operation, BDNF (25 and 50 μg/mL) immersed into atelocollagen sponge was applied to the defects. As a control, only atelocollagen sponge immersed in saline was applied. Two and four weeks after the BDNF application, morphometric analysis was performed. Localizations of osteopontin (OPN) and proliferating cell nuclear antigen (PCNA)-positive cells were evaluated by immunohistochemical analysis.

Two weeks after application of BDNF, periodontal tissue was partially regenerated. Immunohistochemical analyses revealed that cells on the denuded root surface were positive with OPN and PCNA. PCNA-positive cells were also detected in the soft connective tissue of regenerating periodontal tissue. Four weeks after application of BDNF, the periodontal defects were regenerated with cementum, periodontal ligament, and alveolar bone. Along the root surface, abundant OPN-positive cells were observed. Morphometric analyses revealed that percentage of new cementum length and percentage of new bone area of experimental groups were higher than control group and dose-dependently increased.

These findings suggest that BDNF could induce cementum regeneration in early regenerative phase by stimulating proliferation of periodontal ligament cells and differentiation into periodontal tissue cells, resulting in enhancement of periodontal tissue regeneration in inflamed 3-wall intra-bony defects.

The immune system has emerged as a key regulator of central nervous system (CNS) function in health and in disease. Importantly, improved understanding of immune contributions to mood disorders has provided novel opportunities for the treatment of debilitating stress-related mental health conditions such as major depressive disorder (MDD). Yet, the impact to, and involvement of, B lymphocytes in the response to stress is not well-understood, leaving a fundamental gap in our knowledge underlying the immune theory of depression. Several emerging clinical and preclinical findings highlight pronounced consequences for B cells in stress and MDD and may indicate key roles for B cells in modulating mood. This review will describe the clinical and foundational observations implicating B cell-psychological stress interactions, discuss potential mechanisms by which B cells may impact brain function in the context of stress and mood disorders, describe research tools that support the investigation of their neurobiological impacts, and highlight remaining research questions. The goal here is for this discussion to illuminate both the scope and limitations of our current understanding regarding the role of B cells, stress, mood, and depression.

The cornerstones of good health are exercise, proper food, and sound nutrition. Physical exercise should be a lifelong routine, supported by proper food selections to satisfy nutrient requirements based on energy needs, energy management, and variety to achieve optimal metabolism and physiology. The human body is sustained by intermediary and systemic metabolism integrating the physiologic processes for cells, tissues, organs, and systems. Recently, interest in specific metabolites, growth factors, cytokines, and hormones called exerkines has emerged to explain cooperation between nutrient supply organs and the brain during exercise. Exerkines consist of different compounds described as signaling moiety released during and after exercise. Examples of exerkines include oxylipin 12, 13 diHOME, lipid hormone adiponectin, growth factor BDNF, metabolite lactate, reactive oxygen species (ROS), including products of fatty acid oxidation, and cytokines such as interleukin-6. At this point, it is believed that exerkines are immediate, fast, and long-lasting factors resulting from exercise to support body energy needs with an emphasis on the brain. Although exerkines that are directly a product of macronutrient metabolism such as lactate, and result from catabolism is not surprising. Furthermore, other metabolites of macronutrient metabolism seem to be candidate exerkines. The exerkines originate from muscle, adipose, and liver and support brain metabolism, energy, and physiology. The purpose of this review is to integrate the actions of exerkines with respect to metabolism that occurs during exercise and propose other participating factors of exercise and brain physiology. The role of diet and macronutrients that influence metabolism and, consequently, the impact of exercise will be discussed. This review will also describe the evidence for PUFA, their metabolic and physiologic derivatives endocannabinoids, and oxylipins that validate them being exerkines. The intent is to present additional insights to better understand exerkines with respect to systemic metabolism.

B lymphocytes are immune cells studied predominantly in the context of peripheral humoral immune responses against pathogens. Evidence has been accumulating in recent years on the diversity of immunomodulatory functions that B cells undertake, with particular relevance for pathologies of the central nervous system (CNS). This review summarizes current knowledge on B cell populations, localization, infiltration mechanisms, and function in the CNS and associated tissues. Acute and chronic neurodegenerative pathologies are examined in order to explore the complex, and sometimes conflicting, effects that B cells can have in each context, with implications for disease progression and treatment outcomes. Additional factors such as aging modulate the proportions and function of B cell subpopulations over time and are also discussed in the context of neuroinflammatory response and disease susceptibility. A better understanding of the multifactorial role of B cell populations in the CNS may ultimately lead to innovative therapeutic strategies for a variety of neurological conditions.

Despite ample experimental data indicating a role of inflammatory mediators in the behavioral and neurobiological manifestations elicited by exposure to physical and psychologic stressors, causative associations between systemic low-grade inflammation and central nervous system inflammatory processes in posttraumatic stress disorder (PTSD) patients remain largely conceptual. As in other stress-related disorders, pro-inflammatory activity may play an equivocal role in PTSD pathophysiology, one that renders indiscriminate employment of anti-inflammatory agents of questionable relevance. In fact, as several pieces of preclinical and clinical research convergingly suggest, timely and targeted potentiation rather than inhibition of inflammatory responses may actually be beneficial in patients who are characterized by suppressed microglia function in the face of systemic low-grade inflammation. The deleterious impact of chronic stress-associated inflammation on the systemic level may, thus, need to be held in context with the - often not readily apparent - adaptive payoffs of low-grade inflammation at the tissue level.

Cannabis is the most widely used illicit substance. Numerous scientific evidence confirm the strong association between cannabis and psychosis. Exposure to cannabis can induce the development of psychosis and schizophrenia in vulnerable individuals. However, the neurobiological processes underlying this relationship are unknown. Neurotrophins are a class of proteins that serve as survival factors for central nervous system (CNS) neurons. In particular, Nerve Growth Factor (NGF) plays an important role in the survival and function of cholinergic neurons while Brain Derived Neurotrophic Factor (BDNF) is involved in synaptic plasticity and the maintenance of midbrain dopaminergic and cholinergic neurons. Glial Cell Derived Neurotrophic Factor (GDNF) promotes the survival of midbrain dopaminergic neurons and Neuregulin 1 (NrG- 1) contributes to glutamatergic signals regulating the N-methyl-D-aspartate (NMDA). They have a remarkable influence on the neurons involved in the Δ-9-THC (tethra-hydro-cannabinol) action, such as dopaminergic and glutamatergic neurons, and can play dual roles: first, in neuronal survival and death, and, second, in activity-dependent plasticity.

In this brief update, reviewing in a narrative way the relevant literature, we will focus on the effects of cannabis on this class of proteins, which may be implicated, at least in part, in the mechanism of the psychostimulant-induced neurotoxicity and psychosis.

Since altered levels of neurotrophins may participate in the pathogenesis of psychotic disorders which are common in drug users, one possible hypothesis is that repeated cannabis exposure can cause psychosis by interfering with neurotrophins synthesis and utilization by CNS neurons.

Previous studies have suggested association between brain-derived neurotrophic factor (BDNF) and the stress level of workers. However, no studies have investigated the potential of salivary mature BDNF (mBDNF) level as a noninvasive biomarker for psychological distress. This study aimed to explore the reliability of salivary mBDNF as a biomarker for psychological distress in healthcare workers. Furthermore, we examined the relationship between salivary and plasma mBDNF levels and their correlation with age, sex, body mass index (BMI), and exercise habits.

Fifty-one healthy healthcare workers (26 men) from the University of Occupational and Environmental Health, Japan, participated in this study. In this cross-sectional study, participants provided demographic information. Psychological distress was assessed using the Kessler 6 (K6). Saliva and blood samples were collected, and mBDNF was measured by ELISA. Spearman's rank correlation coefficient was performed to analyze the relationship between mBDNF (saliva and plasma) and K6. Statistical analyses were conducted using Stata 17.0, and a significance level of p < .05 was applied.

The median K6 score was 1 (interquartile range [IQR]: 0-3). The median (IQR) salivary mBDNF was 1.36 (1.12-1.96) pg/mL, whereas the mean (standard deviation) plasma mBDNF was 1261.11 (242.98) pg/mL. No correlation was observed between salivary and plasma mBDNF concentrations or with the K6 score. Additionally, there were no associations between salivary or plasma mBDNF concentrations and age, sex, or exercise habits. Finally, an association between plasma mBDNF concentration and BMI was found only in univariate analysis.

Our findings indicate that salivary mBDNF can be accurately measured noninvasively in healthcare workers. Within our study sample, salivary mBDNF did not demonstrate any correlation with K6 and plasma mBDNF. Future studies with a larger study sample and a diverse study population consisting of healthy participants and patients with psychiatric disorders are warranted.

Over the years several lines of evidence have implied a pathological involvement of autonomic nervous system (ANS) in systemic sclerosis (SSc). However, the relationship between autonomic dysfunction and SSc is not yet fully understood. The aims of this scoping review were to map the research done in this field and inform future research to investigate pathogenic hypotheses of ANS involvement.

We performed a scoping review of publications collected through a literature search of MEDLINE and Web of Science databases, looking for dysautonomia in SSc. We included original data from papers that addressed ANS involvement in SSc regarding pathogenesis, clinical presentation and diagnostic tools.

467 papers were identified, 109 studies were selected to be included in the present review, reporting data from a total of 2742 SSc patients. Cardiovascular system was the most extensively investigated, assessing heart rate variability with 24 h HolterECG or Ewing's autonomic tests. Important signs of dysautonomia were also found in digital vasculopathy, gastrointestinal system and SSc skin, assessed both with non-invasive techniques and histologically. Research hypotheses mainly regarding the relationship between sympathetic system - ischemia and the role of neurotrophins were then developed and discussed.

We described the currently available evidence on pathogenesis, clinical presentation and diagnostic assessment of dysautonomia in SSc patients. A strong influence of ANS deregulation on SSc clearly emerges from the literature. Future research is warranted to clarify the mechanisms and timing of autonomic dysfunction in SSc.

Amyotrophic lateral sclerosis (ALS) is a neurodegenerative disease characterized by progressive loss of upper and lower motor neurons. ALS is on a pathogenetic disease spectrum with frontotemporal dementia, referred to as ALS-frontotemporal spectrum disorder (ALS-FTSD). For mutations associated with ALS-FTSD, such as the C9orf72 hexanucleotide repeat expansion, the molecular factors associated with heterogeneity along this spectrum require further characterization. Here, using a targeted NanoString molecular barcoding approach, we interrogate neuroinflammatory dysregulation and heterogeneity at the level of gene expression in post-mortem motor cortex tissue from a cohort of clinically heterogeneous C9-ALS-FTSD cases. We identified 20 dysregulated genes in C9-ALS-FTSD, with enrichment of microglial and inflammatory response gene sets. Two genes with significant correlations to available clinical metrics were selected for validation: FKBP5, a correlate of cognitive function, and brain-derived neurotrophic factor (BDNF), a correlate of disease duration. FKBP5 and its signalling partner, NF-κB, appeared to have a cell type-specific staining distribution, with activated (i.e. nuclear) NF-κB immunoreactivity in C9-ALS-FTSD. Expression of BDNF, a correlate of disease duration, was confirmed to be higher in individuals with long compared to short disease duration using BaseScope™ in situ hybridization. Our analyses also revealed two distinct neuroinflammatory panel signatures (NPS), NPS1 and NPS2, delineated by the direction of expression of proinflammatory, axonal transport and synaptic signalling pathways. We compared NPS between C9-ALS-FTSD cases and those from sporadic ALS and SOD1-ALS cohorts and identified NPS1 and NPS2 across all cohorts. Moreover, a subset of NPS was also able to separate publicly available RNA sequencing data from independent C9-ALS and sporadic ALS cohorts into two inflammatory subgroups. Importantly, NPS subgroups did not clearly segregate with available demographic, genetic, clinical or pathological features, highlighting the value of molecular stratification in clinical trials for inflammatory subgroup identification. Our findings thus underscore the importance of tailoring therapeutic approaches based on distinct molecular signatures that exist between and within ALS-FTSD cohorts.

Over the last decade, a considerable amount of new data have revealed the beneficial effects of exercise on hippocampal neurogenesis and the maintenance or improvement of cognitive function. Investigations with animal models, as well as human studies, have yielded novel understanding of the mechanisms through which endocrine signaling can stimulate neurogenesis, as well as the effects of exercise on acute and/or chronic levels of these circulating hormones. Considering the effects of aging on the decline of specific endocrine factors that affect brain health, insights in this area of research are particularly important. In this review, we discuss how different forms of exercise influence the peripheral production of specific endocrine factors, with particular emphasis on brain-derived neurotrophic factor, growth hormone, insulin-like growth factor-1, ghrelin, estrogen, testosterone, irisin, vascular endothelial growth factor, erythropoietin, and cortisol. We also describe mechanisms through which these endocrine responses to exercise induce cellular changes that increase hippocampal neurogenesis and improve cognitive function.

Among its functions, brain-derived neurotrophic factor (BDNF) regulates endothelial and macrophage activation, possibly playing a role in atherosclerotic plaque pathophysiology. Given contradicting reports, this study sought to investigate whether blood levels of BDNF differed between patients with coronary heart disease (CHD) and controls.

We explored PubMed, Embase, Web of Science, and Cochrane Library for studies comparing BDNF blood levels in patients with CHD and controls. Random-effect meta-analysis was conducted to calculate the standardized mean differences (SMD) and 95% confidence intervals (CI). The Newcastle-Ottawa scale was used to evaluate the quality of included articles, and statistical analyses were conducted using R version 4.0.4.

The final analysis comprised 12 investigations covering 1422 CHD cases and 929 controls with mean ages of 59.66±13.56 and 53.78±13.61 years, respectively. The initial analyses revealed a tendency toward low levels of BDNF in the CHD group compared with the control group (SMD= -0.41; 95% CI, -1.12 to 0.30; P=0.26). After the removal of outliers, the difference achieved statistical difference (SMD= -0.56; 95% CI, -0.93 to -0.19; P<0.01). Subgroup analysis demonstrated no significant difference between serum and plasma BDNF levels (P=0.54); however, subgroup analyses of studies investigating plasma BDNF showed that patients with CHD had significantly lower BDNF levels.

Serum and plasma BDNF concentrations were considerably lower in patients with CHD than in healthy controls. Further studies of higher quality are required on the potential role of BDNF as a biomarker of CHD pathophysiology and severity.

Multiple sclerosis (MS) is predominantly an immune-mediated disease of the central nervous system (CNS) of unknown etiology with a possible genetic predisposition and effect of certain environmental factors. It is generally accepted that the disease begins with an autoimmune inflammatory reaction targeting oligodendrocytes followed by a rapid depletion of their regenerative capacity with subsequent permanent neurodegenerative changes and disability. Recent research highlights the central role of B lymphocytes and the corresponding IgG and IgM autoantibodies in newly forming MS lesions. Thus, their removal along with the modulation of certain bioactive molecules to improve neuroprotection using therapeutic plasma exchange (TPE) becomes of utmost importance. Recently, it has been proposed to determine the levels and precise effects of both beneficial and harmful components in the serum of MS patients undergoing TPE to serve as markers for appropriate TPE protocols. In this review we discuss some relevant examples, focusing on the removal of pathogenic circulating factors and altering the plasma levels of nerve growth factor and sphingosine-1-phosphate by TPE. Altered plasma levels of the reviewed molecular compounds in response to TPE reflect a successful reduction of the pro-inflammatory burden at the expense of an increase in anti-inflammatory potential in the circulatory and CNS compartments.

Spinal cord injury is a traumatic lesion that causes a catastrophic condition in patients, resulting in neuronal deficit and loss of motor and sensory function. That loss is caused by secondary injury events following mechanical damage, which results in cell death. One of the most important events is inflammation, which activates molecules like proinflammatory cytokines (IL-1β, IFN-γ, and TNF-α) that provoke a toxic environment, inhibiting axonal growth and exacerbating CNS damage. As there is no effective treatment, one of the developed therapies is neuroprotection of the tissue to preserve healthy tissue. Among the strategies that have been developed are the use of cell therapy, the use of peptides, and molecules or supplements that have been shown to favor an anti-inflammatory environment that helps to preserve tissue and cells at the site of injury, thus favoring axonal growth and improved locomotor function. In this review, we will explain some of these strategies used in different animal models of spinal cord injury, their activity as modulators of the immune system, and the benefits they have shown.

Brain-derived neurotrophic factor (BDNF) is involved in several drug-induced brain neuroadaptations. The impact of withdrawal from substances that have different neurological mechanisms on BDNF levels is unclear. Our goal was to compare serum BDNF levels in inpatients with alcohol or crack cocaine use disorders during the early withdrawal period, and to evaluate the association with substance-related outcomes. We performed a follow-up study with 101 men under detoxification treatment (drug preference: alcohol [n = 37] and crack cocaine [n = 64]). Blood samples were collected on the 1st and 15th days of hospitalization to measure serum BDNF levels. Serum BDNF levels increased during the early stage of withdrawal (28.2 ± 10.0 vs. 32.6 ± 13.3, p < 0.001), similarly in individuals with alcohol and crack cocaine use. In the alcohol group, BDNF levels on the 15th day of hospitalization were negatively correlated with age (r = -0.394, p = 0.023). Delta BDNF levels were also negatively correlated with BDNF on the 1st day of hospitalization (p = 0.011). No significant correlation was found regarding substance-related outcomes. This is the first study to compare BDNF levels in alcohol and crack cocaine users undergoing similar treatment conditions. These findings could be related to clinical improvement after abstinence or even to drug withdrawal itself, decreasing neuronal injury. Furthermore, age may be a crucial factor, hindering the recovery of neuroplasticity in alcohol users.

The brain-derived neurotrophic factor (BDNF) has been recently shown to have activating effects in isolated platelets. However, BDNF circulates in plasma and a mechanism to preclude constant activation of platelets appears necessary. Hence, we investigated the mechanism regulating BDNF bioavailability in blood. Protein-protein interactions were predicted by molecular docking and validated through immunoprecipitation. Platelet aggregation was assessed using light transmission aggregometry with washed platelets in response to classical agonists or BDNF, in the absence or presence of alpha-2-macroglobulin (α2M), and in platelet-rich plasma. BDNF signaling was assessed with phospho-blots. As little as 25% autologous plasma was sufficient to completely abolish platelet aggregation in response to BDNF. Docking predicted two forms of BDNF binding to native or activated α2M, in parallel and perpendicular arrangements, and the model suggested that the BDNF-α2M complex cannot bind to the high-affinity BDNF receptor, tropomyosin receptor kinase B (TrkB). Experimentally, native and activated α2M formed stable complexes with BDNF preventing BDNF-induced TrkB activation and signal transduction. Both native and activated α2M inhibited BDNF induced-platelet aggregation in a concentration-dependent manner with comparable half-maximal inhibitory concentrations (IC50≈ 125-150 nM). Our study implicates α2M as a physiological regulator of BDNF bioavailability, and as an inhibitor of BDNF-induced platelet activation in blood.

The study aimed to investigate the variation of brain-derived neurotrophic factor (BDNF) levels following acute exercise in patients with rheumatoid arthritis (RA).

This cross-sectional study was conducted with 88 participants (25 males, 63 females; mean age: 45.1±8.3 years; range, 18 to 65 years) between July 2020 and May 2021. Of the participants, 44 were RA patients, and 44 were age-and sex-matched healthy controls. Aerobic exercise was utilized in all participants for a single session. Depression and anxiety levels were evaluated with the Beck Depression Inventory and Hospital Anxiety and Depression Scale. Blood samples were collected from all subjects before and immediately after the intervention.

Serum BDNF levels (both baseline and after exercise) were similar in the RA and control groups. Although serum BDNF levels significantly decreased in both groups after aerobic exercise (Wilcoxon rank p<0.05), ΔBDNF levels were significantly higher in the RA group than in the control group (p=0.047). Additionally, ΔBDNF levels were significantly correlated with the Hospital Anxiety and Depression Scale scores in the RA group (p<0.05) but not in the control group.

A single bout of exercise may effectively decrease serum BDNF levels in patients with RA and healthy subjects. The long-term effect of exercise on BDNF levels should be investigated in prospective studies.

Multiple sclerosis (MS) is a chronic, inflammatory, and degenerative disease of the central nervous system (CNS). Inflammation is observed in all stages of MS, both within and around the lesions, and can have beneficial and detrimental effects on MS pathogenesis. A possible mechanism for the neuroprotective effect in MS involves the release of brain-derived neurotrophic factor (BDNF) by immune cells in peripheral blood and inflammatory lesions, as well as by microglia and astrocytes within the CNS. BDNF is a neurotrophic factor that plays a key role in neuroplasticity and neuronal survival. This review aims to analyze the current understanding of the role that inflammation plays in MS, including the factors that contribute to both beneficial and detrimental effects. Additionally, it explores the potential role of BDNF in MS, as it may modulate neuroinflammation and provide neuroprotection. By obtaining a deeper understanding of the intricate relationship between inflammation and BDNF, new therapeutic strategies for MS may be developed.

Vitellogenin (Vt) is considered the primary protein precursor of egg yolk, serving as a source of protein- and lipid-rich nutrients for the developing embryo. However, recent research has revealed that the functions of Vt and Vt-derived polypeptides, such as yolkin (Y) and yolk glycopeptide 40 (YGP40), extend beyond their nutritional roles as a source of amino acids. Emerging evidence has demonstrated that both Y and YGP40 possess immunomodulatory properties and can contribute to host immune defenses. Additionally, Y polypeptides have been shown to exhibit neuroprotective activity, participating in the modulation of neurons' survival and activity, inhibiting neurodegeneration processes, and improving cognitive functions in rats. These non-nutritional functions not only enhance our understanding of the physiological roles of these molecules during embryonic development but also offer a promising basis for the potential application of these proteins in human health.

Acute injury to the central nervous system (CNS) remains a complex and challenging clinical need. CNS injury initiates a dynamic neuroinflammatory response, mediated by both resident and infiltrating immune cells. Following the primary injury, dysregulated inflammatory cascades have been implicated in sustaining a pro-inflammatory microenvironment, driving secondary neurodegeneration and the development of lasting neurological dysfunction. Due to the multifaceted nature of CNS injury, clinically effective therapies for conditions such as traumatic brain injury (TBI), spinal cord injury (SCI), and stroke have proven challenging to develop. No therapeutics that adequately address the chronic inflammatory component of secondary CNS injury are currently available. Recently, B lymphocytes have gained increasing appreciation for their role in maintaining immune homeostasis and regulating inflammatory responses in the context of tissue injury. Here we review the neuroinflammatory response to CNS injury with particular focus on the underexplored role of B cells and summarize recent results on the use of purified B lymphocytes as a novel immunomodulatory therapeutic for tissue injury, particularly in the CNS.

Although previously restricted to a limited number of medical conditions, there is a growing appreciation that 'autoimmune' (or immune-mediated) processes are important aspects of a wide array of diverse medical conditions, including cancers, neurodegenerative diseases and psychiatric disorders. All of these classes of medical conditions are associated with alterations in mitochondrial function across an array of diverse cell types. Accumulating data indicate the presence of the mitochondrial melatonergic pathway in possibly all body cells, with important consequences for pathways crucial in driving CD8⁺ T cell and B-cell 'autoimmune'-linked processes. Melatonin suppression coupled with the upregulation of oxidative stress suppress PTEN-induced kinase 1 (PINK1)/parkin-driven mitophagy, raising the levels of the major histocompatibility complex (MHC)-1, which underpins the chemoattraction of CD8⁺ T cells and the activation of antibody-producing B-cells. Many factors and processes closely associated with autoimmunity, including gut microbiome/permeability, circadian rhythms, aging, the aryl hydrocarbon receptor, brain-derived neurotrophic factor (BDNF) and its receptor tyrosine receptor kinase B (TrkB) all interact with the mitochondrial melatonergic pathway. A number of future research directions and novel treatment implications are indicated for this wide collection of poorly conceptualized and treated medical presentations. It is proposed that the etiology of many 'autoimmune'/'immune-mediated' disorders should be conceptualized as significantly determined by mitochondrial dysregulation, with alterations in the mitochondrial melatonergic pathway being an important aspect of these pathoetiologies.

Neurotrophins (NTs) are a group of soluble growth factors with analogous structures and functions, identified initially as critical mediators of neuronal survival during development. Recently, the relevance of NTs has been confirmed by emerging clinical data showing that impaired NTs levels and functions are involved in the onset of neurological and pulmonary diseases. The alteration in NTs expression at the central and peripheral nervous system has been linked to neurodevelopmental disorders with an early onset and severe clinical manifestations, often named "synaptopathies" because of structural and functional synaptic plasticity abnormalities. NTs appear to be also involved in the physiology and pathophysiology of several airway diseases, neonatal lung diseases, allergic and inflammatory diseases, lung fibrosis, and even lung cancer. Moreover, they have also been detected in other peripheral tissues, including immune cells, epithelium, smooth muscle, fibroblasts, and vascular endothelium. This review aims to provide a comprehensive description of the NTs as important physiological and pathophysiological players in brain and lung development.

Calorie restriction without malnutrition is likely to improve cardiovascular risk factors.

The aim of this study was to investigate calorie restriction on markers of cardiometabolic risk in overweight/obese adults with cardiovascular risk factors.

In a parallel controlled trial, patients with overweight or obesity and one or more cardiovascular risk factor were randomized to a modest reduced-calorie diet (75% of the total calculated energy requirements) or control (no calorie restriction) groups and followed up for two months. Body weight, dietary intake, fasting plasma levels of C-reactive protein (CRP), monocyte chemoattractant protein-1 (MCP-1), intercellular adhesion molecule 1 (ICAM-1), vascular cell adhesion molecule 1 (VCAM-1), brain-derived neurotrophic factor (BDNF), neuropeptide Y (NPY), lipids, and glycemic factors were measured at baseline, and after two months. The differences were analyzed with analysis of covariance (ANCOVA).

Sixty-six participants (33 in each group) completed the study. Body weight changed in the reduced-calorie diet group (- 3.05 ± 2.65 kg), and blood pressure was improved (systolic -6.96 ± 12.04 and diastolic - 3.90 ± 8.97 mmHg). The reduced-calorie diet improved plasma ICAM-1 (change from baseline - 0.45 ± 1.99 ng/mL, P = 0.033, ANCOVA), MCP-1 (change from baseline - 0.50 pg/mL, P = 0.011, ANCOVA), low-density lipoprotein cholesterol (change from baseline - 9.35 ± 19.61 mg/dL, P < 0.001, ANCOVA), and triglyceride (change from baseline -33.66 ± 49.08, P = 0.001, ANCOVA), but BDNF, NPY, and other cardiometabolic factors were not different.

In overweight/obese subjects with cardiovascular risk factors which have been under medical treatment with risk-reducing medications, a modest weight loss induced by a reduced-calorie diet improved lipid profile, blood pressure, and reduced ICAM-1 and MCP-1 levels but had no effect on plasma BDNF or glycemic factors.

Current research and drug development for multiple sclerosis (MS) is fully influenced by the self-nonself (SNS) model of immunity, suggesting that breakage of immunological tolerance towards self-antigens expressed in the central nervous system (CNS) is responsible for pathogenesis of MS; thus, immune suppressive drugs are recommended for the management of the disease. However, this model provides incomplete understanding of the causes and pathways involved in the onset and progression of MS and limits our ability to effectively treat this neurological disease. Some pre-clinical and clinical reports have been misunderstood; some others have been underappreciated because of the lack of a theoretical model that can explain them. Also, current immunotherapies are guided according to the models that are not designed to explain the functional outcomes of an immune response. The adaptation model of immunity is proposed to offer a new understanding of the existing data and galvanize a new direction for the treatment of MS. According to this model, the immune system continuously communicates with the CNS through the adaptation receptors (AdRs) and adaptation ligands (AdLs) or co-receptors, signal IV, to support cell growth and neuroplasticity. Alterations in the expression of the neuronal AdRs results in MS by shifting the cerebral inflammatory immune responses from remyelination to demyelination. Therefore, novel therapeutics for MS should be focused on the discovery and targeting of the AdR/AdL axis in the CNS rather than carrying on with immune suppressive interventions.

Physical activity is one of the modifiable factors of cognitive decline and dementia with the strongest evidence. Although many influential reviews have illustrated the neurobiological mechanisms of the cognitive benefits of physical activity, none of them have linked the neurobiological mechanisms to normal exercise physiology to help the readers gain a more advanced, comprehensive understanding of the phenomenon. In this review, we address this issue and provide a synthesis of the literature by focusing on five most studied neurobiological mechanisms. We show that the body's adaptations to enhance exercise performance also benefit the brain and contribute to improved cognition. Specifically, these adaptations include, 1), the release of growth factors that are essential for the development and growth of neurons and for neurogenesis and angiogenesis, 2), the production of lactate that provides energy to the brain and is involved in the synthesis of glutamate and the maintenance of long-term potentiation, 3), the release of anti-inflammatory cytokines that reduce neuroinflammation, 4), the increase in mitochondrial biogenesis and antioxidant enzyme activity that reduce oxidative stress, and 5), the release of neurotransmitters such as dopamine and 5-HT that regulate neurogenesis and modulate cognition. We also discussed several issues relevant for prescribing physical activity, including what intensity and mode of physical activity brings the most cognitive benefits, based on their influence on the above five neurobiological mechanisms. We hope this review helps readers gain a general understanding of the state-of-the-art knowledge on the neurobiological mechanisms of the cognitive benefits of physical activity and guide them in designing new studies to further advance the field.

Allergic diseases are accompanied by a variety of symptoms such as pruritus, coughing, sneezing, and watery eyes, which can result in severe physiological and even psychological impairments. The exact mechanisms of these conditions are not yet completely understood. However, recent studies demonstrated a high relevance of neurotrophins in allergic inflammation, as they induce cytokine release, mediate interaction between immune cells and neurons, and exhibit different expression levels in health and disease. In this review, we aim to give an overview of the current state of knowledge concerning the role of neurotrophins in atopic disorders such as atopic dermatitis, allergic asthma, and allergic rhinitis.

In the last decade, increasing evidence has emerged linking alterations in the brain-derived neurotrophic factor (BDNF) expression with the development of Alzheimer's disease (AD). Because of the important role of BDNF in cognition and its association with AD pathogenesis, the aim of this study was to evaluate the potential difference in plasma BDNF concentrations between subjects with mild cognitive impairment (MCI; N = 209) and AD patients (N = 295) and to determine the possible association between BDNF plasma levels and the degree of cognitive decline in these individuals. The results showed a significantly higher (p < 0.001) concentration of plasma BDNF in subjects with AD (1.16; 0.13-21.34) compared with individuals with MCI (0.68; 0.02-19.14). The results of the present study additionally indicated a negative correlation between cognitive functions and BDNF plasma concentrations, suggesting higher BDNF levels in subjects with more pronounced cognitive decline. The correlation analysis revealed a significant negative correlation between BDNF plasma levels and both Mini-Mental State Examination (p < 0.001) and Clock Drawing test (p < 0.001) scores. In conclusion, the results of our study point towards elevated plasma BDNF levels in AD patients compared with MCI subjects, which may be due to the body's attempt to counteract the early and middle stages of neurodegeneration.